Long-Term Adherence and Persistence to Low-Dose Aspirin for the Prevention of Cardiovascular Disease: A Population-Based Cohort Study.

Methods: Using information from electronic health records in Germany and the United Kingdom (UK) in a common data model, we followed adults with ≥2 low-dose aspirin prescriptions (75-100 mg) during 2007-2018 for up to 10 years. Included individuals had no low-dose aspirin prescriptions in the year before the follow-up started (date of first low-dose aspirin prescription) and ≥12 months' observation. Adherence was determined using the medication possession ratio (MPR), and persistence was defined as continuous treatment disregarding gaps between prescriptions of <60 days; analyses were undertaken according to indication (primary/secondary CVD prevention). Results: We identified 144,717 low-dose aspirin users from Germany and 190,907 from the UK. Among patients with 5-10 years' follow-up, median adherence among secondary CVD prevention users was 60% in Germany and 75% in the UK. Among primary prevention users, median adherence was 50% for both countries. Persistence among secondary CVD prevention users was 58.3% at 2 years, 47.0% at 5 years, 35.2% at 10 years (Germany), and 67.5% at 2 years, 58.0% at 5 years, and 46.8% at 10 years (UK). Among primary CVD prevention users, persistence was 52.8% at 2 years, 41.6% at 5 years, 32.1% at 10 years (Germany), 56.3% at 2 years, 45.4% at 5 years, and 33.8% at 10 years (UK). Conclusions: Long-term adherence and persistence to low-dose aspirin are suboptimal; efforts for improvement could translate into a lower CVD burden in the general population.

Time Trends and Treatment Pathways in Prescribing Individual Oral Anticoagulants in Patients with Nonvalvular Atrial Fibrillation: An Observational Study of More than Three Million Patients from Europe and the United States.

Background: Data directly comparing trends in the use of different oral anticoagulants (OACs) among patients with atrial fibrillation (AF) from different countries are limited. We addressed this using a large-scale network cohort study in the United States (US), Belgium, France, Germany, and the United Kingdom (UK). Methods: We used nine databases (claims or electronic health records) that had been converted into the Observational Medical Outcomes Partnership Common Data Model with analysis performed using open-source analytical tools. We identified adults with AF and a first OAC prescription, either vitamin K antagonist (VKA) or direct oral anticoagulant (DOAC), from 2010 to 2017. We described time trends in use, continuation, and switching. Results: In 2010, 87.5%-99.8% of patients started on a VKA. By 2017, the majority started on a DOAC: 87.0% (US), 88.3% (Belgium), 93.1% (France), 88.4% (Germany), and 86.1%-86.7% (UK). In the UK, DOACs became the most common starting OAC in 2015, 2-3 years later than elsewhere. Apixaban was the most common starting OAC by 2017, 50.2%-57.8% (US), 31.4% (Belgium), 45.9% (France), 39.5% (Germany), and 49.8%-50.5% (UK), followed by rivaroxaban, 24.8%-32.5% (US), 25.7% (Belgium), 38.4% (France), 24.9% (Germany), and 30.2%-31.2% (UK). Long-term treatment was less common in the US than in Europe, especially the UK. A minority of patients switched from their index OAC in the short and long term. Conclusions: From 2010 to 2017, VKA use had significantly declined and DOAC use had significantly increased in the US and Europe. Apixaban was the most prescribed OAC in 2017, followed by rivaroxaban.

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

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

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

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

Development and validation of a prognostic model predicting symptomatic hemorrhagic transformation in acute ischemic stroke at scale in the OHDSI network.

BACKGROUND AND PURPOSE: Hemorrhagic transformation (HT) after cerebral infarction is a complex and multifactorial phenomenon in the acute stage of ischemic stroke, and often results in a poor prognosis. Thus, identifying risk factors and making an early prediction of HT in acute cerebral infarction contributes not only to the selections of therapeutic regimen but also, more importantly, to the improvement of prognosis of acute cerebral infarction. The purpose of this study was to develop and validate a model to predict a patient's risk of HT within 30 days of initial ischemic stroke. METHODS: We utilized a retrospective multicenter observational cohort study design to develop a Lasso Logistic Regression prediction model with a large, US Electronic Health Record dataset which structured to the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM). To examine clinical transportability, the model was externally validated across 10 additional real-world healthcare datasets include EHR records for patients from America, Europe and Asia. RESULTS: In the database the model was developed, the target population cohort contained 621,178 patients with ischemic stroke, of which 5,624 patients had HT within 30 days following initial ischemic stroke. 612 risk predictors, including the distance a patient travels in an ambulance to get to care for a HT, were identified. An area under the receiver operating characteristic curve (AUC) of 0.75 was achieved in the internal validation of the risk model. External validation was performed across 10 databases totaling 5,515,508 patients with ischemic stroke, of which 86,401 patients had HT within 30 days following initial ischemic stroke. The mean external AUC was 0.71 and ranged between 0.60-0.78. CONCLUSIONS: A HT prognostic predict model was developed with Lasso Logistic Regression based on routinely collected EMR data. This model can identify patients who have a higher risk of HT than the population average with an AUC of 0.78. It shows the OMOP CDM is an appropriate data standard for EMR secondary use in clinical multicenter research for prognostic prediction model development and validation. In the future, combining this model with clinical information systems will assist clinicians to make the right therapy decision for patients with acute ischemic stroke.

Compressive straining of bilayer phosphorene leads to extraordinary electron mobility at a new conduction band edge.

By means of hybrid DFT calculations and the deformation potential approximation, we show that bilayer phosphorene under slight compression perpendicular to its surface exhibits extraordinary room temperature electron mobility of order 7 × 10(4) cm(2) V(-1) s(-1). This is approximately 2 orders of magnitude higher than is widely reported for ground state phosphorenes and is the result of the emergence of a new conduction band minimum that is decoupled from the in-plane acoustic phonons that dominate carrier scattering.