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Introduction: Concerns of the persistence and severity of the adverse effects of fluoroquinolones, mainly involving the nervous system, muscles and joints, resulted in the 2018 referral procedure led by the European Medicines Agency (EMA). They advised to stop prescribing fluoroquinolones for infections of mild severity or of a presumed self-limiting course and for prevention of infections, plus to restrict prescriptions in cases of milder infections where other treatment options are available, and restrict in at-risk populations. We aimed to examine whether the impact of EMA regulatory interventions implemented throughout 2018–2019 had an impact on fluoroquinolone prescribing rates. Methods: A retrospective population-based cohort study was conducted using electronic health care records from six European countries between 2016 and 2021. We analysed monthly incident fluoroquinolone use rates overall and for each fluoroquinolone active substance through flexible modelling via segmented regression to detect time points of trend changes, in monthly percentage change (MPC). Results: The incidence of fluoroquinolone use ranged from 0.7 to 8.0/1000 persons per month over all calendar years. While changes in fluoroquinolone prescriptions were observed over time across countries, these were inconsistent and did not seem to be temporally related to EMA interventions (e.g., Belgium: February/May 2018, MPC − 33.3%, 95% confidence interval [CI] − 35.9 to − 30.7; Germany: February/May 2019, MPC − 12.6%, 95% CI − 13.7 to − 11.6]; UK: January/April 2016, MPC − 4.9%, 95% CI − 6.2 to − 3.6). Conclusion: The regulatory action associated with the 2018 referral did not seem to have relevant effects on fluoroquinolone prescribing in primary care.

Background: There are few data on the incidence of thrombosis among COVID-19 cases, with most research concentrated on hospitalised patients. We aimed to estimate the incidence of venous thromboembolism, arterial thromboembolism, and death among COVID-19 cases and to assess the impact of these events on the risks of hospitalisation and death. Methods: We conducted a distributed network cohort study using primary care records from the Netherlands, Italy, Spain, and the UK, and outpatient specialist records from Germany. The Spanish database was linked to hospital admissions. Participants were followed up from the date of a diagnosis of COVID-19 or positive RT-PCR test for SARS-CoV-2 (index date) for 90 days. The primary study outcomes were venous thromboembolic events, arterial thromboembolic events, and death, all over the 90 days from the index date. We estimated cumulative incidences for the study outcomes. Multistate models were used to calculate adjusted hazard ratios (HRs) for the association between venous thromboembolism or arterial thromboembolism occurrence and risks of hospitalisation or COVID-19 fatality. Findings: Overall, 909 473 COVID-19 cases and 32 329 patients hospitalised with COVID-19 on or after Sept 1, 2020, were studied. The latest index dates across the databases ranged from Jan 30, 2021, to July 31, 2021. Cumulative 90-day incidence of venous thromboembolism ranged from 0·2% to 0·8% among COVID-19 cases, and up to 4·5% for those hospitalised. For arterial thromboembolism, estimates ranged from 0·1% to 0·8% among COVID-19 cases, increasing to 3·1% among those hospitalised. Case fatality ranged from 1·1% to 2·0% among patients with COVID-19, rising to 14·6% for hospitalised patients. The occurrence of venous thromboembolism in patients with COVID-19 was associated with an increased risk of death (adjusted HRs 4·42 [3·07–6·36] for those not hospitalised and 1·63 [1·39–1·90] for those hospitalised), as was the occurrence of arterial thromboembolism (3·16 [2·65–3·75] and 1·93 [1·57–2·37]). Interpretation: Risks of venous thromboembolism and arterial thromboembolism were up to 1% among COVID-19 cases, and increased with age, among males, and in those who were hospitalised. Their occurrence was associated with excess mortality, underlying the importance of developing effective treatment strategies that reduce their frequency. Funding: European Medicines Agency.

Background:Thrombosis with thrombocytopenia syndrome (TTS) has been reported among individuals vaccinated with adenovirus-vectored COVID-19 vaccines. In this study, we describe the background incidence of non-vaccine induced TTS in six European countries. Methods:Electronic medical records from France, the Netherlands, Italy, Germany, Spain, and the United Kingdom informed the study. Incidence rates of cerebral venous sinus thrombosis (CVST), splanchnic vein thrombosis (SVT), deep vein thrombosis (DVT), pulmonary embolism (PE), and myocardial infarction or ischemic stroke, all with concurrent thrombocytopenia, were estimated among the general population of persons in a database between 2017 and 2019. A range of additional potential adverse events of special interest for COVID-19 vaccinations were also studied in a similar manner. Findings:A total of 38 611 617 individuals were included. Background rates ranged from 1.0 (95% CI: 0.7–1.4) to 8.5 (7.4–9.9) per 100 000 person-years for DVT with thrombocytopenia, from 0.5 (0.3–0.6) to 20.8 (18.9–22.8) for PE with thrombocytopenia, from 0.1 (0.0–0.1) to 2.5 (2.2–2.7) for SVT with thrombocytopenia, and from 1.0 (0.8–1.2) to 43.4 (40.7–46.3) for myocardial infarction or ischemic stroke with thrombocytopenia. CVST with thrombocytopenia was only identified in one database, with incidence rate of 0.1 (0.1–0.2) per 100 000 person-years. The incidence of non-vaccine induced TTS increased with age, and was typically greater among those with more comorbidities and greater medication use than the general population. It was also more often seen in men than women. A large proportion of those affected were seen to have been taking antithrombotic and anticoagulant therapies prior to their event. Interpretation:Although rates vary across databases, non-vaccine induced TTS has consistently been seen to be a very rare event among the general population. While still remaining very rare, rates were typically higher among older individuals, and those affected were also seen to generally be male and have more comorbidities and greater medication use than the general population.

ObjectivesTo assess the uptake of second-line antihyperglycemic agents among patients with type-2 diabetes mellitus (T2DM) receiving metformin.DesignSerial cross-sectional study (2011-2021).SettingTen US and seven non-US electronic health record and administrative claims databases in the Observational Health Data Sciences and Informatics network.Participants4.8 million patients with T2DM receiving metformin.Main Outcomes MeasuresCalendar-year trends in the proportional initiation of second-line antihyperglycemic agents, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), sodium-glucose cotransporter 2 inhibitors (SGLT2is), dipeptidyl peptidase-4 inhibitors, and sulfonylureas, for each database. We also evaluated the relative drug class-level uptake across cardiovascular risk groups.ResultsWe identified 4.6 million patients with T2DM in US databases, 61,382 from Spain, 32,442 from Germany, 25,173 from the UK, 13,270 from France, 5,580 from Scotland, 4,614 from Hong Kong, and 2,322 from Australia. During 2011-2021, the combined proportional initiation of cardioprotective antihyperglycemic agents, GLP-1 RAs and SGLT2is, increased across all data sources, with the combined initiation of these drugs as second-line agents in 2021 ranging from 35.2% to 68.2% in the US databases, 15.4% in France, 34.7% in Spain, 50.1% in Germany, and 54.8% in Scotland. From 2016 to 2021, in some US and non-US databases, uptake of GLP-1 RAs and SGLT2is increased more significantly among populations without cardiovascular disease compared to those with established cardiovascular disease, without any data source providing evidence of a greater increase in their uptake in the populations with cardiovascular disease.ConclusionsDespite the increase in overall uptake of cardioprotective antihyperglycemic agents as second-line treatment for T2DM, their uptake was lower in patients with cardiovascular disease over the last decade. A strategy to ensure medication use concordant with guideline recommendations is essential to improve outcomes of patients with T2DM.

Background: A previous study in Denmark suggested an increased melanoma risk associated with the use of flecainide.Objective: To study the association between flecainide use and the risk of melanoma and non-melanoma skin cancer in Spain and Denmark.Methods: We conducted a multi-database case–control study in (database/study period) Spain (SIDIAP/2005–2017 and BIFAP/2007–2017) and Denmark (Danish registries/2001–2018). We included incident cases of melanoma or non-melanoma skin cancer (NMSC) aged ≥18 with ≥2 years of previous data (≥10 years for Denmark) before the skin cancer and matched them to controls (10:1 by age and sex). We excluded persons with immunosuppression or previous cancer. We defined ever-use as any prescription fill and high-use as a cumulative dose of at least 200 g (reference: never-use). We categorized a cumulative dose for a dose–response assessment. We used conditional logistic regression to compute ORs (95% CI) adjusted for photosensitizing, anti-neoplastic, disease-specific drugs and comorbidities.Results: The total numbers of melanoma/NMSC cases included were 7,809/64,230 in SIDIAP, 4,661/31,063 in BIFAP, and 27,978/152,821 in Denmark. In Denmark, high-use of flecainide was associated with increased adjusted ORs of skin cancer compared with never-use [melanoma: OR 1.97 (1.38–2.81); NMSC: OR 1.34 (1.15–1.56)]. In Spain, an association between high-use of flecainide and NMSC was also observed [BIFAP: OR 1.42 (1.04–1.93); SIDIAP: OR 1.19 (0.95–1.48)]. There was a non-significant dose–response pattern for melanoma in Denmark and no apparent dose–response pattern for NMSC in any of the three databases. We found similar results for ever-use of flecainide.Conclusion: Flecainide use was associated with an increased risk of melanoma (Denmark only) and NMSC (Denmark and Spain) but without substantial evidence of dose–response patterns. Further studies are needed to assess for possible unmeasured confounders.

Summary We estimated and characterized the imminent fracture risk (1–2 years) of high-risk fracture patients through a multinational (UK, Spain, Denmark) cohort study. Older individuals with newly diagnosed osteoporosis and individuals who had a fracture while on treatment with a bisphosphonate were at a high risk of imminent fracture. Purpose To characterize and estimate 1- to 2-year fracture risk in high-risk fracture patients. Methods Multi-cohort study in (database/study period) UK (CPRD/1995–2017), Spain (SIDIAP/2006–2016) and Denmark (DHR/1995–2016) including individuals ≥ 50 years old in NDO (newly diagnosed osteoporosis), OFx (incident osteoporotic fracture), BP (incident oral bisphosphonates use) or FWOT (fracture while on treatment with bisphosphonates). Outcomes (ICD-10/READ): hip, clinical spine, non-hip, non-spine and hip/humerus/distal forearm fracture. Follow-up: from cohort entry until death, migration/transfer or end of the study. Statistics: baseline characteristics and incidence rate (IR per 1000 persons). Results (1-year IR) NDO included 69,899 (UK), 37,901 (Spain) and 158,191 (Denmark) individuals. Spanish-IR was lowest for hip (4.7), clinical spine (2.5) and major osteoporotic fracture (MOF) (17.3) and highest in Denmark (74.2, 26.0 and 120.1, respectively). OFx included 83,514 (UK), 51,044 (Spain) and 509,551 (Denmark) individuals. IR in Denmark was highest for hip (24.1) and MOF (47.2), in Spain was highest for the clinical spine (9.4) and lowest for hip (9.5) and in the UK was lowest for the clinical spine (2.8) and MOF (20.7). BP included 148,507 (UK), 52,037 (Spain) and 204,010 (Denmark) individuals. Spanish-IR was lowest for hip (5.0) and MOF (21.1) and highest in Denmark (20.3 and 48.6, respectively). FWOT included 28,930 (UK), 1,865 (Spain) and 31,882 (Denmark) individuals. Clinical spine-IR was highest for Spain (12.0). Hip-IR was lowest for Spain (7.6) and highest for Denmark (33.6). Comparing young subjects, those who have FWOT started with an increased fracture rate. Conclusion OFx and FWOT individuals experience higher re-fracture incidence rates than those with osteoporosis with or without treatment.

ObjectiveWe aimed to estimate how longitudinal trends in cardiovascular disease, hypertension and type 2 diabetes mellitus incidence in Catalonia, Spain from 2009 to 2018 may differ by age, sex and socioeconomic deprivation.DesignCohort study using prospectively collected data.SettingElectronic health records from primary healthcare centres in Catalonia, Spain.Participants3 247 244 adults (≥40 years).Outcome measuresWe calculated the annual incidence (per 1000 persons-year) and incidence rate ratios (IRR) between three time periods of cardiovascular disease, hypertension and type 2 diabetes mellitus to measure trends and changes in incidence during the study period.ResultsIn 2016–2018 compared with 2009–2012, cardiovascular disease incidence increased in the 40–54 (eg, IRR=1.61, 95% CI: 1.52 to 1.69 in women) and 55–69 age groups. There was no change in cardiovascular disease incidence in women aged 70+ years, and a slight decrease in men aged 70+ years (0.93, 0.90 to 0.95). Hypertension incidence decreased in all age groups for both sexes. Type 2 diabetes mellitus incidence decreased in all age groups for both sexes (eg, 0.72, 0.70 to 0.73 in women aged 55–69 years), except for the 40–54 year age group (eg, 1.09, 1.06 to 1.13 in women). Higher incidence levels were found in the most deprived areas, especially in the 40–54 and 55–69 groups.ConclusionsOverall cardiovascular disease incidence has increased while hypertension and type 2 diabetes mellitus incidence have decreased in the last years in Catalonia, Spain, with differences in trends by age group and socioeconomic deprivation.

Background: It is unclear how cardiovascular disease, hypertension, and type 2 diabetes mellitus incidence trends have evolved in different population subgroups by age, sex, and socioeconomic status. Our study aims to estimate the trends in cardiovascular disease, hypertension, and type 2 diabetes mellitus incidence in Catalonia, Spain from 2009-2018, considering age, sex, and socioeconomic deprivation.Methods: Our study is a population-based cohort study using prospectively collected data from electronic health records from primary care and hospital settings in Catalonia, Spain, from 2009-2018. Our final study population included 3,247,244 adults (≥40 years). We calculated the annual incidence (per 1000 persons-year) and incidence rate ratios (IRR) between three time periods of cardiovascular disease, hypertension, and type 2 diabetes mellitus to measure trends and changes in incidence during the study period.Results: In 2016-2018 compared to 2009-2012, cardiovascular disease incidence increased in the 40-54 (e.g., IRR=1.61, 95%CI: 1.52-1.69 in women) and 55-69 (1.35, 1.31-1.40 in women) age groups. There was no change in cardiovascular disease incidence in women aged 70+ years, and a slight decrease in men aged 70+ years (0.93, 0.90-0.95). Hypertension incidence decreased in all age groups for both sexes. Type 2 diabetes mellitus incidence decreased in all age groups for both sexes (e.g., 0.72, 0.70-0.73 in women aged 55-69 years), except for the 40-54 year age group (e.g., 1.09, 1.06-1.13 in women). Incidence trends by deprivation for all three conditions mirrored overall trends, although there were higher incidence levels in the most deprived areas, especially in the 40-54 and 55-69 year groups. These differences have remained constant or narrowed in recent years.Conclusions: Overall cardiovascular disease incidence has increased while hypertension and type 2 diabetes mellitus incidence have decreased in the last years in Catalonia, Spain. Differences in trends by age group and socioeconomic deprivation were found. Calling attention to these differences can serve to inform policies aimed at reducing the burden of these conditions and health inequities.

ObjectiveTo investigate how trends in incidence of anxiety and depressive disorders have been affected by the COVID-19 pandemic.DesignPopulation-based cohort study.SettingRetrospective cohort study from 2018 to 2021 using the Information System for Research in Primary Care (SIDIAP) database in Catalonia, Spain.Participants3 640 204 individuals aged 18 or older in SIDIAP on 1 March 2018 with no history of anxiety and depressive disorders.Primary and secondary outcomes measuresThe incidence of anxiety and depressive disorders during the prelockdown period (March 2018–February 2020), lockdown period (March–June 2020) and postlockdown period (July 2020–March 2021) was calculated. Forecasted rates over the COVID-19 periods were estimated using negative binomial regression models based on prelockdown data. The percentage of reduction was estimated by comparing forecasted versus observed events, overall and by sex, age and socioeconomic status.ResultsThe incidence rates per 100 000 person-months of anxiety and depressive disorders were 151.1 (95% CI 150.3 to 152.0) and 32.3 (31.9 to 32.6), respectively, during the prelockdown period. We observed an increase of 37.1% (95% prediction interval 25.5 to 50.2) in incident anxiety diagnoses compared with the expected in March 2020, followed by a reduction of 15.8% (7.3 to 23.5) during the postlockdown period. A reduction in incident depressive disorders occurred during the lockdown and postlockdown periods (45.6% (39.2 to 51.0) and 22.0% (12.6 to 30.1), respectively). Reductions were higher among women during the lockdown period, adults aged 18–34 years and individuals living in the most deprived areas.ConclusionsThe COVID-19 pandemic in Catalonia was associated with an initial increase in anxiety disorders diagnosed in primary care but a reduction in cases as the pandemic continued. Diagnoses of depressive disorders were lower than expected throughout the pandemic.

Objective: To characterise patients with and without prevalent hypertension and COVID-19 and to assess adverse outcomes in both inpatients and outpatients. Design and setting: This is a retrospective cohort study using 15 healthcare databases (primary and secondary electronic healthcare records, insurance and national claims data) from the USA, Europe and South Korea, standardised to the Observational Medical Outcomes Partnership common data model. Data were gathered from 1 March to 31 October 2020. Participants: Two non-mutually exclusive cohorts were defined: (1) individuals diagnosed with COVID-19 (diagnosed cohort) and (2) individuals hospitalised with COVID-19 (hospitalised cohort), and stratified by hypertension status. Follow-up was from COVID-19 diagnosis/hospitalisation to death, end of the study period or 30 days. Outcomes: Demographics, comorbidities and 30-day outcomes (hospitalisation and death for the 'diagnosed' cohort and adverse events and death for the 'hospitalised' cohort) were reported. Results: We identified 2 851 035 diagnosed and 563 708 hospitalised patients with COVID-19. Hypertension was more prevalent in the latter (ranging across databases from 17.4% (95% CI 17.2 to 17.6) to 61.4% (95% CI 61.0 to 61.8) and from 25.6% (95% CI 24.6 to 26.6) to 85.9% (95% CI 85.2 to 86.6)). Patients in both cohorts with hypertension were predominantly >50 years old and female. Patients with hypertension were frequently diagnosed with obesity, heart disease, dyslipidaemia and diabetes. Compared with patients without hypertension, patients with hypertension in the COVID-19 diagnosed cohort had more hospitalisations (ranging from 1.3% (95% CI 0.4 to 2.2) to 41.1% (95% CI 39.5 to 42.7) vs from 1.4% (95% CI 0.9 to 1.9) to 15.9% (95% CI 14.9 to 16.9)) and increased mortality (ranging from 0.3% (95% CI 0.1 to 0.5) to 18.5% (95% CI 15.7 to 21.3) vs from 0.2% (95% CI 0.2 to 0.2) to 11.8% (95% CI 10.8 to 12.8)). Patients in the COVID-19 hospitalised cohort with hypertension were more likely to have acute respiratory distress syndrome (ranging from 0.1% (95% CI 0.0 to 0.2) to 65.6% (95% CI 62.5 to 68.7) vs from 0.1% (95% CI 0.0 to 0.2) to 54.7% (95% CI 50.5 to 58.9)), arrhythmia (ranging from 0.5% (95% CI 0.3 to 0.7) to 45.8% (95% CI 42.6 to 49.0) vs from 0.4% (95% CI 0.3 to 0.5) to 36.8% (95% CI 32.7 to 40.9)) and increased mortality (ranging from 1.8% (95% CI 0.4 to 3.2) to 25.1% (95% CI 23.0 to 27.2) vs from 0.7% (95% CI 0.5 to 0.9) to 10.9% (95% CI 10.4 to 11.4)) than patients without hypertension. Conclusions: COVID-19 patients with hypertension were more likely to suffer severe outcomes, hospitalisations and deaths compared with those without hypertension. This work was supported by several funders as follows: the European Health Data and Evidence Network received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement number 806968. The JU received support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. This research received partial support from the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC), US National Institutes of Health (R01 LM006910), US Department of Veterans Affairs, the Health Department from the Generalitat de Catalunya with a grant for research projects on SARS-CoV-2 and COVID-19 disease organised by the Direcció General de Recerca i Innovació en Salut, Janssen Research and Development, TFS, IOMED and IQVIA. The University of Oxford received funding related to this work from the Bill and Melinda Gates Foundation (Investment ID INV-016201 and INV-019257). TFS received funding related to this work from the University of Oxford. This work was also supported with funding (resources and facilities) of the Department of Veterans Affairs (VA) Informatics and Computing Infrastructure (VINCI) (VA HSR RES 13-457).

BackgroundFew datasets have been established that capture the full breadth of COVID-19 patient interactions with a health system. Our first objective was to create a COVID-19 dataset that linked primary care data to COVID-19 testing, hospitalisation, and mortality data at a patient level. Our second objective was to provide a descriptive analysis of COVID-19 outcomes among the general population and describe the characteristics of the affected individuals.MethodsWe mapped patient-level data from Catalonia, Spain, to the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM). More than 3,000 data quality checks were performed to assess the readiness of the database for research. Subsequently, to summarise the COVID-19 population captured, we established a general population cohort as of the 1st March 2020 and identified outpatient COVID-19 diagnoses or positive test results for SARS-CoV-2, hospitalisations with COVID-19, and COVID-19 deaths during follow-up, which went up until 30th June 2021.FindingsMapping data to the OMOP CDM was performed and high data quality was observed. The mapped database was used to identify a total of 5,870,274 individuals, who were included in the general population cohort as of 1st March 2020. Over follow up, 604,472 had either an outpatient COVID-19 diagnosis or positive test result, 58,991 had a hospitalisation with COVID-19, 5,642 had an ICU admission with COVID-19, and 11,233 had a COVID-19 death. People who were hospitalised or died were more commonly older, male, and with more comorbidities. Those admitted to ICU with COVID-19 were generally younger and more often male than those hospitalised in general and those who died.InterpretationWe have established a comprehensive dataset that captures COVID-19 diagnoses, test results, hospitalisations, and deaths in Catalonia, Spain. Extensive data checks have shown the data to be fit for use. From this dataset, a general population cohort of 5.9 million individuals was identified and their COVID-19 outcomes over time were described.FundingGeneralitat de Catalunya and European Health Data and Evidence Network (EHDEN).

Importance Although tramadol is increasingly used to manage chronic noncancer pain, few safety studies have compared it with other opioids. Objective To assess the associations of tramadol, compared with codeine, with mortality and other adverse clinical outcomes as used in outpatient settings. Design, Setting, and Participants Retrospective, population-based, propensity score–matched cohort study using a primary care database with routinely collected medical records and pharmacy dispensations covering more than 80% of the population of Catalonia, Spain (≈6 million people). Patients 18 years or older with 1 or more year of available data and dispensation of tramadol or codeine (2007-2017) were included and followed up to December 31, 2017. Exposures New prescription dispensation of tramadol or codeine (no dispensation in the previous year). Main Outcomes and Measures Outcomes studied were all-cause mortality, cardiovascular events, fractures, constipation, delirium, falls, opioid abuse/dependence, and sleep disorders within 1 year after the first dispensation. Absolute rate differences (ARDs) and hazard ratios (HRs) with 95% confidence intervals were calculated using cause-specific Cox models. Results Of the 1 093 064 patients with a tramadol or codeine dispensation during the study period (326 921 for tramadol, 762 492 for codeine, 3651 for both drugs concomitantly), a total of 368 960 patients (184 480 propensity score–matched pairs) were included after study exclusions and propensity score matching (mean age, 53.1 [SD, 16.1] years; 57.3% women). Compared with codeine, tramadol dispensation was significantly associated with a higher risk of all-cause mortality (incidence, 13.00 vs 5.61 per 1000 person-years; HR, 2.31 [95% CI, 2.08-2.56]; ARD, 7.37 [95% CI, 6.09-8.78] per 1000 person-years), cardiovascular events (incidence, 10.03 vs 8.67 per 1000 person-years; HR, 1.15 [95% CI, 1.05-1.27]; ARD, 1.36 [95% CI, 0.45-2.36] per 1000 person-years), and fractures (incidence, 12.26 vs 8.13 per 1000 person-years; HR, 1.50 [95% CI, 1.37-1.65]; ARD, 4.10 [95% CI, 3.02-5.29] per 1000 person-years). No significant difference was observed for the risk of falls, delirium, constipation, opioid abuse/dependence, or sleep disorders. Conclusions and Relevance In this population-based cohort study, a new prescription dispensation of tramadol, compared with codeine, was significantly associated with a higher risk of subsequent all-cause mortality, cardiovascular events, and fractures, but there was no significant difference in the risk of constipation, delirium, falls, opioid abuse/dependence, or sleep disorders. The findings should be interpreted cautiously, given the potential for residual confounding.

Population-based studies can provide important evidence on the safety of COVID-19 vaccines. Using data from the United Kingdom, here we compare observed rates of thrombosis and thrombocytopenia following vaccination against SARS-CoV-2 and infection with SARS-CoV-2 with background (expected) rates in the general population. First and second dose cohorts for ChAdOx1 or BNT162b2 between 8 December 2020 and 2 May 2021 in the United Kingdom were identified. A further cohort consisted of people with no prior COVID-19 vaccination who were infected with SARS-Cov-2 identified by a first positive PCR test between 1 September 2020 and 2 May 2021. The fourth general population cohort for background rates included those people in the database as of 1 January 2017. In total, we included 3,768,517 ChAdOx1 and 1,832,841 BNT162b2 vaccinees, 401,691 people infected with SARS-CoV-2, and 9,414,403 people from the general population. An increased risk of venous thromboembolism was seen after first dose of ChAdOx1 (standardized incidence ratio: 1.12 [95% CI: 1.05 to 1.20]), BNT162b2 (1.12 [1.03 to 1.21]), and positive PCR test (7.27 [6.86 to 7.72]). Rates of cerebral venous sinus thrombosis were higher than otherwise expected after first dose of ChAdOx1 (4.14 [2.54 to 6.76]) and a SARS-CoV-2 PCR positive test (3.74 [1.56 to 8.98]). Rates of arterial thromboembolism after vaccination were no higher than expected but were increased after a SARS-CoV-2 PCR positive test (1.39 [1.21 to 1.61]). Rates of venous thromboembolism with thrombocytopenia were higher than expected after a SARS-CoV-2 PCR positive test (5.76 [3.19 to 10.40]).

ObjectivesTo investigate how incidence trends of anxiety and depressive disorders have been affected by the COVID-19 pandemic.DesignPopulation-based cohort study.SettingObservational cohort study from 2018 to 2021 using the Information System for Research in Primary Care (SIDIAP) database in Catalonia, Spain.Participants4,255,847 individuals aged 18 or older in SIDIAP on 1 March, 2018 with no prior history of anxiety and depressive disorders.Primary and secondary outcomes measuresIncidence of anxiety and depressive disorders prior to COVID-19 (March, 2018 to February, 2020), during the COVID-19 lockdown (March to June, 2020) and post-lockdown periods (from July, 2020 to March, 2021) were calculated. Forecasted rates over COVID-19 periods were estimated using negative binomial regression models based on previous data. The percentage reduction was estimated by comparing forecasted versus observed events, overall and by age, sex and socioeconomic status.ResultsThe incidence rates per 100,000 person-months of anxiety and depressive disorders were 171.0 (95%CI: 170.2-171.8) and 46.6 (46.2-47.0), respectively, during the pre-lockdown period. We observed an increase of 39.7% (95%PI: 26.5 to 53.3) in incident anxiety diagnoses compared to the expected in March, 2020, followed by a reduction of 16.9% (8.6 to 24.5) during the post-lockdown periods. A reduction of incident depressive disorders occurred during the lockdown and post-lockdown periods (46.6% [38.9 to 53.1] and 23.2% [12.0 to 32.7], respectively). Reductions were higher among adults aged 18 to 34 and individuals living in most deprived areas.ConclusionsThe COVID-19 pandemic in Catalonia was associated with an initial increase in anxiety disorders diagnosed in primary care, but a reduction in cases as the pandemic continued. Diagnoses of depressive disorders were lower than expected throughout the pandemic.Summary boxWhat is already known on this topic-While previous self-reported studies have provided evidence of increased mental health burden during the initial phase of the COVID-19 pandemic, a number of studies observed that fewer diagnoses were made in primary care settings than would have been expected during the initial stages of the pandemic.-Population data that examine the impact of COVID-19 on temporal trends of incident cases of common mental health disorders are lacking in Catalonia, Spain.What this study adds-This study has quantified the impact of the COVID-19 pandemic on trends of incidence of anxiety and depressive disorders among adults living in Catalonia.-Reductions in incident cases of anxiety and depressive disorders were higher for young adults and people living in most deprived areas.-Incident diagnoses of anxiety and depressive disorders have not been fully recovered to what would have been expected.

ObjectivesTo calculate the observed rates of thrombosis and thrombocytopenia following vaccination against SARS-CoV-2, infection with SARS-CoV-2, and to compare them to background (expected) rates in the general population.DesignCohort study using routinely collected primary care records.SettingRoutine practice in the United Kingdom.ParticipantsTwo mutually exclusive vaccinated cohorts included people vaccinated with either ChAdOx1 or BNT162b2 between 8 December 2020 and 6 March 2021. A third cohort consisted of people newly infected with SARS-Cov-2 identified by a first positive RT-PCR test between 1 September 2020 and 28 February 2021. The fourth general population cohort for background rates included those people with a visit between 1 January 2017 and 31 December 2019. In total, we included 1,868,767 ChAdOx1 and 1,661,139 BNT162b2 vaccinees, 299,311 people infected with SARS-CoV-2, and 2,290,537 people from the general population.InterventionsFirst-dose of either ChAdOx1 or BNT162b2Main outcome measuresOutcomes included venous thrombosis, arterial thrombosis, thrombocytopenia, and thrombosis with thrombocytopenia. Outcome rates were estimated for recipients of the ChAdOx1 or BNT162b2 vaccines, for people infected with SARS-CoV-2, and background rates in the general population. Indirectly standardized incidence ratios (SIR) were estimated.ResultsWe included 1,868,767 ChAdOx1 and 1,661,139 BNT162b2 vaccinees, 299,311 people infected with SARS-CoV-2, and 2,290,537 people from the general population for background rates. The SIRs for pulmonary embolism were 1.23 [95% CI, 1.09-1.39] after vaccination with ChAdOx1, 1.21 [1.07-1.36] after vaccination with BNT162b2, and 15.31 [14.08 to 16.65] for infection with SARS-CoV-2. The SIRs for thrombocytopenia after vaccination were 1.25 [1.19 to 1.31] for ChAdOx1 and 0.99 (0.94 to 1.04) for BNT162b2. Rates of deep vein thrombosis and arterial thrombosis were similar among those vaccinated and the general population.ConclusionsChAdOx1 and BNT162b2 had broadly similar safety profiles. Thrombosis rates after either vaccine were mostly similar to those of the general population. Rates of pulmonary embolism increased 1.2-fold after either vaccine and 15-fold with SARS-CoV-2 infection. Thrombocytopenia was more common among recipients of ChAdOx1 but not of BNT162b2.Summary boxWhat is already known on this topicSpontaneous reports of unusual and severe thrombosis with thrombocytopenia syndrome (TTS) raised concerns regarding the safety of adenovirus-based vaccines against SARS-CoV-2In a cohort study including over 280,000 people aged 18-65 years vaccinated with ChAdOx1 in Denmark and Norway, Pottegård et al reported increased rates of venous thromboembolic events as well as thrombocytopenia among vaccine recipients.What this study addsIn this cohort study, ChAdOx1 and BNT162b2 were seen to have broadly similar safety profiles.Rates of thrombosis after either vaccine were generally similar to those of the general population. Rates of pulmonary embolism were though 1.2-fold higher than background rates after either vaccine, which compared to 15-fold higher after SARS-CoV-2 infection.Thrombocytopenia was more common among recipients of ChAdOx1 but not of BNT162b2.

We aimed to develop and validate a fracture risk algorithm for the automatic identification of subjects at high risk of imminent and long-term fracture risk.A cohort of subjects aged 50-85, between 2007 and 2017, was extracted from the Catalan information system for the development of research in primary care database (SIDIAP). Participants were followed until the earliest of death, transfer out, fracture, or 12/31/2017. Potential risk factors were obtained based on the existing literature. Cox regression was used to model 1 and 5-year risk of hip and major fracture. The original cohort was randomly split in 80:20 for development and internal validation purposes respectively. External validation was explored in a cohort extracted from the Spanish database for pharmaco-epidemiological research in primary care.A total of 1.76 million people were included from SIDIAP (50.7 % women with mean age of 65.4 years). Hip and major fracture incidence rates were 3.57 [95%CI 3.53 to 3.60] and 11.61 [95%CI 11.54 to 11.68] per 1000 person-years, respectively. The derived model included 19 risk factors. Internal validity showed good results on calibration and discrimination. The 1-year C-statistic for hip and major fracture were 0.851 (95%CI 0.853 to 0.864), and 0.717 (95%CI 0.742 to 0.749) respectively. The 5-year C-statistic for hip and major fracture were 0.849 (95%CI 0.847 to 0.852) and 0.724 (95%CI 0.721 to 0.727) respectively. External validation showed good performance for hip and major fracture risk prediction.We have developed and validated a clinical prediction tool for 1- and 5-year hip and major osteoporotic fracture risks using electronic primary care data. The proposed algorithm can be automatically estimated at the population level using the available primary care records. Future work is needed on the cost-effectiveness of its use for population-based screening and targeted prevention of osteoporotic fractures.

Background Thrombosis with thrombocytopenia syndrome (TTS) has been reported among individuals vaccinated with adenovirus-vectored COVID-19 vaccines. In this study we describe the background incidence of TTS in 6 European countries. Methods Electronic medical records from France, Netherlands, Italy, Germany, Spain, and the United Kingdom informed the study. Incidence rates of cerebral venous sinus thrombosis (CVST), splanchnic vein thrombosis (SVT), deep vein thrombosis (DVT), pulmonary embolism (PE), and stroke, all with concurrent thrombocytopenia, were estimated among the general population between 2017 to 2019. A range of additional adverse events of special interest for COVID-19 vaccinations were also studied in a similar manner. Findings A total of 20,599,134 individuals were included. Background rates ranged from 1.0 (0.7 to 1.4) to 1.5 (1.0 to 2.0) per 100,000 person-years for DVT with thrombocytopenia, from 0.5 (0.3 to 0.6) to 1.4 (1.1 to 1.8) for PE with thrombocytopenia, from 0.1 (0.0 to 0.1) to 0.7 (0.5 to 0.9) for SVT with thrombocytopenia, and from 0.2 (0.0 to 0.4) to 4.4 (3.9 to 5.0) for stroke with thrombocytopenia. CVST with thrombocytopenia was only identified in one database, with incidence rate of 0.1 (0.0 to 0.2) per 100,000 person-years. The incidence of TTS increased with age, with those affected typically having more comorbidities and greater medication use than the general population. TTS was also more often seen in men than women. A sizeable proportion of those affected were seen to have been taking antithrombotic and anticoagulant therapies prior to their TTS event. Interpretation Although rates vary across databases, TTS has consistently been seen to be a very rare event among the general population. While still very rare, rates of TTS are typically higher among older individuals, and those affected were also seen to generally be male and have more comorbidities and greater medication use than the general population. Funding This study was funded by the European Medicines Agency (EMA/2017/09/PE Lot 3). Research in context Evidence before this study We searched PubMed to identify studies that have previously described the background incidence of the study outcomes. Estimates of the incidence of cerebral venous sinus thrombosis (CVST) among the general population have ranged from 0.3 to 2 per 100,000 person-years. The background incidence of splanchnic vein thrombosis (SVT) is not well-known, although the incidence of portal vein thrombosis, the most commonly involved vein, has been estimated at around 3 per 100,000 person-years. Deep vein thrombosis (DVT) and pulmonary embolism (PE) are far more common with estimates of their incidence among the general population typically around 100 and 60 per 100,000 person-years respectively, while the incidence of stroke is typically estimated to be above 100 per 100,000 person-years. The background incidence of these events with concurrent thrombocytopenia has not, however, previously been described in detail. Added value of this study Based on spontaneous reports from the US, the United Kingdom, and the European Union, thrombosis with thrombocytopenia syndrome (TTS) has been raised as a serious, albeit rare, adverse event that may be caused by adenovirus-vectored COVID-19 vaccines. Assessing this safety signal requires a consideration of whether the rates of TTS being reported after vaccinations against SARS-CoV-2 differ from those normally seen among the general population in the absence of any such vaccinations. This study brings together data from six European countries to estimate the background incidence of TTS. We used six large databases of routinely-collected data allowing for sufficient sample size to study TTS across multiple study populations and in different age and sex strata. Additionally, we characterised patients affected by TTS in historical data, describing their comorbidities and prior medication use. Implications of all the available evidence TTS is very rare and based on the highest estimates among the databases included in this study, one would normally expect approximately 1 case of CVST with thrombocytopenia, 5 of SVT with thrombocytopenia, 11 of DVT with thrombocytopenia, 11 of PE with thrombocytopenia, and 34 of stroke with thrombocytopenia among a general population of 10 million individuals per 28 days. Expected events would however be higher for an older cohort, as patients with TTS are typically older than the general population. Patients with TTS are more often men and appear to typically have more comorbidities and greater medication use, including prior use of antithrombotic and anticoagulant therapies, than the general population. Not only do the rates of TTS being reported among those who had received an adenovirus-based vaccine against SARS-CoV-2 raise a concern, but early evidence from spontaneous reports suggests that TTS among those vaccinated has been more commonly been seen among women and younger persons. While this might be in part explained by potential biases in spontaneous reporting, it also underlines the importance of further evaluation of the safety signal for TTS. As with other adverse events of special interest for COVID-19 vaccines, estimates of TTS vary depending on the data source used. Comparison of observed versus expected TTS rates during the monitoring of COVID-19 vaccines should ideally be done using the same databases for the estimation of post-vaccine (observed) and background (expected) rates, with adjustment for patient characteristics (such as age and sex) done as part of the analysis.

Background: Thromboembolism and thrombocytopenia have emerged as potential adverse events associated with vaccines against SARS-CoV-2. We compared rates of thromboembolism and thrombocytopenia following vaccination with BNT162b2 and ChAdOx1 with expected rates. Rates for people with COVID-19 were estimated to provide context. Methods: Primary care data from Catalonia, Spain, informed the analysis. Study participants were vaccinated with BNT162b2 or ChAdOx1 (27/12/2020-19/05/2021), diagnosed with COVID-19 (1/09/2020-1/03/2021) or present as of 1/01/2017. Outcomes included venous thromboembolism (VTE), arterial thromboembolism (ATE), thrombocytopenia, and thrombosis with thrombocytopenia syndrome (TTS). Incidence rates were estimated in the 21 and 90 days after vaccination and COVID-19 diagnosis, respectively, and up to 31/03/2019 for background rates. Age indirectly standardised incidence ratios (SIR) were estimated. Findings: We included 945,941 BNT162b2 (778,534 with 2 doses), 426,272 ChAdOx1, 222,710 COVID-19, and 4,570,149 background participants. SIRs for VTE were 1.29 [95% CI 1.13-1.48] and 0.90 [0.76-1.07] after first- and second-dose BNT162b2, and 1.15 [0.83-1.58] after first-dose ChAdOx1. The SIR for VTE in COVID-19 was 8.04 [7.37-8.78]. SIRs for thrombocytopenia were 1.35 (1.30-1.41) and 1.19 (1.14-1.25) after first- and second-dose BNT162b2, 1.03 (0.93-1.14) after first-dose ChAdOx1 and 3.52 (3.39 to 3.67) for COVID-19. Rates of ATE were similar to expected rates for BNT162b2 and ChAdOx1, as were rates of TTS for BNT162b2, while fewer than 5 such events were seen for ChAdOx1. Interpretation: Safety profiles of BNT162b2 and ChAdOx1 were similar. A safety signal was seen for VTE after first-dose of BNT162b2. Although confidence intervals were wider, a similar estimate was seen for first-dose of ChAdOx1. The 1.3 fold increase in the rate of VTE after first-dose of BNT162b2 compared with an 8 fold increase after diagnosis of COVID-19. No safety signals were seen for ATE or TTS. Further research is needed to investigate the causality in the observed associations. Funding Information: This study was funded by the European Medicines Agency in the form of a competitive tender (Lot ROC No EMA/2017/09/PE). Declaration of Interests: DPA’s research group has received research grants from the European Medicines Agency, from the Innovative Medicines Initiative, from Amgen, Chiesi, and from UCB Biopharma; and consultancy or speaker fees from Astellas, Amgen and UCB Biopharma. Peter Rijnbeek works for a research institute who receives/received unconditional research grants from Yamanouchi, Pfizer-Boehringer Ingelheim, GSK, Amgen, UCB, Novartis, Astra-Zeneca, Chiesi, Janssen Research and Development, none of which relate to the content of this work. Katia Verhamme works for a research institute who receives/received unconditional research grants from Yamanouchi, Pfizer-Boehringer Ingelheim, GSK, Amgen, UCB, Novartis, Astra-Zeneca, Chiesi, none of which relate to the content of this work .All other authors have no conflicts of interest to declare. Ethics Approval Statement: This study was approved by the Clinical Research Ethics Committee of the IDIAPJGol (project code: 21/054-PCV).

ObjectivesTo assess the association between age, sex, socioeconomic group, weight status and back pain risk in a large general population cohort of children.Design and settingA dynamic cohort of children aged 4 years in the Information System for Research in Primary Care (SIDIAP) electronic primary care records data in Catalonia. Multivariable Cox models were fitted to explore the association between back pain and weight status categories according to the WHO 2007 growth reference groups (body mass index for age z-score). Models were adjusted for age, sex, socioeconomic status and nationality.ParticipantsChildren seen at age 4 years at paediatric primary care clinics between 1 January 2006 and 31 December 2013 and followed up until 31 December 2016 or age 15 years.Outcome measuresIncident back pain registered by paediatricians at primary care using the International Statistical Classification of Diseases and Health Related Problems, 10th Edition code M54.Results466 997 children were followed for a median 5.0 years (IQR 5.1). In multivariable models, overweight and obesity increased back pain risk, with adjusted HRs of 1.18 (95% CI 1.09 to 1.27) and 1.34 (95%CI 1.19 to 1.51) for overweight and obesity, respectively. Females were at greater risk of back pain than males with adjusted HR 1.40 (95%CI 1.35 to 1.46). Adjusted HR was 1.43 (95%CI 1.33 to 1.55) for back pain in children from the most deprived socioeconomic groups compared with the least deprived socioeconomic groups.ConclusionsMaintaining a healthy weight from an early age may reduce the prevalence of back pain in both children and adults. Overweight female children from deprived socioeconomic groups are at greatest risk of back pain and represent a target population for intervention.

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.

Summary: Strontium ranelate use, compared with oral bisphosphonates, is not associated with increased risk of AMI in patients with no contraindications for SR use. However, current strontium ranelate (compared with current bisphosphonate) appears associated with 25–30% excess risk of VTE and 35% excess risk of CVDeath. Introduction: Evaluate the risk of cardiac and thromboembolic events among new users of SR and oral BPs without contraindications for SR. Methods: We conducted three multi-national, multi-database (Aarhus-Denmark, HSD-Italy, IPCI-Netherlands, SIDIAP-Spain, THIN-UK) case-control studies nested within a cohort of new users of SR/BP. We matched cases of acute myocardial infarction (AMI), venous thromboembolism (VTE), and cardiovascular death (CVDeath), up to 10 controls on gender, year of birth, index date, and country. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs) according to current SR vs current BP use and current vs past SR use, adjusting for potential confounders. Data were pooled using random effects meta-analysis. Results: No excess risk of AMI (5477 cases/54,674 controls) was found with current SR vs current BP (OR 0.89 (95%CI 0.70, 1.12)) nor with current vs past SR use (0.71(0.56, 0.91)). For VTE (5614 cases/6036 controls), an excess risk was found with current SR compared with current BP use, 1.24 (0.96, 1.61), and current vs past SR use, 1.30 (1.04, 1.62). For CVDeath (3019 cases/29,871 controls), an increased risk was seen with current SR vs current BP use, 1.35 (1.02, 1.80), but not with current vs past SR use (0.68 (0.48, 0.96)). Conclusion: In patients without contraindications for SR, we found no evidence of an increased risk of AMI but a 25–30% excess risk of VTE and a 35% excess risk of CVDeath with current SR vs current BP users. This is despite a reduction in risk in CVDeath with current vs past SR users. The latter disparity could still be partially explained by cessation of preventative therapies in end-of-life or residual confounding by indication.

Resumen: Objetivo: Determinar si existen diferencias en la prevalencia del uso de fármacos para la osteoporosis entre pacientes diabéticos tipo 2 (DM2) y no diabéticos. Material y método: Estudio de cohortes retrospectivas con datos del Sistema de Información para el Desarrollo de la Investigación en Atención Primaria (SIDIAP), que contiene información clínica anonimizada de más de 5 millones de pacientes de Cataluña. Se seleccionaron todos los pacientes de ≥50 años de edad con diagnóstico de DM2, que fueron apareados con dos sujetos sin diabetes. Se recogió información sobre variables descriptivas, fracturas prevalentes y el uso de fármacos para la osteoporosis agrupados en bifosfonatos (BF), suplementos calcio y vitamina D (CaD), y cualquier fármaco para la osteoporosis (FPO). Mediante regresión logística se calculó la asociación entre la presencia de DM2 y el uso de FPO, ajustando por variables confusoras. Resultados: Se identificaron 166.106 pacientes con DM2 y 332.212 no diabéticos. Los DM2 tenían mayor prevalencia de fractura que los no diabéticos (1,3% vs. 0,3%). El uso de BF en los pacientes con DM2 era del 6,6%, frente al 9,3% en los no diabéticos (p

Summary Type 2 diabetes mellitus (T2DM) is associated with an excess risk of fractures and overall mortality. This study compared hip fracture and post-hip fracture mortality in T2DM and non-diabetic subjects. The salient findings are that subjects in T2DM are at higher risk of dying after suffering a hip fracture. Introduction Previous research suggests that individuals with T2DM are at an excess risk of both fractures and overall mortality, but their combined effect is unknown. Using multi-state cohort analyses, we estimate the association between T2DM and the transition to hip fracture, post-hip fracture mortality, and hip fracture–free all-cause death. Methods Population-based cohort from Catalonia, Spain, including all individuals aged 65 to 80 years with a recorded diagnosis of T2DM on 1 January 2006; and non-T2DM matched (up to 2:1) by year of birth, gender, and primary care practice. Results A total of 44,802 T2DM and 81,233 matched controls (53% women, mean age 72 years old) were followed for a median of 8 years: 23,818 died without fracturing and 3317 broke a hip, of whom 838 subsequently died. Adjusted HRs for hip fracture–free mortality were 1.32 (95% CI 1.28 to 1.37) for men and 1.72 (95% CI 1.65 to 1.79) for women. HRs for hip fracture were 1.24 (95% CI 1.08 to 1.43) and 1.48 (95% CI 1.36 to 1.60), whilst HRs for post-hip fracture mortality were 1.28 (95% CI 1.02 to 1.60) and 1.57 (95% CI 1.31 to 1.88) in men and women, respectively. Conclusion T2DM individuals are at increased risk of hip fracture, post-hip fracture mortality, and hip fracture–free death. After adjustment, T2DM men were at a 28% higher risk of dying after suffering a hip fracture and women had 57% excess risk of post-hip fracture mortality.

Background and aims Several studies aiming to determine the association between iron stores and coronary heart disease (CHD) have reported conflicting results. None of them has been performed in a Mediterranean region. Our aim is to assess the association between the level of serum ferritin and the incidence of CHD in a Mediterranean region. Methods We performed a cohort study using a primary health care population database. Primary outcome was incidence of CHD. Subjects aged between 35 and 74 years with serum ferritin (SF) measurements at baseline (January 1, 2006 to December 31, 2008) were included. Cox regression models were used to compute hazard ratios (HRs) and 95%CIs for the associtation between SF and time until CHD outcome. Results We include 242,084 subjects with SF levels at baseline. Participants were observed for a median of 8.4 years. During follow-up, 1106 incident cases of CHD were identified. Persons with elevated SF did not have an increased CHD risk at follow-up (adjusted hazard ratio = 0.99; 95%CI 0.94–1.05; p = 0.86 in men, and 0.95; 95%CI 0.81–1.13; p = 0.60 in women). Conclusions Our study, by far the largest, showed that high levels of SF do not confer an increased risk of CHD, and questions its role as a risk factor for this disease.

Background With increasing availability of patient data in healthcare, there is an unprecedented opportunity for prediction tools that can be automatically implemented in electronic medical records system. Objectives We aimed to develop and validate a fracture prediction tool that leverages patient data as routinely available in primary care computerized records. Methods We conducted a population-based cohort study. Data was extracted from all subjects registered in the SIDIAP database on 1/1/2012, with data for 1+ years, and aged 50 years or older on that date. SIDIAP contains primary care records linked to pharmacy dispensations for >6 million people, equivalent to >80% of the population of Catalonia. Participants were followed up until the earliest of death, transfer out/migration, or end of 2017. Two models were developed to predict hip fracture (main outcome) and major osteoporotic (hip, clinical vertebral, wrist/forearm, and proximal humerus) fracture risk over 5 years. Potential predictors were pre-specified based on previous literature and combined in Cox models to derive prediction tools. Internal validation was performed using c-statistic for discrimination, and observed vs predicted plots for calibration. Multiple imputation with chained equations was used to minimize the impact of missing data on body mass index, smoking, and alcohol drinking. Bootstrapping methods were used to select key predictors to be combined in the final resulting models. Results A total of 1.76 million people (9.76 million person-years) were included, 50.7% women, of average age 65.4 years old. A 10.1% and 7.4% were lost to follow-up over 5 years due to mortality and migration respectively. Fracture rates were 3.57/1,000 person-years [95%CI 3.53-3.60] for hip and 11.61 [11.54-11.68] for major fracture. Key predictors of increased fracture risk included age, female gender, history of falls or previous fractures, specific medication/s use (insulin, GnRH inhibitors, anticonvulsants, sedatives, SSRI, antipsychotics), and a history of diabetes mellitus (type 1>type 2), cerebrovascular disease, ischemic heart disease, COPD and anorexia nervosa. Variables associated with lower fracture risk included use of statins, thiazidic diuretics, and overweight/obesity. Combined, these resulted in a c-statistic of 84.9% for hip and 72.9% for major fracture. Calibration was excellent for both outcomes. Conclusion We have developed and validated a clinical prediction tool for 5-year hip and major osteoporotic fracture risks. The algorithm has excellent performance and can be installed in electronic primary care records systems for automated risk calculations at the population level. More research is needed on the transportability and external validity of this prediction tool. Acknowledgement Research grant from the Carlos III Institute of Health, Ministry of Economy and Competitiveness (Spain), awarded on the 2017, with reference PI17/00471, co-funded with European Union ERDF funds (European Regional Development Fund) Disclosure of Interests Cristian Tebe: None declared, Natalia Pallares: None declared, Cristina Carbonell-Abella Speakers bureau: AMGEN, LILLY, Carlen Reyes: None declared, Xavier Nogues Speakers bureau: Amgen and Eli Lilly, Adolfo Diez-Perez Speakers bureau: Lilly, Amgen, GSK and UCB, Daniel Martinez-Laguna Speakers bureau: Eli Lilly, Amgen, Ferrer, Rubio and Novartis., Daniel Prieto-Alhambra Grant/research support from: Grants from Amgen, UCB Biopharma and Servier outside the submitted work, Consultant for: UCB Biopharma, Speakers bureau: Amgen

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. © 2019 American Society for Bone and Mineral Research. © 2019 American Society for Bone and Mineral Research.

Objective: Previous cohorts have reported associations between overweight/obesity and knee and hand osteoarthritis (OA). However, no data on the effect of these on the OA burden are available. We aimed to analyse the effect of overweight and obesity on the incidence of routinely diagnosed knee, hip, and hand OA. Methods: Design: population-based cohort Setting: primary care records from the SIDIAP database (>5.5 million subjects) covering >80% of the population of Catalonia, Spain. Participants: ?40 years old with no OA on 01/01/2006 and with body mass index (BMI) data available. Follow-up: from 01/01/2006 to 12/31/2010, loss to follow-up, or death. Measures: BMI World Health Organization categories (exposure), and incident clinical diagnoses of knee, hip, or hand OA (ICD-10 codes). Results: 1,764,061 subjects were observed for a median (inter-quartile range) of 4.45 (4.19 to 4.98) years. Incidence rates (per 1000 PY) of knee, hip and hand OA ranged from 3.7 (3.6 to 3.8), 1.7 (1.7 to 1.8) and 2.6 (2.5 to 2.7) amongst normal-weight, to 19.5 (19.1 to 19.9), 3.8 (3.7 to 4.0) and 4.0 (3.9 to 4.2) in the grade II obese respectively. Compared to normal-weight subjects, being overweight or obese increased the risk of OA at all three sites, especially at the knee: overweight and (grade I, II) obesity increased knee OA risk by a factor of 2, 3.1 and 4.7 fold respectively. Conclusions: Both overweight and obesity increase the risk of hand, hip, and knee OA, especially for the latter, with a dose-response gradient with increasing BMI.

Bisphosphonates are the mainstay of osteoporosis treatment but also play a fundamental role in treating other bone diseases such as Osteogenesis Imperfecta, Pagets' disease, and in the prevention of adverse skeletal effects in certain cancers such as prostate cancer or multiple myeloma. In the last decades, the refinement of bisphosphonates and an increase in the number of new bisphosphonates commercialized has altered the clinical management of these diseases. Despite differences between randomized controlled trials and observational studies, overall all bisphosphonates licensed have proven to reduce the risk of fracture through the inhibition of bone resorption. Other beneficial effects include pain reduction in bone metastasis and potentially a decrease in mortality. However, the chronic nature of most of these disorders implies long-term treatments, which can be associated with long-term adverse effects. Some of the adverse effects identified include an increased risk of atypical femur fractures, osteonecrosis of the jaw, gastrointestinal side effects, or atrial fibrillation. The harm/benefit thinking and the constant update regarding these medications are vital in the day-to-day decision-making in clinical practices. The aims of this review are to compile the basic characteristics of these drugs and outline the most important benefits and side effects and provide a clinical context as well as a research agenda to fill the gaps in our knowledge.

Background:Opioids are not recommended as first-line treatments for chronic pain management in osteoarthritis (OA), but recent data suggest they are commonly used in routine practice in North America and northern Europe.Objectives:To characterise the secular trends of opioid and strong opioids use in patients with incident OA from 2007 to 2016, and to explore the impact of patient characteristics on the use of opioid/s for OA.Methods:Data was obtained from the SIDIAP (The System for the Development of Research in Primary Care) database, which contains primary care records and pharmacy dispensing data for 80 % of the population in Catalonia (~ 6 million people). All persons aged 18 or older at the beginning of each calendar year with an incident OA diagnosis (including both peripheral and central joints) in the study period were included. Index date was the date of first OA diagnosis, and the observation period of opioid use was 1-year after index date. Opioids considered included codeine, tramadol, fentanyl, and morphine, with the latter three classified as strong opioids. The period prevalence of any opioid use was estimated in whole and sub-population stratified by sex, age, socio-economic status (U1 – U5, higher values of the indicator equivalent to deprivation) and residence area (rural/urban).Results:The 1-year prevalence of any opioid use among incident OA patients was around 15% from 2007 to 2012. After that, this figure grew by 10% approaching 25% in 2016. However, strong opioid use increased continuously to nearly triple, from 8% in 2007 to 20% in 2016. The different subgroups followed similar trends over time, with women 4% higher than men, oldest 10% higher than youngest, most deprived 6% higher than least deprived, and rural 1% higher than urban.Conclusion:The use of opioids (and especially strong opioids) has substantially increased in recent years among newly diagnosed OA patients in Catalonia. Our findings call for urgent action for safe opioid prescribing to avoid opioid abuse in OA patients especially amongst older women living in deprived areas.Figure 1.Trends of 1-year prevalence of opioid/s use among incident OA patients, whole and subgroup population.Disclosure of Interests:Junqing Xie: None declared, Aleksandra Turkiewicz: None declared, Gary Collins: None declared, Martin Englund Consultant of: Advisory Board 1 day (2019) Pfizer (Tanezumab)., Victoria Y Strauss: None declared, Carlen Reyes: None declared, Daniel Prieto-Alhambra Grant/research support from: Professor Prieto-Alhambra has received research Grants from AMGEN, UCB Biopharma and Les Laboratoires Servier, Consultant of: DPA’s department has received fees for consultancy services from UCB Biopharma, Speakers bureau: DPA’s department has received fees for speaker and advisory board membership services from Amgen

The original version of this article, published on 26 November 2019 contained a mistake. An author’s name was misspelled. The correct author name reads as follows: Susana Perez-Gutthann. The original article has been corrected.

We have characterised 997 hip fracture patients from a representative 45 Spanish hospitals, and followed them up prospectively for up to 4 months. Despite suboptimal surgical delays (average 59.1 hours), in-hospital mortality was lower than in Northern European cohorts. The secondary fracture prevention gap is unacceptably high at 85%. Purpose To characterise inpatient care, complications, and 4-month mortality following a hip or proximal femur fracture in Spain. Methods Design: prospective cohort study. Consecutive sample of patients >= 50 years old admitted in a representative 45 hospitals for a hip or proximal femur fragility fracture, from June 2014 to June 2016 and followed up for 4 months post-fracture. Patient characteristics, site of fracture, in-patient care (including secondary fracture prevention) and complications, and 4-month mortality are described. Results A total of 997 subjects (765 women) of mean (standard deviation) age 83.6 (8.4) years were included. Previous history of fracture/s (36.9%) and falls (43%) were common, and 10-year FRAX-estimated major and hip fracture risks were 15.2% (9.0%) and 8.5% (7.6%) respectively. Inter-trochanteric (44.6%) and displaced intra-capsular (28.0%) were the most common fracture sites, and fixation with short intramedullary nail (38.6%) with spinal anaesthesia (75.5%) the most common procedures. Surgery and rehabilitation were initiated within a mean 59.1 (56.7) and 61.9 (55.1) hours respectively, and average length of stay was 11.5 (9.3) days. Antithrombotic and antibiotic prophylaxis were given to 99.8% and 98.2% respectively, whilst only 12.4% received secondary fracture prevention at discharge. Common complications included delirium (36.1 %) and kidney failure (14.1%), with in-hospital and 4-month mortality of 2.1% and 11% respectively. Conclusions Despite suboptimal surgical delay, post-hip fracture mortality is low in Spanish hospitals. The secondary fracture prevention gap is unacceptably high at > 85%, in spite of virtually universal anti-thrombotic and antibiotic prophylaxis., Funded in part by CIBER on Frailty and Healthy Aging (CIBERFES), Instituto Carlos III, Spanish Ministry of Economy and Competitiveness, FEDER funds. Unrestricted research grant from Amgen S.A. Amgen did not have any role in study design, collection, analysis and interpretation of data, writing the report, and the decision to submit the report for publication.

Objective: To determine the association between socio-economic status (SES) and risk of hand, hip or knee osteoarthritis (OA) at a population level. Design: Retrospective ecological study using the System for the Development of Research in Primary Care (SIDIAP) database (primary care anonymized records for > 5 million people in Catalonia (Spain)). Urban residents > 15 years old (2009-2012) were eligible. Outcomes: Validated area-based SES deprivation index MEDEA (proportion of unemployed, temporary workers, manual workers, low educational attainment and low educational attainment among youngsters) was estimated for each area based on census data as well as incident diagnoses (ICD-10 codes) of hand, hip or knee OA (2009-2012). Zero-inflated Poisson models were fitted to study the association between MEDEA quintiles and the outcomes. Results: Compared to the least deprived, the most deprived areas were younger (43.29 (17.59) vs 46.83 (18.49), years (Mean SD), had fewer women (49.1% vs 54.8%), a higher percentage of obese (16.2% vs 8.4%), smokers (16.9% vs 11.9%) and high-risk alcohol consumption subjects (1.5% vs 1.3%). Compared to the least deprived, the most deprived areas had an excess risk of OA: age-sex-adjusted Incidence Rate Ratio (IRR) 1.26 (1.11-1.42) for hand, 1.23 (1.17-1.29) hip, and 1.51 (1.45-1.57) knee. Adjustment for obesity attenuated this association: 1.06 (0.93-1.20), 1.04 (0.99-1.09), and 1.23 (1.19-1.28) respectively. Conclusions: Deprived areas have higher rates OA (hand, hip, knee). Their increased prevalence of obesity accounts for a 50% of the excess risk of knee OA observed. Public health interventions to reduce the prevalence of obesity in this population could reduce health inequalities. (C) 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Summary Post-fracture mortality in type 2 diabetes mellitus (T2DM) patients has been poorly studied. We report an absolute and relative excess all-cause mortality following a fracture in these patients compared to non-diabetic patients. Introduction: T2DM and osteoporotic fractures are independently associated with a reduced lifespan, but it is unknown if T2DM confers an excess post-fracture mortality compared to non-diabetic fracture patients. We report post-fracture all-cause mortality according to T2DM status. Methods: This is a population-based cohort study using data from the SIDIAP database. All ≥50 years old T2DM patients registered in SIDIAP in 2006–2013 and two diabetes-free controls matched on age, gender, and primary care center were selected. Study outcome was all-cause mortality following incident fractures. Participants were followed from date of any fracture (AF), hip fracture (HF), and clinical vertebral fracture (VF) until the earliest of death or censoring. Cox regression was used to calculate mortality according to T2DM status after adjustment for age, gender, body mass index, smoking, alcohol intake, and previous ischemic heart and cerebrovascular disease. Results: We identified 166,106 T2DM patients and 332,212 non-diabetic, of which 11,066 and 21,564, respectively, sustained a fracture and were then included. Post-fracture mortality rates (1000 person-years) were (in T2DM vs non-diabetics) 62.7 vs 49.5 after AF, 130.7 vs 112.7 after HF, and 54.9 vs 46.2 after VF. Adjusted HR (95% CI) for post-AF, post-HF, and post-VF mortality was 1.30 (1.23–1.37), 1.28 (1.20–1.38), and 1.20 (1.06–1.35), respectively, for T2DM compared to non-diabetics. Conclusions: T2DM patients have a 30% increased post-fracture mortality compared to non-diabetics and a remarkable excess in absolute mortality risk. More research is needed on the causes underlying such excess risk, and on the effectiveness of measures to reduce post-fracture morbi-mortality in T2DM subjects.

Adherence to anti-osteoporosis medications is poor. We carried out a cohort study using a real-world population database to estimate the persistence of anti-osteoporosis drugs. Unadjusted 2-year persistence ranged from 10.3 to 45.4%. Denosumab users had a 40% lower risk of discontinuation at 2 years compared to alendronate users. The purpose of this study was to estimate real-world persistence amongst incident users of anti-osteoporosis medications. This is a retrospective cohort using data from anonymised records and dispensation data ( www.sidiap.org ). Eligibility comprised the following: women aged ≥50, incident users of anti-osteoporosis medication (2012), with data available for at least 12 months prior to therapy initiation. Exclusions are other bone diseases/treatments and uncommon anti-osteoporosis drugs (N

Serum Lipid Levels; Osteoarthritis; Cohort Studies Nivells de lípids sèrics; Osteoartritis; Estudis de cohorts Niveles de lípidos séricos; Osteoartritis; Estudios de cohortes The development of hand osteoarthritis (HOA) could be linked to hyperlipidaemia. No longitudinal studies have addressed the relationship between serum lipid profile and HOA. The study aim was to determine the association between serum lipid profile and the incidence of radiographic hand osteoarthritis (RHOA). All women in a prospective population-based cohort from the Chingford study with available baseline lipid measurements and without RHOA on a baseline were included. Study outcome was the incidence of RHOA in year 11 of follow-up. Serum lipid profile variables were analysed as continuous variables and categorised into quartiles. The association between serum lipid profile and RHOA was modeled using multivariable logistic regression. Overall RHOA incidence was 51.6% (45.7-57.4%). An inverse association between HDL cholesterol levels and the incidence of RHOA was observed by quartile: OR of 0.36 [95%CI 0.17-0.75], 0.52 [95%CI 0.26-1.06], and 0.48 [95%CI 0.22-1.03]. Triglycerides levels showed a significant trend. No relationship was found with total or LDL cholesterol. Higher levels of HDL cholesterol appear to protect against RHOA after 11 years of follow-up. More research is needed to elucidate HOA risk factors, the mechanisms related to the lipid pathway, and the effects of lipid-lowering agents on reducing the incidence of OA.