Showing papers by "Daniel Prieto-Alhambra published in 2020"

Algorithm for the management of patients at low, high and very high risk of osteoporotic fractures

Abstract: Guidance is provided in an international setting on the assessment and specific treatment of postmenopausal women at low, high and very high risk of fragility fractures. The International Osteoporosis Foundation and European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis published guidance for the diagnosis and management of osteoporosis in 2019. This manuscript seeks to apply this in an international setting, taking additional account of further categorisation of increased risk of fracture, which may inform choice of therapeutic approach. Clinical perspective and updated literature search. The following areas are reviewed: categorisation of fracture risk and general pharmacological management of osteoporosis. A platform is provided on which specific guidelines can be developed for national use to characterise fracture risk and direct interventions.

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

Abstract: Summary 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 I2 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 adult patients hospitalised with COVID-19 in an international network study

Abstract: 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.

Is there a role for menopausal hormone therapy in the management of postmenopausal osteoporosis

Abstract: We provide an evidence base and guidance for the use of menopausal hormone therapy (MHT) for the maintenance of skeletal health and prevention of future fractures in recently menopausal women. Despite controversy over associated side effects, which has limited its use in recent decades, the potential role for MHT soon after menopause in the management of postmenopausal osteoporosis is increasingly recognized. We present a narrative review of the benefits versus risks of using MHT in the management of postmenopausal osteoporosis. Current literature suggests robust anti-fracture efficacy of MHT in patients unselected for low BMD, regardless of concomitant use with progestogens, but with limited evidence of persisting skeletal benefits following cessation of therapy. Side effects include cardiovascular events, thromboembolic disease, stroke and breast cancer, but the benefit-risk profile differs according to the use of opposed versus unopposed oestrogens, type of oestrogen/progestogen, dose and route of delivery and, for cardiovascular events, timing of MHT use. Overall, the benefit-risk profile supports MHT treatment in women who have recently (< 10 years) become menopausal, who have menopausal symptoms and who are less than 60 years old, with a low baseline risk for adverse events. MHT should be considered as an option for the maintenance of skeletal health in women, specifically as an additional benefit in the context of treatment of menopausal symptoms, when commenced at the menopause, or shortly thereafter, in the context of a personalized benefit-risk evaluation.

Ethnicity, comorbidity, socioeconomic status, and their associations with COVID-19 infection in England: a cohort analysis of UK Biobank data

Abstract: Background Recent data suggest higher COVID-19 rates and severity in Black, Asian, and minority ethnic (BAME) communities. We aimed to study the association between ethnicity and risk of COVID-19 and adjust it by deprivation and previous comorbidity. Methods Prospective cohort. UK Biobank participants from England linked to Hospital Episode Statistics (HES) and COVID-19 tests until 14 April 2020. COVID-19 infection was based on a positive PCR test. Ethnicity was self-reported and classified using Office of National Statistics groups. Socioeconomic status was based on index of multiple deprivation quintiles. Comorbidities were extracted from HES. We used Poisson regression to estimate rate ratios of infection according to ethnicity, adjusted for socioeconomic status, alcohol drinking, smoking, BMI, age, sex, and comorbidity. Results 415,582 participants were included, with 2,886 tested and 1,039 positive for COVID-19. The incidence of COVID-19 was 0.85% (0.67% - 1.09%) in Black/Black British participants, 0.47% (0.30%-0.74%) in ‘other’ ethnicities, 0.58% (0.44%-0.76%) in Asian/Asian British, 0.30% (0.11%-0.80%) in Chinese, 0.23% (0.11%-0.52%) in mixed, and 0.23% (0.21%-0.34%) in White. Compared with White participants, Black/Black British participants had an adjusted relative risk (RR) of 2.66 (2.03-3.88), Asian/Asian British participants 2.09 (1.53-2.84), Chinese participants 1.72 (0.64-4.61), ‘other’ ethnicities 1.67 (1.04-2.68), and mixed ethnicities 0.93 (0.41-2.07). Socioeconomic status (adjusted RR 1.73 (1.43-2.1) for the most deprived), was also associated with increased risk of COVID-19. Conclusion COVID-19 rates in England are higher in BAME communities, and in those living in deprived areas. Public health strategies are needed to reduce COVID-19 infections among the most susceptible groups. Key Messages In a cohort of over 480,000 participants from UK Biobank, BAME people are at a 2 to 4-fold higher risk of COVID-19 infection, independent of socioeconomic status, lifestyle, obesity, and comorbidity. Socioeconomic deprivation, obesity, and certain comorbidities (hypertension, diabetes, heart disease, and renal failure) are also independently associated with increased risk of COVID-19 infection. Public health strategies to control COVID-19 transmission must take these increased risks into account to protect the most vulnerable people in the UK and worldwide.

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

Abstract: 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.

Prevalence and Mortality of Individuals With X-Linked Hypophosphatemia: A United Kingdom Real-World Data Analysis.

Abstract: Background X-linked hypophosphatemia (XLH) is a rare multisystemic disease with a prominent musculoskeletal phenotype. We aim here to improve understanding of the prevalence of XLH across the life course and of overall survival among people with XLH. Methods This was a population-based cohort study using a large primary care database in the United Kingdom (UK) from 1995 to 2016. XLH cases were matched by age, gender, and practice to up to 4 controls. Trends in prevalence over the study period were estimated (stratified by age) and survival among cases was compared with that of controls. Findings From 522 potential cases, 122 (23.4%) were scored as at least possible XLH, while 62 (11.9%) were classified as highly likely or likely (conservative definition). In main analyses, prevalence (95% CI) increased from 3.1 (1.5-6.7) per million in 1995-1999 to 14.0 (10.8-18.1) per million in 2012-2016. Corresponding estimates using the conservative definition were 3.0 (1.4-6.5) to 8.1 (5.8-11.4). Nine (7.4%) of the possible cases died during follow-up, at median age of 64 years. Fourteen (2.9%) of the controls died at median age of 72.5 years. Mortality was significantly increased in those with possible XLH compared with controls (hazard ratio [HR] 2.93; 95% CI, 1.24-6.91). Likewise, among those with likely or highly likely XLH (HR 6.65; 1.44-30.72). Conclusions We provide conservative estimates of the prevalence of XLH in children and adults within the UK. There was an unexpected increase in mortality in later life, which may have implications for other fibroblast growth factor 23-related disorders.

Hospitalization and 30-day fatality in 121,263 COVID-19 outpatient cases

Abstract: Background To date, characterisation studies of COVID-19 have focussed on hospitalised or intensive care patients. We report for the first time on the natural history of COVID-19 disease from first diagnosis, including both outpatient and hospital care. Methods Data was obtained from SIDIAP, a primary care records database covering >6 million people (>80% of the population of Catalonia), linked to COVID-19 RT-PCR tests, hospital emergency and inpatient, and mortality registers. All participants >=15 years, diagnosed with COVID-19 in outpatient between 15th March and 24th April 2020 (10th April for outcome studies) were included. Baseline characteristics, testing, and 30-day outcomes (hospitalisation for COVID-19 and all-cause fatality) were analysed. Results A total of 121,263 and 95,467 COVID-19 patients were identified for characterisation and outcome studies, respectively. Women (57.8%) and age 45-54 (20.2%) were predominant. 44,709 were tested, with 32,976 (73.8%) PCR+. From 95,467 cases, a 14.6% [14.4–14.9] were hospitalised in the month after diagnosis, with male predominance (19.2% vs 11.3%), peaking at age 75-84. Overall 30-day fatality was 4.0% [95%CI 3.9%-4.2%], higher in men (4.8%) than women (3.4%), increasing with age, and highest in those residing in nursing homes (25.3% [24.2% to 26.4%]). Conclusions COVID-19 is seen in all age-sex strata, but severe forms of disease cluster in older men and nursing home residents. Although initially managed in primary care, 15% of cases require hospitalization within a month, with overall fatality of 4%.

Secular trends in the initiation of therapy in secondary fracture prevention in Europe: a multi-national cohort study including data from Denmark, Catalonia, and the United Kingdom

Abstract: This paper demonstrates a large post-fracture anti-osteoporosis treatment gap in the period 2005 to 2015. The gap was stable in Denmark at around 88–90%, increased in Catalonia from 80 to 88%, and started to increase in the UK towards the end of our study. Improved post-fracture care is needed. Patients experiencing a fragility fracture are at high risk of subsequent fractures, particularly within the first 2 years after the fracture. Previous studies have demonstrated that only a small proportion of fracture patients initiate therapy with an anti-osteoporotic medication (AOM), despite the proven fracture risk reduction of such therapies. The aim of this paper is to evaluate the changes in this post-fracture treatment gap across three different countries from 2005 to 2015. This analysis, which is part of a multinational cohort study, included men and women, aged 50 years or older, sustaining a first incident fragility fracture. Using routinely collected patient data from three administrative health databases covering Catalonia, Denmark, and the United Kingdom, we estimated the treatment gap as the proportion of patients not treated with AOM within 1 year of their first incident fracture. A total of 648,369 fracture patients were included. Mean age 70.2–78.9 years; 22.2–31.7% were men. In Denmark, the treatment gap was stable at approximately 88–90% throughout the 2005 to 2015 time period. In Catalonia, the treatment gap increased from 80 to 88%. In the UK, an initially decreasing treatment gap—though never smaller than 63%—was replaced by an increasing gap towards the end of our study. The gap was more pronounced in men than in women. Despite repeated calls for improved secondary fracture prevention, an unacceptably large treatment gap remains, with time trends indicating that the problem may be getting worse in recent years.

Atopic eczema and fracture risk in adults: A population-based cohort study

Abstract: Background Limited evidence suggests increased fracture risk in people with atopic eczema. Any link could have substantial effect; atopic eczema is common, and fractures have associated morbidity and mortality. Objective We sought to examine whether atopic eczema is associated with fracture and whether fracture risk varies with eczema severity. Methods We performed a matched cohort study set in primary care (Clinical Practice Research Datalink GOLD 1998-2016) and linked hospital admissions data (Hospital Episode Statistics), including adults (≥18 years old) with atopic eczema matched (by age, sex, general practice, and cohort entry date) with up to 5 individuals without eczema. We estimated hazard ratios (HRs) from stratified Cox regression comparing risk of major osteoporotic (hip, pelvis, spine, wrist, and proximal humerus) fractures individually and any fracture in those with and without atopic eczema. Results We identified 526,808 people with atopic eczema and 2,569,030 people without atopic eczema. Those with eczema had increased risk of hip (HR, 1.10; 99% CI, 1.06-1.14), pelvic (HR, 1.10; 99% CI, 1.02-1.19), spinal (HR, 1.18; 99% CI, 1.10-1.27), and wrist (HR, 1.07; 99% CI, 1.03,-1.11) fractures. We found no evidence of increased proximal humeral (HR, 1.06; 99% CI, 0.97-1.15) fracture risk. Fracture risk increased with increasing eczema severity, with the strongest associations in people with severe eczema (compared with those without) for spinal (HR, 2.09; 99% CI, 1.66-2.65), pelvic (HR, 1.66; 99% CI, 1.26-2.20), and hip (HR, 1.50; 99% CI, 1.30-1.74) fractures. Associations persisted after oral glucocorticoid adjustment. Conclusions People with atopic eczema have increased fracture risk, particularly major osteoporotic fractures.

Assessment of cardiovascular safety of anti-osteoporosis drugs

Abstract: The incidence of osteoporosis and cardiovascular disease increases with age, and there are potentially shared mechanistic associations between the two conditions It is therefore highly relevant to understand the cardiovascular implications of osteoporosis medications These are presented in this narrative review Calcium supplementation could theoretically cause atheroma formation via calcium deposition, and in one study was found to be associated with myocardial infarction, but this has not been replicated Vitamin D supplementation has been extensively investigated for cardiac benefit, but no consistent effect has been found Despite findings in the early 21st century that menopausal hormone therapy was associated with coronary artery disease and venous thromboembolism (VTE), this therapy is now thought to be potentially safe (from a cardiac perspective) if started within the first 10 years of the menopause Selective estrogen receptor modulators (SERMs) are associated with increased risk of VTE and may be related to fatal strokes (a subset of total strokes) Bisphosphonates could theoretically provide protection against atheroma However, data from randomised trials and observational studies have neither robustly supported this nor consistently demonstrated the potential association with atrial fibrillation Denosumab does not appear to be associated with cardiovascular disease and, although parathyroid hormone analogues are associated with palpitations and dizziness, no association with a defined cardiovascular pathology has been demonstrated Finally, romosozumab has been shown to have a possible cardiovascular signal, and therefore post-market surveillance of this therapy will be vital

Long-term patient-reported symptoms of COVID-19: an analysis of social media data

Abstract: As the COVID-19 virus continues to infect people across the globe, there is little understanding of the long term implications for recovered patients. There have been reports of persistent symptoms after confirmed infections on patients even after three months of initial recovery. While some of these patients have documented follow-ups on clinical records, or participate in longitudinal surveys, these datasets are usually not publicly available or standardized to perform longitudinal analyses on them. Therefore, there is a need to use additional data sources for continued follow-up and identification of latent symptoms that might be underreported in other places. In this work we present a preliminary characterization of post-COVID-19 symptoms using social media data from Twitter. We use a combination of natural language processing and clinician reviews to identify long term self-reported symptoms on a set of Twitter users.

Baseline characteristics, management, and outcomes of 55,270 children and adolescents diagnosed with COVID-19 and 1,952,693 with influenza in France, Germany, Spain, South Korea and the United States: an international network cohort study

Abstract: Objectives To characterize the demographics, comorbidities, symptoms, in-hospital treatments, and health outcomes among children/adolescents diagnosed or hospitalized with COVID-19. Secondly, to describe health outcomes amongst children/adolescents diagnosed with previous seasonal influenza. Design International network cohort. Setting Real-world data from European primary care records (France/Germany/Spain), South Korean claims and US claims and hospital databases. Participants Diagnosed and/or hospitalized children/adolescents with COVID-19 at age Main outcome measures Baseline demographics and comorbidities, symptoms, 30-day in-hospital treatments and outcomes including hospitalization, pneumonia, acute respiratory distress syndrome (ARDS), multi-system inflammatory syndrome (MIS-C), and death. Results A total of 55,270 children/adolescents diagnosed and 3,693 hospitalized with COVID-19 and 1,952,693 diagnosed with influenza were studied. Comorbidities including neurodevelopmental disorders, heart disease, and cancer were all more common among those hospitalized vs diagnosed with COVID-19. The most common COVID-19 symptom was fever. Dyspnea, bronchiolitis, anosmia and gastrointestinal symptoms were more common in COVID-19 than influenza. In-hospital treatments for COVID-19 included repurposed medications ( Hospitalization was observed in 0.3% to 1.3% of the COVID-19 diagnosed cohort, with undetectable (N Conclusions Despite negligible fatality, complications including pneumonia, ARDS and MIS-C were more frequent in children/adolescents with COVID-19 than with influenza. Dyspnea, anosmia and gastrointestinal symptoms could help differential diagnosis. A wide range of medications were used for the inpatient management of pediatric COVID-19. What is already known on this topic? Most of the early COVID-19 studies were targeted at adult patients, and data concerning children and adolescents are limited. Clinical manifestations of COVID-19 are generally milder in the pediatric population compared with adults. Hospitalization for COVID-19 affects mostly infants, toddlers, and children with pre-existing comorbidities. What this study adds ⍰This study comprehensively characterizes a large international cohort of pediatric COVID-19 patients, and almost 2 million with previous seasonal influenza across 5 countries. ⍰Although uncommon, pneumonia, acute respiratory distress syndrome (ARDS) and multi-system inflammatory syndrome (MIS-C) were more frequent in children and adolescents diagnosed with COVID-19 than in those with seasonal influenza. ⍰Dyspnea, bronchiolitis, anosmia and gastrointestinal symptoms were more frequent in COVID-19, and could help to differentiate pediatric COVID-19 from influenza. ⍰A plethora of medications were used during the management of COVID-19 in children and adolescents, with great heterogeneity in the use of antiviral therapies as well as of adjunctive therapies.

Preschool Obesity Is Associated With an Increased Risk of Childhood Fracture: A Longitudinal Cohort Study of 466,997 Children and Up to 11 Years of Follow-up in Catalonia, Spain

Abstract: This study aimed to determine if having an overweight or obese range body mass index (BMI) at time of beginning school is associated with increased fracture incidence in childhood. A dynamic cohort was created from children presenting for routine preschool primary care screening, collected in the Information System for Research in Primary Care (SIDIAP) platform in Catalonia, Spain. Data were collected from 296 primary care centers representing 74% of the regional pediatric population. A total of 466,997 children (48.6% female) with a validated weight and height measurement within routine health care screening at age 4 years (±6 months) between 2006 and 2013 were included, and followed up to the age of 15, migration out of region, death, or until December 31, 2016. BMI was calculated at age 4 years and classified using WHO growth tables, and fractures were identified using previously validated ICD10 codes in electronic primary care records, divided by anatomical location. Actuarial lifetables were used to calculate cumulative incidence. Cox regression was used to investigate the association of BMI category and fracture risk with adjustment for socioeconomic status, age, sex, and nationality. Median follow-up was 4.90 years (interquartile range [IQR] 2.50 to 7.61). Cumulative incidence of any fracture during childhood was 9.20% (95% confidence interval [CI] 3.79% to 14.61%) for underweight, 10.06% (9.82% to 10.29%) for normal weight, 11.28% (10.22% to 12.35%) for overweight children, and 13.05% (10.69% to 15.41%) for children with obesity. Compared with children of normal range weight, having an overweight and obese range BMI was associated with an excess risk of lower limb fracture (adjusted hazard ratio [HR] = 1.42 [1.26 to 1.59]; 1.74 [1.46 to 2.06], respectively) and upper limb fracture (adjusted HR = 1.10 [1.03 to 1.17]; 1.19 [1.07 to 1.31]). Overall, preschool children with an overweight or obese range BMI had increased incidence of upper and lower limb fractures in childhood compared with contemporaries of normal weight. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

Seek COVER: Development and validation of a personalized risk calculator for COVID-19 outcomes in an international network

Abstract: Importance COVID-19 is causing high mortality worldwide. Developing models to quantify the risk of poor outcomes in infected patients could help develop strategies to shield the most vulnerable during de-confinement. Objective To develop and externally validate COVID-19 Estimated Risk (COVER) scores that quantify a patient9s risk of hospital admission (COVER-H), requiring intensive services (COVER-I), or fatality (COVER-F) in the 30-days following COVID-19 diagnosis. Design Multinational, distributed network cohorts. Setting We analyzed a federated network of electronic medical records and administrative claims data from 13 data sources and 6 countries, mapped to a common data model. Participants Model development used a patient population consisting of >2 million patients with a general practice (GP), emergency room (ER), or outpatient (OP) visit with diagnosed influenza or flu-like symptoms any time prior to 2020. The model was validated on patients with a GP, ER, or OP visit in 2020 with a confirmed or suspected COVID-19 diagnosis across four databases from South Korea, Spain and the United States. Outcomes Age, sex, historical conditions, and drug use prior to index date were considered as candidate predictors. Outcomes included i) hospitalization with pneumonia, ii) hospitalization with pneumonia requiring intensive services or death, and iii) death in the 30 days after index date. Results Overall, 43,061 COVID-19 patients were included for model validation, after initial model development and validation using 6,869,127 patients with influenza or flu-like symptoms. We identified 7 predictors (history of cancer, chronic obstructive pulmonary disease, diabetes, heart disease, hypertension, hyperlipidemia, and kidney disease) which combined with age and sex could discriminate which patients would experience any of our three outcomes. The models achieved high performance in influenza. When transported to COVID-19 cohorts, the AUC ranges were, COVER-H: 0.73-0.81, COVER-I: 0.73-0.91, and COVER-F: 0.82-0.90. Calibration was overall acceptable, with overestimated risk in the most elderly and highest risk strata. Conclusions and relevance A 9-predictor model performs well for COVID-19 patients for predicting hospitalization, intensive services and death. The models could aid in providing reassurance for low risk patients and shield high risk patients from COVID-19 during de-confinement to reduce the virus9 impact on morbidity and mortality.

The natural history of symptomatic COVID-19 in Catalonia, Spain: a multi-state model including 109,367 outpatient diagnoses, 18,019 hospitalisations, and 5,585 COVID-19 deaths among 5,627,520 people

Abstract: Background The natural history of Coronavirus Disease 2019 (COVID-19) has yet to be fully described, with most previous reports focusing on hospitalised patients. Using linked patient-level data, we set out to describe the associations between age, gender, and comorbidities and the risk of outpatient COVID-19 diagnosis, hospitalisation, and/or related mortality. Methods A population-based cohort study including all individuals registered in Information System for Research in Primary Care (SIDIAP). SIDIAP includes primary care records covering > 80% of the population of Catalonia, Spain, and was linked to region-wide testing, hospital and mortality records. Outpatient diagnoses of COVID-19, hospitalisations with COVID-19, and deaths with COVID-19 were identified between 1st March and 6th May 2020. A multi-state model was used, with cause-specific Cox survival models estimated for each transition. Findings A total of 5,627,520 individuals were included. Of these, 109,367 had an outpatient diagnosis of COVID-19, 18,019 were hospitalised with COVID-19, and 5,585 died after either being diagnosed or hospitalised with COVID-19. Half of those who died were not admitted to hospital prior to their death. Risk of a diagnosis with COVID-19 peaked first in middle-age and then again for oldest ages, risk for hospitalisation after diagnosis peaked around 70 years old, with all other risks highest at oldest ages. Male gender was associated with an increased risk for all outcomes other than outpatient diagnosis. The comorbidities studied (autoimmune condition, chronic kidney disease, chronic obstructive pulmonary disease, dementia, heart disease, hyperlipidemia, hypertension, malignant neoplasm, obesity, and type 2 diabetes) were all associated with worse outcomes. Interpretation There is a continued need to protect those at high risk of poor outcomes, particularly the elderly, from COVID-19 and provide appropriate care for those who develop symptomatic disease. While risks of hospitalisation and death are lower for younger populations, there is a need to limit their role in community transmission. These findings should inform public health strategies, including future vaccination campaigns.

Renin-angiotensin system blockers and susceptibility to COVID-19: a multinational open science cohort study

Abstract: Introduction: Angiotensin converting enzyme inhibitors (ACEs) and angiotensin receptor blockers (ARBs) could influence infection risk of coronavirus disease (COVID-19). Observational studies to date lack pre-specification, transparency, rigorous ascertainment adjustment and international generalizability, with contradictory results. Methods: Using electronic health records from Spain (SIDIAP) and the United States (Columbia University Irving Medical Center and Department of Veterans Affairs), we conducted a systematic cohort study with prevalent ACE, ARB, calcium channel blocker (CCB) and thiazide diuretic (THZ) use to determine relative risk of COVID-19 diagnosis and related hospitalization outcomes. The study addressed confounding through large-scale propensity score adjustment and negative control experiments. Results: Following over 1.1 million antihypertensive users identified between November 2019 and January 2020, we observed no significant difference in relative COVID-19 diagnosis risk comparing ACE/ARB vs CCB/THZ monotherapy (hazard ratio: 0.98; 95% CI 0.84 - 1.14), nor any difference for mono/combination use (1.01; 0.90 - 1.15). ACE alone and ARB alone similarly showed no relative risk difference when compared to CCB/THZ monotherapy or mono/combination use. Directly comparing ACE vs. ARB demonstrated a moderately lower risk with ACE, non-significant for monotherapy (0.85; 0.69 - 1.05) and marginally significant for mono/combination users (0.88; 0.79 - 0.99). We observed, however, no significant difference between drug- classes for COVID-19 hospitalization or pneumonia risk across all comparisons. Conclusion: There is no clinically significant increased risk of COVID-19 diagnosis or hospitalization with ACE or ARB use. Users should not discontinue or change their treatment to avoid COVID-19.

Incidence, risk factors and re-exacerbation rate of severe asthma exacerbations in a multinational, multidatabase pediatric cohort study.

Abstract: Background: There are sparse real-world data on severe asthma exacerbations (SAE) in children. This multinational cohort study assessed the incidence of and risk factors for SAE and the incidence of asthma-related rehospitalization in children with asthma. Methods: Asthma patients 5-17 years old with ≥1 year of follow-up were identified in six European electronic databases from the Netherlands, Italy, the UK, Denmark and Spain in 2008-2013. Asthma was defined as ≥1 asthma-specific disease code within 3 months of prescriptions/dispensing of asthma medication. Severe asthma was defined as high-dosed inhaled corticosteroids plus a second controller. SAE was defined by systemic corticosteroids, emergency department visit and/or hospitalization all for reason of asthma. Risk factors for SAE were estimated by Poisson regression analyses. Results: The cohort consisted of 212 060 paediatric asthma patients contributing to 678 625 patient-years (PY). SAE rates ranged between 17 and 198/1000 PY and were higher in severe asthma and highest in severe asthma patients with a history of exacerbations. Prior SAE (incidence rate ratio 3-45) and younger age increased the SAE risk in all countries, whereas obesity, atopy and GERD were a risk factor in some but not all countries. Rehospitalization rates were up to 79% within 1 year. Conclusions: In a real-world setting, SAE rates were highest in children with severe asthma with a history of exacerbations. Many severe asthma patients were rehospitalized within 1 year. Asthma management focusing on prevention of SAE is important to reduce the burden of asthma.

Oral Bisphosphonate use Reduces Cardiovascular Events in a Cohort of Danish Patients Referred for Bone Mineral Density.

Abstract: Context The cardiovascular (CV) safety of oral bisphosphonates (oBPs) is uncertain. Objective Determine the risk of CV events in oBP users referred for bone mineral density (BMD) testing compared with matched controls. Design Cohort study. Setting Danish national prescription registry enriched with local hospital data from Odense. Participants Individuals aged ≥45 years referred for BMD testing. Exposure oBP. Outcomes Hospitalization for any CV event. Secondary study outcomes were specific CV events. Negative (inguinal hernia surgery and ingrown toenail) and positive (fragility fracture) control outcomes assessed systemic bias. Cox proportional hazards models were fitted to estimate hazard ratio (HR) and 95% confidence intervals. Results There were 2565 oBP users (82.6% women) and 4568 (82.3% women) propensity score-matched controls. Alendronate accounted for 96% of oBP prescription. A total of 406 (15.8%) CV events occurred in oBP users (rate = 73.48 [66.67-80.98]); rate = events divided by person-time; and 837 (18.3%) events in controls (rate = 104.73 [97.87-112.07]) with an adjusted HR of 0.68 (95% CI 0.60-0.77). Additional adjustment for BMD did not attenuate estimates (HR 0.67; 95% CI 0.58-0.78]. Similar results were seen for secondary outcomes where risk reductions were seen regarding atrial fibrillation, stroke, heart failure, and aneurysms. Positive and negative control outcome analyses identified minimal residual confounding. Conclusion Oral BP users experienced a 33% reduced risk of CV events. This observational real-world study adds to a growing body of evidence for cardioprotection by oBP that warrants testing in a randomized setting.

Increased Fracture Risk in Women Treated With Aromatase Inhibitors Versus Tamoxifen: Beneficial Effect of Bisphosphonates.

Abstract: Aromatase inhibitors have been associated with accelerated bone loss and an increased risk of osteoporotic fractures. Currently, bisphosphonates are recommended to reduce fracture risk in these patients. The aim of this study is to evaluate the fracture risk in breast cancer patients receiving aromatase inhibitors, compared to tamoxifen users, and to assess the effectiveness of oral bisphosphonates in reducing fracture risk. We performed an observational cohort study up to 10 years of follow-up. Data were extracted from primary care records in a population database. Women diagnosed with breast cancer between 2006 and 2015 and treated with tamoxifen or aromatase inhibitors (n = 36,472) were stratified according to low (without osteoporosis diagnosis nor bisphosphonates exposure) or high (with osteoporosis and/or treated with bisphosphonates) fracture risk. Cox models were used to calculate hazard ratios (HR [95% CI]) of fracture from the propensity score-matched patients. Sensitivity analyses account for competing risk of death were performed (subdistribution hazard ratio [SHR] [95% CI]). In postmenopausal women, fracture risk in aromatase inhibitor users showed an HR 1.40 [95% CI,1.05 to 1.87] and SHR 1.48 [95% CI, 1.11 to 1.98], compared to tamoxifen. Observing aromatase inhibitors patients at high risk of fracture, bisphosphonate-treated patients had an HR 0.73 [95% CI, 0.51 to 1.04] and SHR 0.69 [95% CI, 0.48 to 0.98] compared to nontreated. In conclusion, fracture risk in postmenopausal women during aromatase inhibitor treatment, in real-life conditions, was >40% compared to tamoxifen, corroborating previous randomized controlled trials results. In high-risk patients, bisphosphonate users had lower significant fracture incidence during aromatase inhibitor therapy than nonbisphosphonate users. Monitoring fracture risk and related risk factors in aromatase inhibitor patients is advisable. © 2019 American Society for Bone and Mineral Research.

The impact of the enhanced recovery pathway and other factors on outcomes and costs following hip and knee replacement: routine data study

Abstract: Background There is limited evidence concerning the effectiveness of enhanced recovery programmes in hip and knee replacement surgery, particularly when applied nationwide across a health-care system. Objectives To determine the effect of hospital organisation, surgical factors and the enhanced recovery after surgery pathway on patient outcomes and NHS costs of hip and knee replacement. Design (1) Statistical analysis of national linked data to explore geographical variations in patient outcomes of surgery. (2) A natural experimental study to determine clinical effectiveness of enhanced recovery after surgery. (3) A qualitative study to identify barriers to, and facilitators of, change. (4) Health economics analysis to establish NHS costs and cost-effectiveness. Setting Data from the National Joint Registry, linked to English Hospital Episode Statistics and patient-reported outcome measures in both the geographical variation and natural experiment studies, together with the economic evaluation. The ethnographic study took place in four hospitals in a region of England. Participants Qualitative study – 38 health professionals working in hip and knee replacement services in secondary care and 37 patients receiving hip or knee replacement. Interventions Natural experiment – implementation of enhanced recovery after surgery at each hospital between 2009 and 2011. Enhanced recovery after surgery is a complex intervention focusing on several areas of patients’ care pathways through surgery: preoperatively (patient is in best possible condition for surgery), perioperatively (patient has best possible management during and after operation) and postoperatively (patient experiences best rehabilitation). Main outcome measures Patient-reported pain and function (Oxford Hip Score/Oxford Knee Score); 6-month complications; length of stay; bed-day costs; and revision surgery within 5 years. Results Geographical study – there are potentially unwarranted variations in patient outcomes of hip and knee replacement surgery. This variation cannot be explained by differences in patients, case mix, surgical or hospital organisational factors. Qualitative – successful implementation depends on empowering patients to work towards their recovery, providing post-discharge support and promoting successful multidisciplinary team working. Care processes were negotiated between patients and health-care professionals. ‘Good care’ remains an aspiration, particularly in the post-discharge period. Natural experiment – length of stay has declined substantially, pain and function have improved, revision rates are in decline and complication rates remain stable. The introduction of a national enhanced recovery after surgery programme maintained improvement, but did not alter the rate of change already under way. Health economics – costs are high in the year of joint replacement and remain higher in the subsequent year after surgery. There is a strong economic incentive to identify ways of reducing revisions and complications following joint replacement. Published cost-effectiveness evidence supports enhanced recovery pathways as a whole. Limitations Short duration of follow-up data prior to enhanced recovery after surgery implementation and missing data, particularly for hospital organisation factors. Conclusion No evidence was found to show that enhanced recovery after surgery had a substantial impact on longer-term downwards trends in costs and length of stay. Trends of improving outcomes were seen across all age groups, in those with and without comorbidity, and had begun prior to the formal enhanced recovery after surgery roll-out. Reductions in length of stay have been achieved without adversely affecting patient outcomes, yet, substantial variation remains in outcomes between hospital trusts. Future work There is still work to be done to reduce and understand unwarranted variations in outcome between individual hospitals. Study registration This study is registered as PROSPERO CRD42017059473. Funding This project was funded by the National Institute for Health Research (NIHR) Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research; Vol. 8, No. 4. See the NIHR Journals Library website for further project information.

Methotrexate and relative risk of dementia amongst patients with rheumatoid arthritis: a multi-national multi-database case-control study.

Abstract: Inflammatory processes have been shown to play a role in dementia. To understand this role, we selected two anti-inflammatory drugs (methotrexate and sulfasalazine) to study their association with dementia risk. A retrospective matched case-control study of patients over 50 with rheumatoid arthritis (486 dementia cases and 641 controls) who were identified from electronic health records in the UK, Spain, Denmark and the Netherlands. Conditional logistic regression models were fitted to estimate the risk of dementia. Prior methotrexate use was associated with a lower risk of dementia (OR 0.71, 95% CI 0.52–0.98). Furthermore, methotrexate use with therapy longer than 4 years had the lowest risk of dementia (odds ratio 0.37, 95% CI 0.17–0.79). Sulfasalazine use was not associated with dementia (odds ratio 0.88, 95% CI 0.57–1.37). Further studies are still required to clarify the relationship between prior methotrexate use and duration as well as biological treatments with dementia risk.

Osteoporosis epidemiology using international cohorts.

Abstract: Purpose of review The field of osteoporosis research has been active for the past 20 years and has allowed significant advancement in the management of osteoporosis. This review will give an overview of the latest data from international cohorts that relate to current and recent osteoporosis research. Recent findings The clinical diagnosis of osteoporosis relies heavily on bone mineral density (BMD) measured at femoral neck or spine and although BMD has excellent predictive value for future fractures, fracture risk assessment has evolved over the years, resulting in the birth of fracture prediction tools. Fracture risk factors not currently featured in these tools are being considered for inclusion, including imminent risk fracture following a sentinel fracture, number of falls, and previous vertebral fractures. Data from groups with comorbidities such as chronic obstructive pulmonary disease are helping us understand how to best manage patients with multiple comorbidities. Finally, the prevalence of vertebral fracture in the older general population and other selected populations has been explored, alongside the global burden of osteoporosis and its consequences. Summary Our understanding of osteoporosis continues to expand, but knowledge gaps remain.

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

Abstract: Author(s): Lane, Jennifer CE; Weaver, James; Kostka, Kristin; Duarte-Salles, Talita; Abrahao, Maria Tereza F; Alghoul, Heba; Alser, Osaid; Alshammari, Thamir M; Areia, Carlos; Biedermann, Patricia; Banda, Juan M; Burn, Edward; Casajust, Paula; Fister, Kristina; Hardin, Jill; Hester, Laura; Hripcsak, George; Kaas-Hansen, Benjamin Skov; Khosla, Sajan; Kolovos, Spyros; Lynch, Kristine E; Makadia, Rupa; Mehta, Paras P; Morales, Daniel R; Morgan-Stewart, Henry; Mosseveld, Mees; Newby, Danielle; Nyberg, Fredrik; Ostropolets, Anna; Woong Park, Rae; Prats-Uribe, Albert; Rao, Gowtham A; Reich, Christian; Rijnbeek, Peter; Sena, Anthony G; Shoaibi, Azza; Spotnitz, Matthew; Subbian, Vignesh; Suchard, Marc A; Vizcaya, David; Wen, Haini; Wilde, Marcel de; Xie, Junqing; You, Seng Chan; Zhang, Lin; Lovestone, Simon; Ryan, Patrick; Prieto-Alhambra, Daniel; OHDSI-COVID-19 consortium | Abstract: ObjectivesConcern 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.MethodsWe 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 l40%.ResultsA 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.ConclusionHCQ 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 registrationRegistered 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.

Serious complications and risk of re-operation after Dupuytren's disease surgery: a population-based cohort study of 121,488 patients in England

Abstract: Dupuytren's disease (DD) is a common fibro-proliferative disorder of the palm. We estimated the risk of serious local and systemic complications and re-operation after DD surgery. We queried England's Hospital Episode Statistics database and included all adult DD patients who were surgically treated. A longitudinal cohort study and self-controlled case series were conducted. Between 1 April 2007 and 31 March 2017, 121,488 adults underwent 158,119 operations for DD. The cumulative incidence of 90-day serious local complications was low at 1.2% (95% CI 1.1-1.2). However, the amputation rate for re-operation by limited fasciectomy following dermofasciectomy was 8%. 90-day systemic complications were also uncommon at 0.78% (95% CI 0.74-0.83), however operations routinely performed under general or regional anaesthesia carried an increased risk of serious systemic complications such as myocardial infarction. Re-operation was lower than previous reports (33.7% for percutaneous needle fasciotomy, 19.5% for limited fasciectomy, and 18.2% for dermofasciectomy). Overall, DD surgery performed in England was safe; however, re-operation by after dermofasciectomy carries a high risk of amputation. Furthermore, whilst serious systemic complications were unusual, the data suggest that high-risk patients should undergo treatment under local anaesthesia. These data will inform better shared decision-making regarding this common condition.

Smoking and alcohol intake but not muscle strength in young men increase fracture risk at middle age: a cohort study linked to the Swedish National Patient Registry

Abstract: We aimed to determine the relationship between handgrip strength, smoking, and alcohol consumption in young men and fracture risk at middle age. Thus, we carried out a cohort study including young men undergoing conscription examination in Sweden from September 1969 to May 1970 at a typical age of 18 years. Data on muscle strength, height, weight, and lifestyle factors were linked to the National Patient Register 1987–2010. Handgrip strength was considered the main exposure and smoking and alcohol consumption as secondary exposures. Outcomes were all fractures (except face, skull, digits), major osteoporotic fractures (thoracic/lumbar spine, proximal humerus, distal forearm or hip), and major traumatic fractures (shaft of humerus, forearm, femur, or lower leg) based on ICD-9 and -10 codes. We used Cox regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI) according to handgrip strength as a continuous variable (per 1 SD), after adjustment for weight, height, parental education, smoking, and alcohol consumption. A total of 40,112 men were included, contributing 892,572 person-years. Overall, 3974 men fractured in middle age with the incidence rate (95% CI) of 44.5 (43.2–45.9) per 1000 person-years. The corresponding rates were12.2 and 5.6 per 1000 person-years for major osteoporotic and traumatic fractures, respectively. Handgrip strength-adjusted HR (95% CI) was 1.01 (0.98–1.05), 0.94 (0.88–1.00), and 0.98 (0.88–1.08) per SD for all, major osteoporotic, and major traumatic fractures, respectively. Adjusted HR (95% CI) for smokers (>21 cigarettes/d) was 1.44 (1.21, 1.71) for all fractures, while the association between alcohol consumption and hazards of fracture was J-shaped. Therefore, young adult handgrip strength was not associated with fracture risk in middle-age men, although smoking and high alcohol consumption did confer an increased risk. (Less)