Showing papers by "Daniel Prieto-Alhambra published in 2021"

Renin-angiotensin system blockers and susceptibility to COVID-19: an international, open science, cohort analysis.

Abstract: Summary Background Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have been postulated to affect susceptibility to COVID-19. Observational studies so far have lacked rigorous ascertainment adjustment and international generalisability. We aimed to determine whether use of ACEIs or ARBs is associated with an increased susceptibility to COVID-19 in patients with hypertension. Methods In this international, open science, cohort analysis, we used electronic health records from Spain (Information Systems for Research in Primary Care [SIDIAP]) and the USA (Columbia University Irving Medical Center data warehouse [CUIMC] and Department of Veterans Affairs Observational Medical Outcomes Partnership [VA-OMOP]) to identify patients aged 18 years or older with at least one prescription for ACEIs and ARBs (target cohort) or calcium channel blockers (CCBs) and thiazide or thiazide-like diuretics (THZs; comparator cohort) between Nov 1, 2019, and Jan 31, 2020. Users were defined separately as receiving either monotherapy with these four drug classes, or monotherapy or combination therapy (combination use) with other antihypertensive medications. We assessed four outcomes: COVID-19 diagnosis; hospital admission with COVID-19; hospital admission with pneumonia; and hospital admission with pneumonia, acute respiratory distress syndrome, acute kidney injury, or sepsis. We built large-scale propensity score methods derived through a data-driven approach and negative control experiments across ten pairwise comparisons, with results meta-analysed to generate 1280 study effects. For each study effect, we did negative control outcome experiments using a possible 123 controls identified through a data-rich algorithm. This process used a set of predefined baseline patient characteristics to provide the most accurate prediction of treatment and balance among patient cohorts across characteristics. The study is registered with the EU Post-Authorisation Studies register, EUPAS35296. Findings Among 1 355 349 antihypertensive users (363 785 ACEI or ARB monotherapy users, 248 915 CCB or THZ monotherapy users, 711 799 ACEI or ARB combination users, and 473 076 CCB or THZ combination users) included in analyses, no association was observed between COVID-19 diagnosis and exposure to ACEI or ARB monotherapy versus CCB or THZ monotherapy (calibrated hazard ratio [HR] 0·98, 95% CI 0·84–1·14) or combination use exposure (1·01, 0·90–1·15). ACEIs alone similarly showed no relative risk difference when compared with CCB or THZ monotherapy (HR 0·91, 95% CI 0·68–1·21; with heterogeneity of >40%) or combination use (0·95, 0·83–1·07). Directly comparing ACEIs with ARBs demonstrated a moderately lower risk with ACEIs, which was significant with combination use (HR 0·88, 95% CI 0·79–0·99) and non-significant for monotherapy (0·85, 0·69–1·05). We observed no significant difference between drug classes for risk of hospital admission with COVID-19, hospital admission with pneumonia, or hospital admission with pneumonia, acute respiratory distress syndrome, acute kidney injury, or sepsis across all comparisons. Interpretation No clinically significant increased risk of COVID-19 diagnosis or hospital admission-related outcomes associated with ACEI or ARB use was observed, suggesting users should not discontinue or change their treatment to decrease their risk of COVID-19. Funding Wellcome Trust, UK National Institute for Health Research, US National Institutes of Health, US Department of Veterans Affairs, Janssen Research & Development, IQVIA, South Korean Ministry of Health and Welfare Republic, Australian National Health and Medical Research Council, and European Health Data and Evidence Network.

Characterising the background incidence rates of adverse events of special interest for covid-19 vaccines in eight countries: multinational network cohort study

Abstract: Objective To quantify the background incidence rates of 15 prespecified adverse events of special interest (AESIs) associated with covid-19 vaccines. Design Multinational network cohort study. Setting Electronic health records and health claims data from eight countries: Australia, France, Germany, Japan, the Netherlands, Spain, the United Kingdom, and the United States, mapped to a common data model. Participants 126 661 070 people observed for at least 365 days before 1 January 2017, 2018, or 2019 from 13 databases. Main outcome measures Events of interests were 15 prespecified AESIs (non-haemorrhagic and haemorrhagic stroke, acute myocardial infarction, deep vein thrombosis, pulmonary embolism, anaphylaxis, Bell's palsy, myocarditis or pericarditis, narcolepsy, appendicitis, immune thrombocytopenia, disseminated intravascular coagulation, encephalomyelitis (including acute disseminated encephalomyelitis), Guillain-Barrea syndrome, and transverse myelitis). Incidence rates of AESIs were stratified by age, sex, and database. Rates were pooled across databases using random effects meta-analyses and classified according to the frequency categories of the Council for International Organizations of Medical Sciences. Results Background rates varied greatly between databases. Deep vein thrombosis ranged from 387 (95% confidence interval 370 to 404) per 100 000 person years in UK CPRD GOLD data to 1443 (1416 to 1470) per 100 000 person years in US IBM MarketScan Multi-State Medicaid data among women aged 65 to 74 years. Some AESIs increased with age. For example, myocardial infarction rates in men increased from 28 (27 to 29) per 100 000 person years among those aged 18-34 years to 1400 (1374 to 1427) per 100 000 person years in those older than 85 years in US Optum electronic health record data. Other AESIs were more common in young people. For example, rates of anaphylaxis among boys and men were 78 (75 to 80) per 100 000 person years in those aged 6-17 years and 8 (6 to 10) per 100 000 person years in those older than 85 years in Optum electronic health record data. Meta-analytic estimates of AESI rates were classified according to age and sex. Conclusion This study found large variations in the observed rates of AESIs by age group and sex, showing the need for stratification or standardisation before using background rates for safety surveillance. Considerable population level heterogeneity in AESI rates was found between databases.

European Consensus Statement on the diagnosis and management of osteoporosis in chronic kidney disease stages G4–G5D

Abstract: Controlling the excessive fracture burden in patients with chronic kidney disease (CKD) Stages G4-G5D remains an impressive challenge. The reasons are 2-fold. First, the pathophysiology of bone fragility in patients with CKD G4-G5D is complex and multifaceted, comprising a mixture of age-related (primary male/postmenopausal), drug-induced and CKD-related bone abnormalities. Second, our current armamentarium of osteoporosis medications has not been developed for, or adequately studied in patients with CKD G4-G5D, partly related to difficulties in diagnosing osteoporosis in this specific setting and fear of complications. Doubts about the optimal diagnostic and therapeutic approach fuel inertia in daily clinical practice. The scope of the present consensus paper is to review and update the assessment and diagnosis of osteoporosis in patients with CKD G4-G5D and to discuss the therapeutic interventions available and the manner in which these can be used to develop management strategies for the prevention of fragility fracture. As such, it aims to stimulate a cohesive approach to the management of osteoporosis in patients with CKD G4-G5D to replace current variations in care and treatment nihilism.

Timing, Complications, and Safety of Tracheotomy in Critically Ill Patients With COVID-19.

Abstract: Importance The current coronavirus disease 2019 (COVID-19) pandemic has led to unprecedented needs for invasive ventilation, with 10% to 15% of intubated patients subsequently requiring tracheotomy. Objective To assess the complications, safety, and timing of tracheotomy performed for critically ill patients with COVID-19. Design, Setting, and Participants This prospective cohort study assessed consecutive patients admitted to the intensive care unit (ICU) who had COVID-19 that required tracheotomy. Patients were recruited from March 16 to April 10, 2020, at a tertiary referral center. Exposures A surgical tracheotomy was performed for all patients following recommended criteria for use of personal protective equipment (PPE). Main Outcomes and Measures The number of subthyroid operations, the tracheal entrance protocol, and use of PPE. Infections among the surgeons were monitored weekly by reverse-transcriptase polymerase chain reaction of nasopharyngeal swab samples. Short-term complications, weaning, and the association of timing of tracheotomy (early [≤10 days] vs late [>10 days]) with total required days of invasive ventilation were assessed. Results A total of 50 patients (mean [SD] age, 63.8 [9.2] years; 33 [66%] male) participated in the study. All tracheotomies were performed at the bedside. The median time from intubation to tracheotomy was 9 days (interquartile range, 2-24 days). A subthyroid approach was completed for 46 patients (92%), and the tracheal protocol was adequately achieved for 40 patients (80%). Adequate PPE was used, with no infection among surgeons identified 4 weeks after the last tracheotomy. Postoperative complications were rare, with minor bleeding (in 6 patients [12%]) being the most common complication. The successful weaning rate was higher in the early tracheotomy group than in the late tracheotomy group (adjusted hazard ratio, 2.55; 95% CI, 0.96-6.75), but the difference was not statistically significant. There was less time of invasive mechanical ventilatory support with early tracheotomy compared with late tracheotomy (mean [SD], 18 [5.4] vs 22.3 [5.7] days). The reduction of invasive ventilatory support was achieved at the expense of the pretracheotomy period. Conclusions and Relevance In this cohort study, with the use of a standardized protocol aimed at minimizing COVID-19 risks, bedside open tracheotomy was a safe procedure for patients and surgeons, with minimal complications. Timing of tracheotomy may be important in reducing time of invasive mechanical ventilation, with potential implications to intensive care unit availability during the COVID-19 pandemic.

Associations of BNT162b2 vaccination with SARS-CoV-2 infection and hospital admission and death with covid-19 in nursing homes and healthcare workers in Catalonia: prospective cohort study.

Abstract: Objective To determine associations of BNT162b2 vaccination with SARS-CoV-2 infection and hospital admission and death with covid-19 among nursing home residents, nursing home staff, and healthcare workers. Design Prospective cohort study. Setting Nursing homes and linked electronic medical record, test, and mortality data in Catalonia on 27 December 2020. Participants 28 456 nursing home residents, 26 170 nursing home staff, and 61 791 healthcare workers. Main outcome measures Participants were followed until the earliest outcome (confirmed SARS-CoV-2 infection, hospital admission or death with covid-19) or 26 May 2021. Vaccination status was introduced as a time varying exposure, with a 14 day run-in after the first dose. Mixed effects Cox models were fitted to estimate hazard ratios with index month as a fixed effect and adjusted for confounders including sociodemographics, comorbidity, and previous medicine use. Results Among the nursing home residents, SARS-CoV-2 infection was found in 2482, 411 were admitted to hospital with covid-19, and 450 died with covid-19 during the study period. In parallel, 1828 nursing home staff and 2968 healthcare workers were found to have SARS-CoV-2 infection, but fewer than five were admitted or died with covid-19. The adjusted hazard ratio for SARS-CoV-2 infection after two doses of vaccine was 0.09 (95% confidence interval 0.08 to 0.11) for nursing home residents, 0.20 (0.17 to 0.24) for nursing home staff, and 0.13 (0.11 to 0.16) for healthcare workers. Adjusted hazard ratios for hospital admission and mortality after two doses of vaccine were 0.05 (0.04 to 0.07) and 0.03 (0.02 to 0.04), respectively, for nursing home residents. Nursing home staff and healthcare workers recorded insufficient events for mortality analysis. Conclusions Vaccination was associated with 80-91% reduction in SARS-CoV-2 infection in all three cohorts and greater reductions in hospital admissions and mortality among nursing home residents for up to five months. More data are needed on longer term effects of covid-19 vaccines.

Characterizing the incidence of adverse events of special interest for COVID-19 vaccines across eight countries: a multinational network cohort study

Abstract: Summary Background As large-scale immunization programs against COVID-19 proceed around the world, safety signals will emerge that need rapid evaluation We report population-based, age- and sex- specific background incidence rates of potential adverse events of special interest (AESI) in eight countries using thirteen databases Methods This multi-national network cohort study included eight electronic medical record and five administrative claims databases from Australia, France, Germany, Japan, Netherlands, Spain, the United Kingdom, and the United States, mapped to a common data model People observed for at least 365 days before 1 January 2017, 2018, or 2019 were included We based study outcomes on lists published by regulators: acute myocardial infarction, anaphylaxis, appendicitis, Bell’s palsy, deep vein thrombosis, disseminated intravascular coagulation, encephalomyelitis, Guillain-Barre syndrome, hemorrhagic and non-hemorrhagic stroke, immune thrombocytopenia, myocarditis/pericarditis, narcolepsy, pulmonary embolism, and transverse myelitis We calculated incidence rates stratified by age, sex, and database We pooled rates across databases using random effects meta-analyses We classified meta-analytic estimates into Council of International Organizations of Medical Sciences categories: very common, common, uncommon, rare, or very rare Findings We analysed 126,661,070 people Rates varied greatly between databases and by age and sex Some AESI (eg, myocardial infarction, Guillain-Barre syndrome) increased with age, while others (eg, anaphylaxis, appendicitis) were more common in young people As a result, AESI were classified differently according to age For example, myocardial infarction was very rare in children, rare in women aged 35-54 years, uncommon in men and women aged 55-84 years, and common in those aged ≥85 years Interpretation We report robust baseline rates of prioritised AESI across 13 databases Age, sex, and variation between databases should be considered if background AESI rates are compared to event rates observed with COVID-19 vaccines

Use of repurposed and adjuvant drugs in hospital patients with covid-19: multinational network cohort study.

Abstract: Objective To investigate the use of repurposed and adjuvant drugs in patients admitted to hospital with covid-19 across three continents. Design Multinational network cohort study. Setting Hospital electronic health records from the United States, Spain, and China, and nationwide claims data from South Korea. Participants 303 264 patients admitted to hospital with covid-19 from January 2020 to December 2020. Main outcome measures Prescriptions or dispensations of any drug on or 30 days after the date of hospital admission for covid-19. Results Of the 303 264 patients included, 290 131 were from the US, 7599 from South Korea, 5230 from Spain, and 304 from China. 3455 drugs were identified. Common repurposed drugs were hydroxychloroquine (used in from Conclusions Multiple drugs were used in the first few months of the covid-19 pandemic, with substantial geographical and temporal variation. Hydroxychloroquine, azithromycin, lopinavir-ritonavir, and umifenovir (in China only) were the most prescribed repurposed drugs. Antithrombotics, antibiotics, H2 receptor antagonists, and corticosteroids were often used as adjunctive treatments. Research is needed on the comparative risk and benefit of these treatments in the management of covid-19.

Safety of Oral Bisphosphonates in Moderate-to-Severe Chronic Kidney Disease: A Binational Cohort Analysis

Abstract: Bisphosphonates are the first-line treatment for preventing fractures in osteoporosis patients. However, their use is contraindicated or to be used with caution in chronic kidney disease (CKD) patients, primarily because of a lack of information about their safety and effectiveness. We aimed to investigate the safety of oral bisphosphonates in patients with moderate to severe CKD, using primary-care electronic records from two cohorts, CPRD GOLD (1997-2016) and SIDIAP (2007-2015) in the UK and Catalonia, respectively. Both databases were linked to hospital records. SIDIAP was also linked to end-stage renal disease registry data. Patients with CKD stages 3b to 5, based on two or more estimated glomerular filtration rate measurements less than 45 mL/min/1.73 m2 , aged 40 years or older were identified. New bisphosphonate users were propensity score-matched with up to five non-users to minimize confounding within this population. Our primary outcome was CKD stage worsening (estimated glomerular filtration rate [eGFR] decline or renal replacement therapy). Secondary outcomes were acute kidney injury, gastrointestinal bleeding/ulcers, and severe hypocalcemia. Hazard ratios (HRs) were estimated using Cox regression and Fine and Gray sub-HRs were calculated for competing risks. We matched 2447 bisphosphonate users with 8931 non-users from CPRD and 1399 users with 6547 non-users from SIDIAP. Bisphosphonate use was associated with greater risk of CKD progression in CPRD (sub-HR [95% CI]: 1.14 [1.04, 1.26]) and SIDIAP (sub-HR: 1.15 [1.04, 1.27]). No risk differences were found for acute kidney injury, gastrointestinal bleeding/ulcers, or hypocalcemia. Hence, we can conclude a modest (15%) increased risk of CKD progression was identified in association with bisphosphonate use. No other safety concerns were identified. Our findings should be considered before prescribing bisphosphonates to patients with moderate to severe CKD. © 2020 American Society for Bone and Mineral Research (ASBMR).

Temporal relationship between osteoarthritis and comorbidities: a combined case control and cohort study in the UK primary care setting.

Abstract: OBJECTIVE: To determine the burden of comorbidities in OA and their temporal relationships in the UK. METHODS: The Clinical Practice Research Datalink (CPRD) GOLD was used to identify people with incident OA and age, gender and practice matched non-OA controls from UK primary care. Controls were assigned the same index date as matched cases (date of OA diagnosis). Associations between OA and 49 individual comorbidities and multimorbidities (two or more comorbidities excluding OA) both before and after OA diagnosis were estimated, adjusting for covariates, using odds ratios (aORs) and hazard ratios (aHRs), respectively. RESULTS: During 1997-2017, we identified 221 807 incident OA cases and 221 807 matched controls. Of 49 comorbidities examined, 38 were associated with OA both prior to and following the diagnosis of OA and 2 (dementia and systemic lupus erythematosus) were associated with OA only following the diagnosis of OA. People with OA had a higher risk of developing heart failure [aHR 1.63 (95% CI 1.56, 1.71)], dementia [aHR 1.62 (95% CI 1.56, 1.68)], liver diseases [aHR 1.51 (95% CI 1.37, 1.67)], irritable bowel syndrome [aHR 1.51 (95% CI 1.45, 1.58)], gastrointestinal bleeding [aHR 1.49 (95% CI 1.39, 1.59)], 10 musculoskeletal conditions and 25 other conditions following OA diagnosis. The aOR for multimorbidity prior to the index date was 1.71 (95% CI 1.69, 1.74), whereas the aHR for multimorbidity after the index date was 1.29 (95% CI 1.28, 1.30). CONCLUSIONS: People with OA are more likely to have other chronic conditions both before and after the OA diagnosis. Further study on shared aetiology and causality of these associations is needed.

Filling the gaps in the characterization of the clinical management of COVID-19: 30-day hospital admission and fatality rates in a cohort of 118 150 cases diagnosed in outpatient settings in Spain.

Abstract: Background Currently, there is a missing link in the natural history of COVID-19, from first (usually milder) symptoms to hospitalization and/or death To fill in this gap, we characterized COVID-19 patients at the time at which they were diagnosed in outpatient settings and estimated 30-day hospital admission and fatality rates Methods This was a population-based cohort study Data were obtained from Information System for Research in Primary Care (SIDIAP)-a primary-care records database covering >6 million people (>80% of the population of Catalonia), linked to COVID-19 reverse transcriptase polymerase chain reaction (RT-PCR) tests and hospital emergency, inpatient and mortality registers We included all patients in the database who were ≥15 years old and diagnosed with COVID-19 in outpatient settings between 15 March and 24 April 2020 (10 April for outcome studies) Baseline characteristics included socio-demographics, co-morbidity and previous drug use at the time of diagnosis, and polymerase chain reaction (PCR) testing and results Study outcomes included 30-day hospitalization for COVID-19 and all-cause fatality Results We identified 118 150 and 95 467 COVID-19 patients for characterization and outcome studies, respectively Most were women (587%) and young-to-middle-aged (eg 211% were 45-54 years old) Of the 44 575 who were tested with PCR, 32 723 (734%) tested positive In the month after diagnosis, 148% (146-150) were hospitalized, with a greater proportion of men and older people, peaking at age 75-84 years Thirty-day fatality was 35% (95% confidence interval: 34% to 36%), higher in men, increasing with age and highest in those residing in nursing homes [245% (234% to 256%)] Conclusion COVID-19 infections were widespread in the community, including all age-sex strata However, severe forms of the disease clustered in older men and nursing-home residents Although initially managed in outpatient settings, 15% of cases required hospitalization and 4% died within a month of first symptoms These data are instrumental for designing deconfinement strategies and will inform healthcare planning and hospital-bed allocation in current and future COVID-19 outbreaks

Thirty-Day Outcomes of Children and Adolescents With COVID-19: An International Experience.

Abstract: OBJECTIVES To characterize the demographics, comorbidities, symptoms, in-hospital treatments, and health outcomes among children and adolescents diagnosed or hospitalized with coronavirus disease 2019 (COVID-19) and to compare them in secondary analyses with patients diagnosed with previous seasonal influenza in 2017–2018. METHODS International network cohort using real-world data from European primary care records (France, Germany, and Spain), South Korean claims and US claims, and hospital databases. We included children and adolescents diagnosed and/or hospitalized with COVID-19 at age RESULTS A total of 242 158 children and adolescents diagnosed and 9769 hospitalized with COVID-19 and 2 084 180 diagnosed with influenza were studied. Comorbidities including neurodevelopmental disorders, heart disease, and cancer were more common among those hospitalized with versus diagnosed with COVID-19. Dyspnea, bronchiolitis, anosmia, and gastrointestinal symptoms were more common in COVID-19 than influenza. In-hospital prevalent treatments for COVID-19 included repurposed medications ( CONCLUSIONS Despite negligible fatality, complications including hospitalization, hypoxemia, and pneumonia were more frequent in children and adolescents with COVID-19 than with influenza. Dyspnea, anosmia, and gastrointestinal symptoms could help differentiate diagnoses. A wide range of medications was used for the inpatient management of pediatric COVID-19.

COVID-19 in patients with autoimmune diseases: characteristics and outcomes in a multinational network of cohorts across three countries.

Abstract: OBJECTIVE: Patients with autoimmune diseases were advised to shield to avoid COVID-19, but information on their prognosis is lacking. We characterised 30-day outcomes and mortality after hospitalisation with COVID-19 among patients with prevalent autoimmune diseases, and compared outcomes after hospital admissions among similar patients with seasonal influenza. METHODS: A multinational network cohort study was conducted using electronic health records data from Columbia University Irving Medical Center (CUIMC) (United States [US]), Optum [US], Department of Veterans Affairs (VA) (US), Information System for Research in Primary Care-Hospitalisation Linked Data (SIDIAP-H) (Spain), and claims data from IQVIA Open Claims (US) and Health Insurance and Review Assessment (HIRA) (South Korea). All patients with prevalent autoimmune diseases, diagnosed and/or hospitalised between January and June 2020 with COVID-19, and similar patients hospitalised with influenza in 2017-2018 were included. Outcomes were death and complications within 30 days of hospitalisation. RESULTS: We studied 133 589 patients diagnosed and 48 418 hospitalised with COVID-19 with prevalent autoimmune diseases. Most patients were female, aged ≥50 years with previous comorbidities. The prevalence of hypertension (45.5-93.2%), chronic kidney disease (14.0-52.7%) and heart disease (29.0-83.8%) was higher in hospitalised vs diagnosed patients with COVID-19. Compared with 70 660 hospitalised with influenza, those admitted with COVID-19 had more respiratory complications including pneumonia and acute respiratory distress syndrome, and higher 30-day mortality (2.2% to 4.3% vs 6.3% to 24.6%). CONCLUSIONS: Compared with influenza, COVID-19 is a more severe disease, leading to more complications and higher mortality.

Association of Tramadol vs Codeine Prescription Dispensation With Mortality and Other Adverse Clinical Outcomes.

Abstract: 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.

Characteristics and outcomes of 627 044 COVID-19 patients living with and without obesity in the United States, Spain, and the United Kingdom.

Abstract: Background A detailed characterization of patients with COVID-19 living with obesity has not yet been undertaken. We aimed to describe and compare the demographics, medical conditions, and outcomes of COVID-19 patients living with obesity (PLWO) to those of patients living without obesity. Methods We conducted a cohort study based on outpatient/inpatient care and claims data from January to June 2020 from Spain, the UK, and the US. We used six databases standardized to the OMOP common data model. We defined two non-mutually exclusive cohorts of patients diagnosed and/or hospitalized with COVID-19; patients were followed from index date to 30 days or death. We report the frequency of demographics, prior medical conditions, and 30-days outcomes (hospitalization, events, and death) by obesity status. Results We included 627 044 (Spain: 122 058, UK: 2336, and US: 502 650) diagnosed and 160 013 (Spain: 18 197, US: 141 816) hospitalized patients with COVID-19. The prevalence of obesity was higher among patients hospitalized (39.9%, 95%CI: 39.8-40.0) than among those diagnosed with COVID-19 (33.1%; 95%CI: 33.0-33.2). In both cohorts, PLWO were more often female. Hospitalized PLWO were younger than patients without obesity. Overall, COVID-19 PLWO were more likely to have prior medical conditions, present with cardiovascular and respiratory events during hospitalization, or require intensive services compared to COVID-19 patients without obesity. Conclusion We show that PLWO differ from patients without obesity in a wide range of medical conditions and present with more severe forms of COVID-19, with higher hospitalization rates and intensive services requirements. These findings can help guiding preventive strategies of COVID-19 infection and complications and generating hypotheses for causal inference studies.

Serious postoperative complications and reoperation after carpal tunnel decompression surgery in England: a nationwide cohort analysis.

Abstract: Summary Background Carpal tunnel decompression surgery to treat carpal tunnel syndrome is a common procedure, yet data on safety and effectiveness of the operation in the general population remain scarce. We aimed to estimate the incidence of reoperation and serious postoperative complications (requiring admission to hospital or further surgery) following carpal tunnel decompression in routine clinical practice and to identify the patient factors associated with these adverse outcomes. Methods We did a nationwide cohort analysis including all carpal tunnel decompression surgeries in patients aged 18 years or older, done in the National Health Service in England between April 1, 1998, and March 31, 2017, using the Hospital Episode Statistics dataset linked to mortality records. Patients were followed-up until death or until the end of the study (March 31, 2017). Primary outcomes were the overall incidence of carpal tunnel decompression reoperation and serious postoperative complications (surgical site infection or dehiscence, or neurovascular or tendon injury, requiring admission to hospital or further surgery) within 30 days and 90 days after surgery. Multivariable Cox regression analysis was used to identify factors influencing complications and reoperation, and the Fine and Gray method was used to adjust for the competing risk of mortality. This study is registered with ClinicalTrials.gov , NCT03573765 . Findings 855 832 carpal tunnel decompression surgeries were done between April 1, 1998, and March 31, 2017 (incidence rate 1·10 per 1000 person-years [95% CI 1·02–1·17]). 29 288 procedures (3·42%) led to carpal tunnel decompression reoperation (incidence rate 3·18 per 1000 person-years [95% CI 3·12–3·23]). Of the 855 832 initial surgeries, 620 procedures (0·070% [95% CI 0·067–0·078]) led to a serious complication within 30 days after surgery, and 698 procedures (0·082% [0·076–0·088]) within 90 days. Local complications within 90 days after surgery were associated with male sex (adjusted hazard ratio 2·32 [95% CI 1·74–3·09]) and age category 18–29 years (2·25 [1·10–4·62]). Male sex (adjusted subhazard ratio 1·09 [95% CI 1·06–1·13]), old age (>80 years vs 50–59 years: 1·09 [1·03–1·15]), and greater levels of comorbidity (Charlson score ≥5 vs 0: 1·25 [1·19–1·32]) and socioeconomic deprivation (most deprived 10% vs least deprived 10%: 1·18 [1·10–1·27]) were associated with increased reoperation risk. Interpretation To our knowledge, this is the largest national study on carpal tunnel decompression to date, providing strong evidence on serious postoperative complication and reoperation rates. Carpal tunnel decompression appears to be a safe operation in most patients, with an overall serious complication rate (requiring admission to hospital or further surgery) of less than 0·1%. Funding Versus Arthritis; Medical Research Council; Royal College of Surgeons of England and National Joint Registry research fellowship; University of Oxford; National Institute for Health Research; and National Institute for Health Research Biomedical Research Centre, Oxford.

Body Mass Index and Risk of COVID-19 Diagnosis, Hospitalization, and Death: A Cohort Study of 2 524 926 Catalans.

Abstract: CONTEXT A comprehensive understanding of the association between body mass index (BMI) and coronavirus disease 2019 (COVID-19) is still lacking. OBJECTIVE To investigate associations between BMI and risk of COVID-19 diagnosis, hospitalization with COVID-19, and death after a COVID-19 diagnosis or hospitalization (subsequent death), accounting for potential effect modification by age and sex. DESIGN Population-based cohort study. SETTING Primary care records covering >80% of the Catalan population, linked to regionwide testing, hospital, and mortality records from March to May 2020. PARTICIPANTS Adults (≥18 years) with at least 1 measurement of weight and height. MAIN OUTCOME MEASURES Hazard ratios (HR) for each outcome. RESULTS We included 2 524 926 participants. After 67 days of follow-up, 57 443 individuals were diagnosed with COVID-19, 10 862 were hospitalized with COVID-19, and 2467 had a subsequent death. BMI was positively associated with being diagnosed and hospitalized with COVID-19. Compared to a BMI of 22 kg/m2, the HR (95% CI) of a BMI of 31 kg/m2 was 1.22 (1.19-1.24) for diagnosis and 1.88 (1.75-2.03) and 2.01 (1.86-2.18) for hospitalization without and with a prior outpatient diagnosis, respectively. The association between BMI and subsequent death was J-shaped, with a modestly higher risk of death among individuals with BMIs ≤ 19 kg/m2 and a more pronounced increasing risk for BMIs ≥ 40 kg/m2. The increase in risk for COVID-19 outcomes was particularly pronounced among younger patients. CONCLUSIONS There is a monotonic association between BMI and COVID-19 diagnosis and hospitalization risks but a J-shaped relationship with mortality. More research is needed to unravel the mechanisms underlying these relationships.

Global epidemiology of hip fractures: a study protocol using a common analytical platform among multiple countries

Abstract: Introduction Hip fractures are associated with a high burden of morbidity and mortality. Globally, there is wide variation in the incidence of hip fracture in people aged 50 years and older. Longitudinal and cross-geographical comparisons of health data can provide insights on aetiology, risk factors, and healthcare practices. However, systematic reviews of studies that use different methods and study periods do not permit direct comparison across geographical regions. Thus, the objective of this study is to investigate global secular trends in hip fracture incidence, mortality and use of postfracture pharmacological treatment across Asia, Oceania, North and South America, and Western and Northern Europe using a unified methodology applied to health records. Methods and analysis This retrospective cohort study will use a common protocol and an analytical common data model approach to examine incidence of hip fracture across population-based databases in different geographical regions and healthcare settings. The study period will be from 2005 to 2018 subject to data availability in study sites. Patients aged 50 years and older and hospitalised due to hip fracture during the study period will be included. The primary outcome will be expressed as the annual incidence of hip fracture. Secondary outcomes will be the pharmacological treatment rate and mortality within 12 months following initial hip fracture by year. For the primary outcome, crude and standardised incidence of hip fracture will be reported. Linear regression will be used to test for time trends in the annual incidence. For secondary outcomes, the crude mortality and standardised mortality incidence will be reported. Ethics and dissemination Each participating site will follow the relevant local ethics and regulatory frameworks for study approval. The results of the study will be submitted for peer-reviewed scientific publications and presented at scientific conferences.

Smoking and COVID-19 Infection and Related Mortality: A Prospective Cohort Analysis of UK Biobank Data

Abstract: Background Several papers have shown contradictory evidence about the relationship between smoking and COVID-19-related deaths. There is little evidence about smoking and risk of infection. We aim to examine association between smoking and COVID-19 infection and subsequent mortality. Methods This was a prospective study with participants from the UK Biobank cohort. Participants who lived in England were followed up from 01/02/2020 to 28/06/2020 with data linked to hospital episode statistics, Office for National Statistics and Public Health England PCR tests. We compared current-smokers, previous-smokers with never-smokers and estimated risk ratio (RR) of COVID-19 infection and subsequent mortality using Poisson regression adjusting for age, sex, ethnicity, body mass index and socio-economic status. Interactions between smoking status and age and sex were tested for using multiplicative interactions, and analyses were stratified by median age (49-68 years, 69-86 years) and sex. Results In total, 402,978 participants were included in the analyses. The majority were never smokers, 226,294 (56.2%), 140,090 (34.8%) were previous smokers, and 39,974 (9.9%) current smokers. COVID-19 infection was identified in 1591 (0.39%) people, and 372/1591 (23.4%) died. Amongst the younger participants, smokers were nearly twice as likely to become infected with COVID-19 than never smokers (RR 1.88 [1.49-2.38]) whereas there was no difference for those aged 69+ (RR 1.05 [0.82-1.34]). In contrast, amongst the older participants, smokers were twice as likely to die from COVID-19 compared to non-smokers (RR 2.15 [1.11-4.16]) whereas there was no difference for those under the age of 69 (RR 1.22[0.83-1.79]). Similar patterns were observed for previous smokers. The impact of smoking was similar in men and women. Conclusion The association between smoking and COVID-19 infection and subsequent death is modified by age. Smokers and previous smokers aged under 69 were at higher risk of COVID-19 infection, suggesting the risk is associated with increased exposure to SARS-COV-2 virus. Once infected, older smokers were twice as likely to die from COVID-19 than never smokers, possibly mediated by increased risk of chronic conditions/illnesses.

Cancer and the risk of COVID-19 diagnosis, hospitalisation, and death: a population-based multi-state cohort study including 4,618,377 adults in Catalonia, Spain

Abstract: The relationship between cancer and coronavirus disease 2019 (COVID-19) infection and severity remains poorly understood. We conducted a population-based cohort study between 1 March and 6 May 2020 describing the associations between cancer and risk of COVID-19 diagnosis, hospitalisation and COVID-19-related death. Data were obtained from the Information System for Research in Primary Care (SIDIAP) database, including primary care electronic health records from ~80% of the population in Catalonia, Spain. Cancer was defined as any primary invasive malignancy excluding non-melanoma skin cancer. We estimated adjusted hazard ratios (aHRs) for the risk of COVID-19 (outpatient) clinical diagnosis, hospitalisation (with or without a prior COVID-19 diagnosis) and COVID-19-related death using Cox proportional hazard regressions. Models were estimated for the overall cancer population and by years since cancer diagnosis (<1 year, 1-5 years and ≥5 years), sex, age and cancer type; and adjusted for age, sex, smoking status, deprivation and comorbidities. We included 4 618 377 adults, of which 260 667 (5.6%) had a history of cancer. A total of 98 951 individuals (5.5% with cancer) were diagnosed, and 6355 (16.4% with cancer) were directly hospitalised with COVID-19. Of those diagnosed, 6851 were subsequently hospitalised (10.7% with cancer), and 3227 died without being hospitalised (18.5% with cancer). Among those hospitalised, 1963 (22.5% with cancer) died. Cancer was associated with an increased risk of COVID-19 diagnosis (aHR: 1.08; 95% confidence interval [1.05-1.11]), direct COVID-19 hospitalisation (1.33 [1.24-1.43]) and death following hospitalisation (1.12 [1.01-1.25]). These associations were stronger for patients recently diagnosed with cancer, aged <70 years, and with haematological cancers. These patients should be prioritised in COVID-19 vaccination campaigns and continued non-pharmaceutical interventions.

Effects of BNT162b2 mRNA Vaccination on COVID-19 Disease, Hospitalisation and Mortality in Nursing Homes and Healthcare Workers: A Prospective Cohort Study Including 28,594 Nursing Home Residents, 26,238 Nursing Home Staff, and 61,951 Healthcare Workers in Catalonia

Abstract: Background: Spain began vaccinating priority groups against COVID-19 with BNT162b2 in late December 2020. We report associations of vaccination with COVID-19 infection, hospitalisation, and mortality among nursing home residents, nursing home staff, and healthcare workers. Methods: We analysed three cohorts of all nursing home residents, nursing home staff, and healthcare workers in Catalonia on 27 December 2020. Data were obtained from linked primary care, RT-PCR and lateral flow test, hospital, and mortality records. Those with a pre-study COVID-19 diagnosis or no linked electronic medical records were excluded. Two doses of BNT162b2 were administered 3 weeks apart. Participants were followed until the earliest of an outcome (confirmed COVID-19 infection, hospitalisation, and mortality) or 5 March 2021. Participants could contribute data to the unvaccinated, one-dose, and two-dose groups. Analyses were conducted using time-varying Cox regression. Multivariable adjustment for imbalances in socio-demographics, comorbidity, and polypharmacy. Findings: We included 28,594 nursing home residents, 26,238 nursing home staff, and 61,951 healthcare workers, of whom 2,405, 1,584, and 2,672 received COVID-19 diagnoses; 383, 35, and 76 were hospitalised; and 409, 0, and 1 died. The adjusted hazard ratio (HR) (95% confidence interval) for COVID-19 infection after two-dose vaccination was 0·08 (0·07-0·09) for nursing home residents, 0·12 (0·10-0·15) for nursing home staff, and 0·05 (0·04-0·07) for healthcare workers. The adjusted HRs for hospitalisation and mortality after two-dose vaccination were 0·03 (0·02-0·05) and 0·02 (0·01-0·03), respectively, for nursing home residents. Nursing home staff and healthcare workers recorded insufficient events for mortality analysis. Interpretation Vaccination was associated with 85%-96% reduction in SARS-CoV-2 infection in all three cohorts, and bigger reductions in hospitalisations and mortality amongst nursing home residents for up to two months. More data are needed on the long-term effects of COVID-19 vaccines. Funding: Partially supported by National Institute of Health Research UK, We do not have any other funding acknowledgements. Declaration of Interest: None to declare. Ethical Approval: The study was approved by the Clinical Research Ethics Committee of the IDIAP Jordi Gol with reference number 21/045-PCV.

The natural history of symptomatic COVID-19 during the first wave in Catalonia.

Abstract: The natural history of coronavirus disease 2019 (COVID-19) has yet to be fully described. Here, we use patient-level data from the Information System for Research in Primary Care (SIDIAP) to summarise COVID-19 outcomes in Catalonia, Spain. We included 5,586,521 individuals from the general population. Of these, 102,002 had an outpatient diagnosis of COVID-19, 16,901 were hospitalised with COVID-19, and 5273 died after either being diagnosed or hospitalised with COVID-19 between 1st March and 6th May 2020. Older age, being male, and having comorbidities were all generally associated with worse outcomes. These findings demonstrate the continued need to protect those at high risk of poor outcomes, particularly older people, from COVID-19 and provide appropriate care for those who develop symptomatic disease. While risks of hospitalisation and death were lower for younger populations, there is a need to limit their role in community transmission.

Mortality, falls and fracture risk are positively associated with frailty: a SIDIAP cohort study of 890,000 patients.

Abstract: Background Frail subjects are at increased risk of adverse outcomes. We aimed to assess their risk of falls, all-cause mortality, and fractures. Methods We used a retrospective cohort study using the SIDIAP database (>6 million residents). Subjects ≥75 years old with ≥1 year of valid data (2007- 2015) were included. Follow-up: from (the latest of) date of cohort entry up to migration, end of the study period or outcome (whichever came first). The eFRAGICAP classified subjects as Fit, Mild, Moderate or Severely Frail. Outcomes (ICD-10) were incident falls, fractures (overall/hip/vertebral) and all-cause mortality during the study period. Statistics: Hazard Ratios (HR), 95% CI adjusted (per age, sex and socio-economic status) and un-adjusted cause-specific Cox models, accounting for competing risk of death (Fit group as the reference). Results 893,211 subjects were analyzed. 54.4% were classified as Fit, 34.0% as mild, 9.9% as moderate and 1.6% as severely frail. Compared with the fit, frail had an increased risk of falls (adjusted HR of 1.55 (1.52-1.58), 2.74 (2.66-2.84) and 5.94 (5.52-6.40)), all-cause mortality (adjusted HR of 1.36 (1.35-1.37), 2.19 (2.16-2.23) and 4.29 (4.13-4.45)) and fractures (adjusted HR of 1.21(1.20-1.23), 1.51(1.47-1.55) and 2.36 (2.20-2.53)) for mild, moderate and severe frailty respectively. Severely frail had a high risk of vertebral (HR of 2.49 (1.99-3.11)) and hip fracture (HR of 1.85 (1.50-2.28)). Accounting for competing risk of death unchanged results. Conclusion Frail subjects are at increased risk of death, fractures and falls. The eFRAGICAP tool can easily assess frailty in electronic primary-care databases in Spain.

Bias, Precision and Timeliness of Historical (Background) Rate Comparison Methods for Vaccine Safety Monitoring: An Empirical Multi-Database Analysis

Abstract: Using real-world data and past vaccination data, we conducted a large-scale experiment to quantify bias, precision and timeliness of different study designs to estimate historical background (expected) compared to post-vaccination (observed) rates of safety events for several vaccines. We used negative (not causally related) and positive control outcomes. The latter were synthetically generated true safety signals with incident rate ratios ranging from 1.5 to 4. Observed vs. expected analysis using within-database historical background rates is a sensitive but unspecific method for the identification of potential vaccine safety signals. Despite good discrimination, most analyses showed a tendency to overestimate risks, with 20%-100% type 1 error, but low (0% to 20%) type 2 error in the large databases included in our study. Efforts to improve the comparability of background and post-vaccine rates, including age-sex adjustment and anchoring background rates around a visit, reduced type 1 error and improved precision but residual systematic error persisted. Additionally, empirical calibration dramatically reduced type 1 to nominal but came at the cost of increasing type 2 error.

The impact of prioritisation and dosing intervals on the effects of COVID-19 vaccination in Europe: an agent-based cohort model.

Abstract: Different strategies have been used to maximise the effect of COVID-19 vaccination campaigns in Europe. We modelled the impact of different prioritisation choices and dose intervals on infections, hospitalisations, mortality, and public health restrictions. An agent-based model was built to quantify the impact of different vaccination strategies over 6 months. Input parameters were derived from published phase 3 trials and official European figures. We explored the effect of prioritising vulnerable people, care-home staff and residents, versus contagious groups; and the impact of dose intervals ranging from 3 to 12 weeks. Prioritising vulnerable people, rather than the most contagious, led to higher numbers of COVID-19 infections, whilst reducing mortality, hospital admissions, and public health restrictions. At a realistic vaccination speed of ≤ 0·1% population/day, separating doses by 12 weeks (vs a baseline scenario of 3 weeks) reduced hospitalisations, mortality, and restrictions for vaccines with similar first- and second-dose efficacy (e.g., the Oxford-AstraZeneca and Moderna vaccines), but not for those with lower first vs second-dose efficacy (e.g., the Pfizer/BioNTech vaccine). Mass vaccination will dramatically reduce the effect of COVID-19 on Europe's health and economy. Early vaccination of vulnerable populations will reduce mortality, hospitalisations, and public health restrictions compared to prioritisation of the most contagious people. The choice of interval between doses should be based on expected vaccine availability and first-dose efficacy, with 12-week intervals preferred over shorter intervals in most realistic scenarios.

Does pre-existing morbidity influences risks and benefits of total hip replacement for osteoarthritis: a prospective study of 6682 patients from linked national datasets in England.

Abstract: Total hip arthroplasty (THA) surgery for elderly people with multimorbidity increases the risk of serious health hazards including mortality. Whether such background morbidity reduces the clinical benefit is less clear. Objective To evaluate how pre-existing health status, using multiple approaches, influences risks of, and quality of life benefits from, THA. Setting Longitudinal record linkage study of a UK sample linking their primary care to their secondary care records. Participants A total of 6682 patients were included, based on the recording of the diagnosis of hip osteoarthritis in a national primary care register and the recording of the receipt of THA in a national secondary care register. Data were extracted from the primary care register on background health and morbidity status using five different constructs: Charlson Comorbidity Index, Electronic Frailty Index (eFI) and counts of comorbidity disorders (from list of 17), prescribed medications and number of primary care visits prior to recording of THA. Outcome measures (1) Postoperative complications and mortality; (2) postoperative hip pain and function using the Oxford Hip Score (OHS) and health-related quality of life using the EuroQoL (EQ)-5D score. Results Perioperative complication rate was 3.2% and mortality was 0.9%, both increased with worse preoperative health status although this relationship varied depending on the morbidity construct: the eFI showing the strongest relationship but number of visits having no predictive value. By contrast, the benefits were not reduced in those with worse preoperative health, and improvement in both OHS and EQ-5D was observed in all the morbidity categories. Conclusions Independent of preoperative morbidity, THA leads to similar substantial improvements in quality of life. These are offset by an increase in medical complications in some subgroups of patients with high morbidity, depending on the definition used. For most elderly people, their other health disorders should not be a barrier for THA.

Background rates of five thrombosis with thrombocytopenia syndromes of special interest for COVID-19 vaccine safety surveillance: incidence between 2017 and 2019 and patient profiles from 20.6 million people in six European countries

Abstract: 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.

Unraveling COVID-19: a large-scale characterization of 4.5 million COVID-19 cases using CHARYBDIS

Abstract: Background: Routinely collected real world data (RWD) have great utility in aiding the novel coronavirus disease (COVID-19) pandemic response [1,2]. Here we present the international Observational Health Data Sciences and Informatics (OHDSI) [3] Characterizing Health Associated Risks, and Your Baseline Disease In SARS-COV-2 (CHARYBDIS) framework for standardisation and analysis of COVID-19 RWD. Methods: We conducted a descriptive cohort study using a federated network of data partners in the United States, Europe (the Netherlands, Spain, the UK, Germany, France and Italy) and Asia (South Korea and China). The study protocol and analytical package were released on 11 th June 2020 and are iteratively updated via GitHub [4]. Findings: We identified three non-mutually exclusive cohorts of 4,537,153 individuals with a clinical COVID-19 diagnosis or positive test, 886,193 hospitalized with COVID-19 , and 113,627 hospitalized with COVID-19 requiring intensive services . All comorbidities, symptoms, medications, and outcomes are described by cohort in aggregate counts, and are available in an interactive website: https://data.ohdsi.org/Covid19CharacterizationCharybdis/. Interpretation: CHARYBDIS findings provide benchmarks that contribute to our understanding of COVID-19 progression, management and evolution over time. This can enable timely assessment of real-world outcomes of preventative and therapeutic options as they are introduced in clinical practice.

Thromboembolic Events and Thrombosis With Thrombocytopenia After COVID-19 Infection and Vaccination in Catalonia, Spain

Abstract: 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).

Implementation of the COVID-19 Vulnerability Index Across an International Network of Health Care Data Sets: Collaborative External Validation Study

Abstract: Background: SARS-CoV-2 is straining health care systems globally. The burden on hospitals during the pandemic could be reduced by implementing prediction models that can discriminate patients who require hospitalization from those who do not. The COVID-19 vulnerability (C-19) index, a model that predicts which patients will be admitted to hospital for treatment of pneumonia or pneumonia proxies, has been developed and proposed as a valuable tool for decision-making during the pandemic. However, the model is at high risk of bias according to the “prediction model risk of bias assessment” criteria, and it has not been externally validated. Objective: The aim of this study was to externally validate the C-19 index across a range of health care settings to determine how well it broadly predicts hospitalization due to pneumonia in COVID-19 cases. Methods: We followed the Observational Health Data Sciences and Informatics (OHDSI) framework for external validation to assess the reliability of the C-19 index. We evaluated the model on two different target populations, 41,381 patients who presented with SARS-CoV-2 at an outpatient or emergency department visit and 9,429,285 patients who presented with influenza or related symptoms during an outpatient or emergency department visit, to predict their risk of hospitalization with pneumonia during the following 0-30 days. In total, we validated the model across a network of 14 databases spanning the United States, Europe, Australia, and Asia. Results: The internal validation performance of the C-19 index had a C statistic of 0.73, and the calibration was not reported by the authors. When we externally validated it by transporting it to SARS-CoV-2 data, the model obtained C statistics of 0.36, 0.53 (0.473-0.584) and 0.56 (0.488-0.636) on Spanish, US, and South Korean data sets, respectively. The calibration was poor, with the model underestimating risk. When validated on 12 data sets containing influenza patients across the OHDSI network, the C statistics ranged between 0.40 and 0.68. Conclusions: Our results show that the discriminative performance of the C-19 index model is low for influenza cohorts and even worse among patients with COVID-19 in the United States, Spain, and South Korea. These results suggest that C-19 should not be used to aid decision-making during the COVID-19 pandemic. Our findings highlight the importance of performing external validation across a range of settings, especially when a prediction model is being extrapolated to a different population. In the field of prediction, extensive validation is required to create appropriate trust in a model.