Multinational cost-effectiveness analysis of empagliflozin for heart failure patients with ejection fraction >40.

AIMS: Heart failure is a chronic progressive condition, with considerable burden on patients' quality of life and economic burden for the healthcare systems. Before the approval of empagliflozin, there were no proven effective treatments for patients with heart failure with left ventricular ejection fraction (HF LVEF) > 40%. The aim of this study was to evaluate the cost-effectiveness of empagliflozin + standard of care (SoC) compared with SoC alone for patients with HF LVEF > 40%, from the perspective of the healthcare systems of the United Kingdom (UK), Spain, and France, and to quantify the healthcare costs for these patients. METHODS AND RESULTS: A lifetime Markov cohort state-transition model was developed based on discrete health states defined by Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score quartiles to track disease severity. Model inputs relied primarily on the EMPEROR-Preserved trial data or obtained from published literature or country-specific databases, as well as local guidelines for the requirements for the conduct of the economic evaluation of healthcare technologies. The total lifetime cost of receiving SoC per patient was £10 092, €15 765, and €14 958 in the UK, Spain, and France, respectively, which increased by £1407, €1148, and €1485, respectively, with the addition of empagliflozin to the SoC. Empagliflozin + SoC was associated with significantly reduced number of hospitalization for HF or cardiovascular death compared with SoC alone, which was a key driver offsetting its drug acquisition costs. The incremental cost-effectiveness ratio per quality-adjusted life year (QALY) gained was consistently favourable at £14 851, €11 706, and €15 447 in the UK, Spain, and France, respectively. Scenario analysis using the New York Heart Association functional class showed similar results. Probabilistic sensitivity analyses showed more than 50% probability for cost-effectiveness for a willingness-to-pay (WTP) threshold of £/€20 000/QALY for the three countries. CONCLUSIONS: Empagliflozin was found to be the first targeted treatment option that is clinically effective and cost-effective for patients with HF LVEF > 40%. Prescribing empagliflozin with SoC to patients with HF LVEF > 40% is expected to improve clinical outcomes and patients' quality of life and substantially below accepted WTP threshold for the healthcare systems in the UK, Spain, and France.

Cost-effectiveness of empagliflozin in heart failure patients irrespective of ejection fraction in England.

AIMS: Heart failure (HF) is a complex syndrome commonly categorized into two main phenotypes [left ventricular ejection fraction (LVEF) below or above 40%], and although empagliflozin is the first approved medication with proven clinical effectiveness for both phenotypes, its cost-effectiveness of treating the entire HF population remains unknown. METHODS: The analysis was performed utilizing two preexisting, LVEF phenotype-specific cost-effectiveness models to estimate the cost-effectiveness of empagliflozin in adults for the treatment of symptomatic chronic HF, irrespective of ejection fraction (EF). The results of the phenotype-specific models were combined using a population-weighted approach to estimate the deterministic and probabilistic incremental cost-effectiveness ratios (ICERs). RESULTS: Based on combined results, empagliflozin + standard of care (SoC) is associated with 6.13 life-years (LYs) and 3.92 quality-adjusted life-years (QALYs) compared with 5.98 LYs and 3.76 QALYs for SoC alone over a lifetime, resulting in an incremental difference of 0.15 LYs and 0.16 QALYs, respectively. Total lifetime healthcare costs per patient are £15 246 for empagliflozin + SoC and £13 982 for SoC giving an incremental difference of £1264. The ICER is £7757/QALY, which is substantially lower than the willingness-to-pay (WTP) of £30 000 per QALY used by NICE. The results of the probabilistic sensitivity analyses are in line with the deterministic results. CONCLUSION: Empagliflozin is the first efficacious, approved, and cost-effective treatment option for all HF patients, irrespective of EF. The combined ICER was consistently below the WTP threshold. Therefore, empagliflozin offers value for money for the treatment of the full HF population in England.

Association between outpatient follow-up and incidence of revision after knee and hip replacements: a population-based cohort study.

BACKGROUND: Follow-up visits 5 or 7 years after surgery were recommended for people having primary hip or knee replacement. The benefits of this practice to patients and the healthcare system, however, have not yet been specifically examined. The aim of this study was to investigate the association between long-term follow-up outpatient hospital visits and revision rates for patients who undergo primary knee or hip replacement surgery. METHODS: Cohorts were identified for patients undergoing knee or hip replacement surgery using medical records from primary care practices within the UK Clinical Practice Research Datalink (CPRD) GOLD dataset linked to hospital records from the English Hospital Episodes Statistics (HES) data. Two groups of patients were compared in terms of revision and mortality rates: those with at least one long-term (between five and 10 years since primary surgery) follow-up visit at the orthopaedic department ('Follow-up' group), and those without ('No follow-up' group). RESULTS: A total of 9856 (4349 in the Follow-up group) patients with knee replacement and 10,837 (4870 in the Follow-up group) with hip replacement were included in the analysis. For knee replacement, the incidence of revision was 3.6% for those followed-up and 0.6% for those not followed-up. An adjusted regression model confirmed the difference in the hazard ratio (HR) for revision was statistically significant (HR: 5.65 [95% CI 3.62 to 8.81]). Mortality at 4 years was lower for the Follow-up (17%) compared to the No follow-up group (21%), but this difference was not statistically significant (HR: 0.95 [0.84 to 1.07]). For hip replacement, the incidence of revision rates were 3.2 and 1.4% for the follow-up and not follow-up groups, respectively, the difference being statistically significant (HR: 2.34 [1.71 to 3.20]). Mortality was lower for the Follow-up (15%) compared to the No follow-up group (21%), but the difference was not statistically significant (HR: 0.91 [0.81 to 1.02]). CONCLUSION: Patients attending follow-up orthopaedic consultations show a higher risk of revision surgery compared to those who are not followed-up. A cause for this difference could not be identified in this study but a likely explanation is that surgeons play an effective role as ultimate arbitrators when identifying patients to be included in long-term follow-up lists.

Patient-reported outcomes measures of X-linked hypophosphataemia participants: findings from a prospective cohort study in the UK.

BACKGROUND: X-linked hypophosphataemia (XLH) is a rare genetic condition passed on through the X chromosome which causes multiple symptoms including weakened teeth, bones, and muscles. Due to the rarity of the condition, little is known about the health outcomes as reported by people with the disease. The objectives of this study were threefold: to characterise key patient reported outcome measures (PROMs) in adults with XLH, to identify clusters of symptom-severity groups based on PROMs, and to analyse the longitudinal progression of available PROMs. METHODS: Data from 48 participants from the Rare and Undiagnosed Diseases cohort Study (RUDY) was used to analyse both cross-sectional and longitudinal patient-reported outcomes. We analysed data for health-related quality of life (HRQL): EuroQol 5 dimensions-5 levels (EQ-5D-5L), Short-form 36 (SF-36) Physical Component Score (PCS), and SF-36 Mental Component Score (MCS), sleep: Pittsburgh sleep quality index (PSQI) and Epworth Sleepiness scale (ESS), fatigue: Fatigue Severity Scale (FSS) and Functional assessment of chronic illness therapy-fatigue (FACIT-F), pain: Short form McGill pain questionnaire version 2 (SF-MPQ-2) and PainDETECT, and mental well-being: Hospital anxiety and depression scale (HADS) anxiety and depression. Summary statistics, tests of mean differences, mixed-effects models, and cluster analysis were used to describe and examine the various health dimensions of individuals with XLH. RESULTS: Overall mean scores were EQ-5D-5L = 0.65, SF-36-PCS = 32.7, and SF-36-MCS = 48.4 for HRQL, ESS = 5.9 and PSQI = 8.9 for sleep, FSS = 32.8 and FACIT-F = 104.4 for fatigue, SF-MPQ-2 = 1.9 for pain, and HADS-depression = 4.7 and HADS-anxiety = 6.2 for mental well-being. 7% reported neuropathic pain (PainDETECT). Whilst many adults with XLH reported good outcomes, extreme or severe problems were reported across all outcomes. Cluster analysis identified that adults with XLH could be divided into two distinct groups, one reporting worse (35.3%) and the other better outcomes (64.7%) (less pain, fatigue, depression, and higher levels of sleep). Longitudinal analysis showed that FACIT-F and HADS-anxiety scores worsened slightly over two years with statistically significant (p < 0.05) time coefficients (b = - 2.135 and b = 0.314, respectively). CONCLUSION: Although about two thirds of adult participants of the RUDY cohort with XLH report good health outcomes, for a considerable third much worse outcomes are reported. More research is needed to examine why some experience good and others poor health outcomes and the characteristics which identify them.

Comparative efficacy and safety of targeted therapies for BRAF-mutant unresectable or metastatic melanoma: Results from a systematic literature review and a network meta-analysis.

BACKGROUND: The objective of this study was to estimate the relative efficacy and safety of targeted therapies for the treatment of metastatic melanoma using a network meta-analysis (NMA). METHODS: A systematic literature review (SLR) identified studies in Medline, Embase and Cochrane published until November 2020. Screening used prespecified eligibility criteria. Following a transitivity assessment across included studies, Bayesian NMA was conducted. RESULTS: A total of 43 publications reporting 15 targeted therapy trials and 42 reporting 18 immunotherapy trials were retained from the SLR and considered for the NMA. Due to substantial between-study heterogeneity with immunotherapy trials, the analysis considered a network restricted to targeted therapies. Among combination therapies, encorafenib + binimetinib was superior to dabrafenib + trametinib for overall response rate (OR = 1.86; 95 % credible interval [CrI] 1.10, 3.17), superior to vemurafenib + cobimetinib with fewer serious adverse events (SAEs) (OR = 0.51; 95 % CrI 0.29, 0.91) and fewer discontinuations due to AEs (OR = 0.45; 95 % CrI 0.21, 0.96), and superior to atezolizumab + vemurafenib + cobimetinib with fewer SAEs (OR = 0.41; 95 % CrI 0.21, 0.82). Atezolizumab + vemurafenib + cobimetinib and encorafenib + binimetinib were generally comparable for efficacy endpoints. Among double combination therapies, encorafenib + binimetinib showed high probabilities of being better for all efficacy and safety endpoints. CONCLUSIONS: This NMA confirms that combination therapies are more efficacious than monotherapies. Encorafenib + binimetinib has a favourable efficacy profile compared to other double combination therapies and a favourable safety profile compared to both double and triple combination therapies.

Primary care consultations and pain medicine prescriptions: a comparison between patients with and without chronic pain after total knee replacement.

BACKGROUND: Approximately 20% of patients experience chronic pain after total knee replacement (TKR). The impact of chronic pain after TKR on primary care services in the UK is currently unknown. The aim of this study was to compare primary care consultations and pain medicine prescriptions between patients with and without chronic pain after TKR. METHODS: Data from 5,055 patients who received TKR between 2009 and 2016 with anonymised linked data from the Clinical Practice Research Datalink Gold (CPRD) and English Hospital Episode Statistics (HES) Patient Reported Outcome Measures (PROMs) programme were analysed. The exposure time was from 10 years pre-operative to eight years post-operative. Patients with a score ≤ 14 on the Oxford Knee Score pain component scale at 6 months post-operative were classified as having chronic pain after TKR. Primary care consultations and prescribed pain medicines were quantified, and costs calculated based on national cost data. RESULTS: 721 patients (14%) had chronic pain after TKR. The prevalence and costs of primary care consultations and pain medicine prescriptions per year were consistently higher for patients with chronic pain after TKR compared with those without chronic pain after TKR; these differences were observed both before and after surgery. There was a substantial and sustained increase in the cost of opioid prescriptions after surgery for patients with chronic pain after TKR, peaking at seven years post-operative. CONCLUSIONS: Increased primary care consultations and pain medicine prescriptions associated with chronic pain after TKR represent a considerable financial cost to primary care services. Evaluation of interventions to reduce the risk of developing this pain condition and improve the early management of pain after TKR are needed to improve outcomes for patients and reduce costs to healthcare services.

Progression of chronic pain and associated health-related quality of life and healthcare resource use over 5 years after total knee replacement: evidence from a cohort study.

OBJECTIVE: As part of the STAR Programme, a comprehensive study exploring long-term pain after surgery, we investigated how pain and function, health-related quality of life (HRQL), and healthcare resource use evolved over 5 years after total knee replacement (TKR) for those with and without chronic pain 1 year after their primary surgery. METHODS: We used data from the Clinical Outcomes in Arthroplasty Study prospective cohort study, which followed patients undergoing TKR from two English hospitals for 5 years. Chronic pain was defined using the Oxford Knee Score Pain Subscale (OKS-PS) where participants reporting a score of 14 or lower were classified as having chronic pain 1-year postsurgery. Pain and function were measured with the OKS, HRQL using the EuroQoL-5 Dimension, resource use from yearly questionnaires, and costs estimated from a healthcare system perspective. We analysed the changes in OKS-PS, HRQL and resource use over a 5-year follow-up period. Multiple imputation accounted for missing data. RESULTS: Chronic pain was reported in 70/552 operated knees (12.7%) 1 year after surgery. The chronic pain group had worse pain, function and HRQL presurgery and postsurgery than the non-chronic pain group. Those without chronic pain markedly improved right after surgery, then plateaued. Those with chronic pain improved slowly but steadily. Participants with chronic pain reported greater healthcare resource use and costs than those without, especially 1 year after surgery, and mostly from hospital readmissions. 64.7% of those in chronic pain recovered during the following 4 years, while 30.9% fluctuated in and out of chronic pain. CONCLUSION: Although TKR is often highly beneficial, some patients experienced chronic pain postsurgery. Although many fluctuated in their pain levels and most recovered over time, identifying people most likely to have chronic pain and supporting their recovery would benefit patients and healthcare systems.

Unicompartmental compared with total knee replacement for patients with multimorbidities: a cohort study using propensity score stratification and inverse probability weighting.

BACKGROUND: Although routine NHS data potentially include all patients, confounding limits their use for causal inference. Methods to minimise confounding in observational studies of implantable devices are required to enable the evaluation of patients with severe systemic morbidity who are excluded from many randomised controlled trials. OBJECTIVES: Stage 1 - replicate the Total or Partial Knee Arthroplasty Trial (TOPKAT), a surgical randomised controlled trial comparing unicompartmental knee replacement with total knee replacement using propensity score and instrumental variable methods. Stage 2 - compare the risk benefits and cost-effectiveness of unicompartmental knee replacement with total knee replacement surgery in patients with severe systemic morbidity who would have been ineligible for TOPKAT using the validated methods from stage 1. DESIGN: This was a cohort study. SETTING: Data were obtained from the National Joint Registry database and linked to hospital inpatient (Hospital Episode Statistics) and patient-reported outcome data. PARTICIPANTS: Stage 1 - people undergoing unicompartmental knee replacement surgery or total knee replacement surgery who met the TOPKAT eligibility criteria. Stage 2 - participants with an American Society of Anesthesiologists grade of ≥ 3. INTERVENTION: The patients were exposed to either unicompartmental knee replacement surgery or total knee replacement surgery. MAIN OUTCOME MEASURES: The primary outcome measure was the postoperative Oxford Knee Score. The secondary outcome measures were 90-day postoperative complications (venous thromboembolism, myocardial infarction and prosthetic joint infection) and 5-year revision risk and mortality. The main outcome measures for the health economic analysis were health-related quality of life (EuroQol-5 Dimensions) and NHS hospital costs. RESULTS: In stage 1, propensity score stratification and inverse probability weighting replicated the results of TOPKAT. Propensity score adjustment, propensity score matching and instrumental variables did not. Stage 2 included 2256 unicompartmental knee replacement patients and 57,682 total knee replacement patients who had severe comorbidities, of whom 145 and 23,344 had linked Oxford Knee Scores, respectively. A statistically significant but clinically irrelevant difference favouring unicompartmental knee replacement was observed, with a mean postoperative Oxford Knee Score difference of < 2 points using propensity score stratification; no significant difference was observed using inverse probability weighting. Unicompartmental knee replacement more than halved the risk of venous thromboembolism [relative risk 0.33 (95% confidence interval 0.15 to 0.74) using propensity score stratification; relative risk 0.39 (95% confidence interval 0.16 to 0.96) using inverse probability weighting]. Unicompartmental knee replacement was not associated with myocardial infarction or prosthetic joint infection using either method. In the long term, unicompartmental knee replacement had double the revision risk of total knee replacement [hazard ratio 2.70 (95% confidence interval 2.15 to 3.38) using propensity score stratification; hazard ratio 2.60 (95% confidence interval 1.94 to 3.47) using inverse probability weighting], but half of the mortality [hazard ratio 0.52 (95% confidence interval 0.36 to 0.74) using propensity score stratification; insignificant effect using inverse probability weighting]. Unicompartmental knee replacement had lower costs and higher quality-adjusted life-year gains than total knee replacement for stage 2 participants. LIMITATIONS: Although some propensity score methods successfully replicated TOPKAT, unresolved confounding may have affected stage 2. Missing Oxford Knee Scores may have led to information bias. CONCLUSIONS: Propensity score stratification and inverse probability weighting successfully replicated TOPKAT, implying that some (but not all) propensity score methods can be used to evaluate surgical innovations and implantable medical devices using routine NHS data. Unicompartmental knee replacement was safer and more cost-effective than total knee replacement for patients with severe comorbidity and should be considered the first option for suitable patients. FUTURE WORK: Further research is required to understand the performance of propensity score methods for evaluating surgical innovations and implantable devices. TRIAL REGISTRATION: This trial is registered as EUPAS17435. 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. 66. See the NIHR Journals Library website for further project information.

We compared the risks and benefits of partial and total knee replacements in NHS patients with a complex medical history who would normally be excluded from randomised trials on this topic. We used information that was collected during hospital appointments for people who had a knee replacement between 2009 and 2016. It is difficult to directly compare the two groups because each individual patient has a different medical history. We tested advanced statistical methods to account for these differences. In stage 1, we showed that some of these advanced statistical methods could replicate the results of a recently published surgical trial using routine data from the NHS. We compared patients in the trial with similar patients who were operated on in the NHS. Three of the proposed methods showed results similar to those obtained from the Total or Partial Knee Arthroplasty Trial (TOPKAT). In stage 2, we used the successful methods from stage 1 to study the risks, benefits and costs of partial and total knee replacement surgery in patients with complex medical histories. Two of the statistical methods found that patients who had a partial knee replacement had less self-reported pain and better function after surgery than patients who had a total knee replacement. All three methods found that partial knee replacement was safer, was associated with a lower risk of blood clots (a known complication of knee surgery) and had lower mortality over 5 years. However, patients who had a partial knee replacement were twice as likely as those with a total knee replacement to need a second surgery within 5 years. We found that partial knee replacements were less costly to the NHS and were associated with better overall quality of life for patients than total knee replacement.

Guided Internet-Based Cognitive Behavioral Therapy for Depression: Implementation Cost-Effectiveness Study.

BACKGROUND: Major depressive disorder is a chronic condition; its prevalence is expected to grow with the aging trend of high-income countries. Internet-based cognitive-behavioral therapy has proven efficacy in treating major depressive disorder. OBJECTIVE: The objective of this study was to assess the cost-effectiveness of implementing a community internet-based cognitive behavioral therapy intervention (Super@, the Spanish program for the MasterMind project) for treating major depressive disorder. METHODS: The cost-effectiveness of the Super@ program was assessed with the Monitoring and Assessment Framework for the European Innovation Partnership on Active and Healthy Ageing tool, using a 3-state Markov model. Data from the cost and effectiveness of the intervention were prospectively collected from the implementation of the program by a health care provider in Badalona, Spain; the corresponding data for usual care were gathered from the literature. The health states, transition probabilities, and utilities were computed using Patient Health Questionnaire-9 scores. RESULTS: The analysis was performed using data from 229 participants using the Super@ program. Results showed that the intervention was more costly than usual care; the discounted (3%) and nondiscounted incremental cost-effectiveness ratios were €29,367 and €26,484 per quality-adjusted life-year, respectively (approximately US $35,299 and $31,833, respectively). The intervention was cost-effective based on the €30,000 willingness-to-pay threshold typically applied in Spain (equivalent to approximately $36,060). According to the deterministic sensitivity analyses, the potential reduction of costs associated with intervention scale-up would reduce the incremental cost-effectiveness ratio of the intervention, although it remained more costly than usual care. A discount in the incremental effects up to 5% exceeded the willingness-to-pay threshold of €30,000. CONCLUSIONS: The Super@ program, an internet-based cognitive behavioral therapy intervention for treating major depressive disorder, cost more than treatment as usual. Nevertheless, its implementation in Spain would be cost-effective from health care and societal perspectives, given the willingness-to-pay threshold of €30,000 compared with treatment as usual.

Association of sleep, screen time and physical activity with overweight and obesity in Mexico.

PURPOSE: Approximately 70% of adults in Mexico are overweight or obese. Unhealthy lifestyle behaviors are also prevalent. We examined the association of three lifestyle behaviors with body mass index (BMI) categories in adults from Mexico. METHODS: We used publicly available data from the ENSANUT 2016 survey (n = 6419). BMI was used to categorize participants. Differences in sleep duration, suffering from symptoms of insomnia, TV watching time, time in front of any screen, vigorous physical activity (yes vs no), moderate physical activity (> 30 min/day-yes vs. no) and walking (> 60 min/day-yes vs. no) were compared across BMI groups using adjusted linear and logistic regression analyses. RESULTS: Thirty-nine percent of participants were overweight and 37% obese. Time in front of TV, in front of any screen, sleep duration and physical activity were significantly associated with overweight and obesity. Compared to normal weight participants, participants in the obese II category spend on average 0.60 h/day (95% CI 0.36-0.84, p = 0.001) and participants in the obese III category 0.54 h/day (95% CI 0.19-0.89, p < 0.001) more in front of any screen; participants in the obese II category reported 0.55 h/day less sleep (95% CI - 0.67 to - 0.43, p < 0.001); participants in the obese III category were less likely to engage in vigorous activity (OR = 0.60, 95% CI 0.43-0.84, p ≤ 0.003), or walking (OR = 0.65, 95% CI 0.49-0.88, p = 0.005). CONCLUSION: Screen time, sleeping hours, and physical activity were associated with overweight and obesity. However, these associations were not consistent across all BMI categories. Assuming established causal connections, overweight individuals and individuals with obesity would benefit from reduced screen time and engaging in moderate/vigorous physical activity. LEVEL OF EVIDENCE: Level III: observational case-control analytic study.

Risk of depression, suicide and psychosis with hydroxychloroquine treatment for rheumatoid arthritis: a multinational network cohort study.

OBJECTIVES: Concern has been raised in the rheumatology community regarding recent regulatory warnings that HCQ used in the coronavirus disease 2019 pandemic could cause acute psychiatric events. We aimed to study whether there is risk of incident depression, suicidal ideation or psychosis associated with HCQ as used for RA. METHODS: We performed a new-user cohort study using claims and electronic medical records from 10 sources and 3 countries (Germany, UK and USA). RA patients ≥18 years of age and initiating HCQ were compared with those initiating SSZ (active comparator) and followed up in the short (30 days) and long term (on treatment). Study outcomes included depression, suicide/suicidal ideation and hospitalization for psychosis. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate database-specific calibrated hazard ratios (HRs), with estimates pooled where I2 <40%. RESULTS: A total of 918 144 and 290 383 users of HCQ and SSZ, respectively, were included. No consistent risk of psychiatric events was observed with short-term HCQ (compared with SSZ) use, with meta-analytic HRs of 0.96 (95% CI 0.79, 1.16) for depression, 0.94 (95% CI 0.49, 1.77) for suicide/suicidal ideation and 1.03 (95% CI 0.66, 1.60) for psychosis. No consistent long-term risk was seen, with meta-analytic HRs of 0.94 (95% CI 0.71, 1.26) for depression, 0.77 (95% CI 0.56, 1.07) for suicide/suicidal ideation and 0.99 (95% CI 0.72, 1.35) for psychosis. CONCLUSION: HCQ as used to treat RA does not appear to increase the risk of depression, suicide/suicidal ideation or psychosis compared with SSZ. No effects were seen in the short or long term. Use at a higher dose or for different indications needs further investigation. TRIAL REGISTRATION: Registered with EU PAS (reference no. EUPAS34497; http://www.encepp.eu/encepp/viewResource.htm? id=34498). The full study protocol and analysis source code can be found at https://github.com/ohdsi-studies/Covid19EstimationHydroxychloroquine2.

Deep phenotyping of 34,128 adult patients hospitalised with COVID-19 in an international network study.

Comorbid conditions appear to be common among individuals hospitalised with coronavirus disease 2019 (COVID-19) but estimates of prevalence vary and little is known about the prior medication use of patients. Here, we describe the characteristics of adults hospitalised with COVID-19 and compare them with influenza patients. We include 34,128 (US: 8362, South Korea: 7341, Spain: 18,425) COVID-19 patients, summarising between 4811 and 11,643 unique aggregate characteristics. COVID-19 patients have been majority male in the US and Spain, but predominantly female in South Korea. Age profiles vary across data sources. Compared to 84,585 individuals hospitalised with influenza in 2014-19, COVID-19 patients have more typically been male, younger, and with fewer comorbidities and lower medication use. While protecting groups vulnerable to influenza is likely a useful starting point in the response to COVID-19, strategies will likely need to be broadened to reflect the particular characteristics of individuals being hospitalised with COVID-19.

Risk of hydroxychloroquine alone and in combination with azithromycin in the treatment of rheumatoid arthritis: a multinational, retrospective study.

BACKGROUND: Hydroxychloroquine, a drug commonly used in the treatment of rheumatoid arthritis, has received much negative publicity for adverse events associated with its authorisation for emergency use to treat patients with COVID-19 pneumonia. We studied the safety of hydroxychloroquine, alone and in combination with azithromycin, to determine the risk associated with its use in routine care in patients with rheumatoid arthritis. METHODS: In this multinational, retrospective study, new user cohort studies in patients with rheumatoid arthritis aged 18 years or older and initiating hydroxychloroquine were compared with those initiating sulfasalazine and followed up over 30 days, with 16 severe adverse events studied. Self-controlled case series were done to further establish safety in wider populations, and included all users of hydroxychloroquine regardless of rheumatoid arthritis status or indication. Separately, severe adverse events associated with hydroxychloroquine plus azithromycin (compared with hydroxychloroquine plus amoxicillin) were studied. Data comprised 14 sources of claims data or electronic medical records from Germany, Japan, the Netherlands, Spain, the UK, and the USA. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate calibrated hazard ratios (HRs) according to drug use. Estimates were pooled where the I 2 value was less than 0·4. FINDINGS: The study included 956 374 users of hydroxychloroquine, 310 350 users of sulfasalazine, 323 122 users of hydroxychloroquine plus azithromycin, and 351 956 users of hydroxychloroquine plus amoxicillin. No excess risk of severe adverse events was identified when 30-day hydroxychloroquine and sulfasalazine use were compared. Self-controlled case series confirmed these findings. However, long-term use of hydroxychloroquine appeared to be associated with increased cardiovascular mortality (calibrated HR 1·65 [95% CI 1·12-2·44]). Addition of azithromycin appeared to be associated with an increased risk of 30-day cardiovascular mortality (calibrated HR 2·19 [95% CI 1·22-3·95]), chest pain or angina (1·15 [1·05-1·26]), and heart failure (1·22 [1·02-1·45]). INTERPRETATION: Hydroxychloroquine treatment appears to have no increased risk in the short term among patients with rheumatoid arthritis, but in the long term it appears to be associated with excess cardiovascular mortality. The addition of azithromycin increases the risk of heart failure and cardiovascular mortality even in the short term. We call for careful consideration of the benefit-risk trade-off when counselling those on hydroxychloroquine treatment. FUNDING: National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, NIHR Senior Research Fellowship programme, US National Institutes of Health, US Department of Veterans Affairs, Janssen Research and Development, IQVIA, Korea Health Industry Development Institute through the Ministry of Health and Welfare Republic of Korea, Versus Arthritis, UK Medical Research Council Doctoral Training Partnership, Foundation Alfonso Martin Escudero, Innovation Fund Denmark, Novo Nordisk Foundation, Singapore Ministry of Health's National Medical Research Council Open Fund Large Collaborative Grant, VINCI, Innovative Medicines Initiative 2 Joint Undertaking, EU's Horizon 2020 research and innovation programme, and European Federation of Pharmaceutical Industries and Associations.

Deep phenotyping of 34,128 patients hospitalised with COVID-19 and a comparison with 81,596 influenza patients in America, Europe and Asia: an international network study.

Background In this study we phenotyped individuals hospitalised with coronavirus disease 2019 (COVID-19) in depth, summarising entire medical histories, including medications, as captured in routinely collected data drawn from databases across three continents. We then compared individuals hospitalised with COVID-19 to those previously hospitalised with influenza. Methods We report demographics, previously recorded conditions and medication use of patients hospitalised with COVID-19 in the US (Columbia University Irving Medical Center [CUIMC], Premier Healthcare Database [PHD], UCHealth System Health Data Compass Database [UC HDC], and the Department of Veterans Affairs [VA OMOP]), in South Korea (Health Insurance Review & Assessment [HIRA]), and Spain (The Information System for Research in Primary Care [SIDIAP] and HM Hospitales [HM]). These patients were then compared with patients hospitalised with influenza in 2014-19. Results 34,128 (US: 8,362, South Korea: 7,341, Spain: 18,425) individuals hospitalised with COVID-19 were included. Between 4,811 (HM) and 11,643 (CUIMC) unique aggregate characteristics were extracted per patient, with all summarised in an accompanying interactive website (http://evidence.ohdsi.org/Covid19CharacterizationHospitalization/). Patients were majority male in the US (CUIMC: 52%, PHD: 52%, UC HDC: 54%, VA OMOP: 94%,) and Spain (SIDIAP: 54%, HM: 60%), but were predominantly female in South Korea (HIRA: 60%). Age profiles varied across data sources. Prevalence of asthma ranged from 4% to 15%, diabetes from 13% to 43%, and hypertensive disorder from 24% to 70% across data sources. Between 14% and 33% were taking drugs acting on the renin-angiotensin system in the 30 days prior to hospitalisation. Compared to 81,596 individuals hospitalised with influenza in 2014-19, patients admitted with COVID-19 were more typically male, younger, and healthier, with fewer comorbidities and lower medication use. Conclusions We provide a detailed characterisation of patients hospitalised with COVID-19. Protecting groups known to be vulnerable to influenza is a useful starting point to minimize the number of hospital admissions needed for COVID-19. However, such strategies will also likely need to be broadened so as to reflect the particular characteristics of individuals hospitalised with COVID-19.

Five-year cost-effectiveness analysis of the European Fans in Training (EuroFIT) physical activity intervention for men versus no intervention.

OBJECTIVES: Increasing physical activity reduces the risk of chronic illness including Type 2 diabetes, cardiovascular disease and certain types of cancer. Lifestyle interventions can increase physical activity but few successfully engage men. This study aims to investigate the 5 year cost-effectiveness of EuroFIT, a program to improve physical activity tailored specifically for male football (soccer) fans compared to a no intervention comparison group. METHODS: We developed a Markov cohort model in which the impact of improving physical activity on five chronic health conditions (colorectal cancer, Type 2 diabetes, coronary heart disease, stroke and depression) and mortality was modelled. We estimated costs from a societal perspective and expressed benefits as quality adjusted life years (QALYs). We obtained data from a 4-country (England, Netherlands, Portugal and Norway) pragmatic randomised controlled trial evaluating EuroFIT, epidemiological and cohort studies, and meta-analyses. We performed deterministic and probabilistic sensitivity analyses to assess the impact of uncertainty in the model's parameter values on the cost-effectiveness results. We used Monte Carlo simulations to estimate uncertainty and presented this using cost-effectiveness acceptability curves (CEACs). We tested the robustness of the base case analysis using five scenario analyses. RESULTS: Average costs over 5 years per person receiving EuroFIT were €14,663 and per person receiving no intervention €14,598. Mean QALYs over 5 years were 4.05 per person for EuroFIT and 4.04 for no intervention. Thus, the average incremental cost per person receiving EuroFIT was €65 compared to no intervention, while the average QALY gain was 0.01. This resulted in an ICER of €5206 per QALY gained. CEACs show that the probability of EuroFIT being cost-effective compared to no intervention is 0.53, 0.56 and 0.58 at thresholds of €10,000, €22,000 and €34,000 per QALY gained, respectively. When using a time horizon of 10 years, the results suggest that EuroFIT is more effective and less expensive compared to (i.e. dominant over) no intervention with a probability of cost-effectiveness of 0.63 at a threshold of €22,000 per QALY gained. CONCLUSIONS: We conclude the EuroFIT intervention is not cost-effective compared to no intervention over a period of 5 years from a societal perspective, but is more effective and less expensive (i.e. dominant) after 10 years. We thus suggest that EuroFIT can potentially improve public health in a cost-effective manner in the long term.

Unplanned admissions for patients with myeloma in the UK: Low frequency but high costs.

BACKGROUND: Multiple myeloma (MM) is associated with high healthcare resource utilisation and increasing hospitalisation rates. The aim of this study was to characterise the hospital use by patients with MM in the English National Health Service (NHS). METHODS: Routinely-collected aggregate data about all NHS-funded hospital admissions of patients with MM were analysed. Data were obtained from the English Hospital Episodes Statistics on admissions between 1 April 2014 and 31 March 2018. RESULTS: A total of 754,345 admissions were reported over four years, equivalent to a mean of 188,586 admissions per year. Of the 41,845 patients admitted during this period, 42% were women and 58% men. From the total admissions, 90% were elective and 10% unplanned. Mean annual estimated costs over the period were £46 million for elective and £56 million for unplanned admissions. The number of elective admissions increased by 4.5% with costs increasing 1.5% per year; for unplanned admissions, these figures were 4.1% and 9.0%, respectively. CONCLUSIONS: MM is associated with a significant number of hospital admissions and NHS costs. The majority of the hospital admissions are elective, but the highest burden in terms of costs relates to unplanned admissions, with numbers increasing over time.

Correction: The effect of a programme to improve men's sedentary time and physical activity: The European Fans in Training (EuroFIT) randomised controlled trial.

[This corrects the article DOI: 10.1371/journal.pmed.1002736.].

The effect of a programme to improve men's sedentary time and physical activity: The European Fans in Training (EuroFIT) randomised controlled trial.

BACKGROUND: Reducing sitting time as well as increasing physical activity in inactive people is beneficial for their health. This paper investigates the effectiveness of the European Fans in Training (EuroFIT) programme to improve physical activity and sedentary time in male football fans, delivered through the professional football setting. METHODS AND FINDINGS: A total of 1,113 men aged 30-65 with self-reported body mass index (BMI) ≥27 kg/m2 took part in a randomised controlled trial in 15 professional football clubs in England, the Netherlands, Norway, and Portugal. Recruitment was between September 19, 2015, and February 2, 2016. Participants consented to study procedures and provided usable activity monitor baseline data. They were randomised, stratified by club, to either the EuroFIT intervention or a 12-month waiting list comparison group. Follow-up measurement was post-programme and 12 months after baseline. EuroFIT is a 12-week, group-based programme delivered by coaches in football club stadia in 12 weekly 90-minute sessions. Weekly sessions aimed to improve physical activity, sedentary time, and diet and maintain changes long term. A pocket-worn device (SitFIT) allowed self-monitoring of sedentary time and daily steps, and a game-based app (MatchFIT) encouraged between-session social support. Primary outcome (objectively measured sedentary time and physical activity) measurements were obtained for 83% and 85% of intervention and comparison participants. Intention-to-treat analyses showed a baseline-adjusted mean difference in sedentary time at 12 months of -1.6 minutes/day (97.5% confidence interval [CI], -14.3-11.0; p = 0.77) and in step counts of 678 steps/day (97.5% CI, 309-1.048; p < 0.001) in favor of the intervention. There were significant improvements in diet, weight, well-being, self-esteem, vitality, and biomarkers of cardiometabolic health in favor of the intervention group, but not in quality of life. There was a 0.95 probability of EuroFIT being cost-effective compared with the comparison group if society is willing to pay £1.50 per extra step/day, a maximum probability of 0.61 if society is willing to pay £1,800 per minute less sedentary time/day, and 0.13 probability if society is willing to pay £30,000 per quality-adjusted life-year (QALY). It was not possible to blind participants to group allocation. Men attracted to the programme already had quite high levels of physical activity at baseline (8,372 steps/day), which may have limited room for improvement. Although participants came from across the socioeconomic spectrum, a majority were well educated and in paid work. There was an increase in recent injuries and in upper and lower joint pain scores post-programme. In addition, although the five-level EuroQoL questionnaire (EQ-5D-5L) is now the preferred measure for cost-effectiveness analyses across Europe, baseline scores were high (0.93), suggesting a ceiling effect for QALYs. CONCLUSION: Participation in EuroFIT led to improvements in physical activity, diet, body weight, and biomarkers of cardiometabolic health, but not in sedentary time at 12 months. Within-trial analysis suggests it is not cost-effective in the short term for QALYs due to a ceiling effect in quality of life. Nevertheless, decision-makers may consider the incremental cost for increase in steps worth the investment. TRIAL REGISTRATION: International Standard Randomised Controlled Trials, ISRCTN-81935608.