The immunomodulatory drug leflunomide is frequently used for treating polyomavirus-associated nephropathy, yet its antiviral mechanism is unclear. We characterized the effects of the active leflunomide metabolite A771726 (LEF-A) on the polyomavirus BK (BKV) life cycle in human renal tubular epithelial cells. LEF-A at 10 g/ml reduced the extracellular BKV load by 90% (IC 90 ) but with significant host cytostatic effects. BKV genome replication, late protein expression, and virion assembly and release were inhibited with visible disruption of the nuclear replication architecture. Both host cell and antiviral effects were largely reversed by uridine addition, implicating nonspecific pyrimidine depletion as the major anti-BKV mechanism of leflunomide.

Use of DOACs for anticoagulation in atrial fibrillation became more prevalent between 2010 and 2015 in Norway, at the expense of warfarin.

Aims To assess persistence and adherence to non-vitamin K antagonist oral anticoagulant (NOAC) treatment in patients with atrial fibrillation (AF) in five Western European healthcare settings. Methods and results We conducted a multi-country observational cohort study, including 559 445 AF patients initiating NOAC therapy from Stockholm (Sweden), Denmark, Scotland, Norway, and Germany between 2011 and 2018. Patients were followed from their first prescription until they switched to a vitamin K antagonist, emigrated, died, or the end of follow-up. We measured persistence and adherence over time and defined adequate adherence as medication possession rate ≥90% among persistent patients only. Results Overall, persistence declined to 82% after 1 year and to 63% after 5 years. When including restarters of NOAC treatment, 85% of the patients were treated with NOACs after 5 years. The proportion of patients with adequate adherence remained above 80% throughout follow-up. Persistence and adherence were similar between countries and was higher in patients starting treatment in later years. Both first year persistence and adherence were lower with dabigatran (persistence: 77%, adherence: 65%) compared with apixaban (86% and 75%) and rivaroxaban (83% and 75%) and were statistically lower after adjusting for patient characteristics. Adherence and persistence with dabigatran remained lower throughout follow-up. Conclusion Persistence and adherence were high among NOAC users in five Western European healthcare settings and increased in later years. Dabigatran use was associated with slightly lower persistence and adherence compared with apixaban and rivaroxaban.

Objective To compare effectiveness and safety of warfarin and the direct oral anticoagulants (DOAC) dabigatran, rivaroxaban and apixaban in non-valvular atrial fibrillation in routine care. Methods From nationwide registries, we identified treatment-naïve patients initiating warfarin, dabigatran, rivaroxaban or apixaban for non-valvular atrial fibrillation from July 2013 to December 2015 in Norway. We assessed prescription duration using reverse waiting time distribution. Adjusting for confounding in a Cox proportional hazards model, we estimated one-year risks for ischemic stroke, transient ischemic attack (TIA) or systemic embolism, major or clinically relevant non-major bleeding; intracranial; gastrointestinal; and other bleeding. We censored at switch of treatment or 365 days of follow-up. Results We included 30,820 treatment-naïve patients. Compared to warfarin, the adjusted hazard ratios (HR) for ischemic stroke, TIA or systemic embolism were 0.96 (95% CI 0.71–1.28) for dabigatran, 1.12 (95% CI 0.87–1.45) for rivaroxaban and 0.97 (95% CI 0.75–1.26) for apixaban. Corresponding hazard ratios for major or clinically relevant non-major bleeding were 0.73 (95% CI 0.62–0.86) for dabigatran, 0.97 (95% CI 0.84–1.12) for rivaroxaban and 0.71 (95% CI 0.62–0.82) for apixaban. Statistically significant differences of other safety outcomes compared to warfarin were fewer intracranial bleedings with dabigatran (HR 0.28, 95% CI 0.14–0.56), rivaroxaban (HR 0.40, 95% CI 0.23–0.69) and apixaban (HR 0.56, 95% CI 0.34–0.92); fewer gastrointestinal bleedings with apixaban (HR 0.70, 95% CI 0.52–0.93); and fewer other bleedings with dabigatran (HR 0.67, 95% CI 0.55–0.81) and apixaban (HR 0.70, 95% CI 0.59–0.83). Conclusion After 1 year follow-up in treatment-naïve patients initiating oral anticoagulation for non-valvular atrial fibrillation, all DOACs were similarly effective as warfarin in prevention of ischemic stroke, TIA or systemic embolism. Safety from bleedings was similar or better, including fewer intracranial bleedings with all direct oral anticoagulants, fewer gastrointestinal bleedings with apixaban and fewer other bleedings with dabigatran and apixaban.

ObjectiveTo study time trends in incidence of atrial fibrillation (AF) in the entire Norwegian population from 2004 to 2014, by age and sex, and to estimate the prevalence of AF at the end of the study period.MethodsA national cohort of patients with AF (≥18 years) was identified from inpatient admissions with AF and deaths with AF as underlying cause (1994–2014), and AF outpatient visits (2008–2014) in the Cardiovascular Disease in Norway (CVDNOR) project. AF admissions or out-of-hospital death from AF, with no AF admission the previous 10 years defined incident AF. Age-standardised incidence rates (IR) and incidence rate ratios (IRR) were calculated. All AF cases identified through inpatient admissions and outpatient visits and alive as of 31 December 2014 defined AF prevalence.ResultsWe identified 175 979 incident AF cases (30% primary diagnosis, 69% secondary diagnosis, 0.6% out-of-hospital deaths). AF IRs (95% confidence intervals) per 100 000 person years were stable from 2004 (433 (426–440)) to 2014 (440 (433–447)). IRs were stable or declining across strata of sex and age with the exception of an average yearly increase of 2.4% in 18–44 year-olds: IRR 1.024 (1.014–1.034). In 2014, the prevalence of AF in the adult population was 3.4%.ConclusionsWe found overall stable IRs of AF for the adult Norwegian population from 2004 to 2014. The prevalence of AF was 3.4% at the end of 2014, which is higher than reported in previous studies. Signs of an increasing incidence of early-onset AF (<45 years) are worrying and need further investigation.

Purpose A pervasive problem in registry‐based pharmacoepidemiological studies is what exposure duration to assign to individual prescriptions. The parametric waiting time distribution (WTD) has been proposed as a method to estimate such durations. However, when prescription durations vary due to seasonal stockpiling, WTD estimates will vary with choice of index date. To counter this, we propose using random index dates. Methods Within a calendar period of a given length, δ, we randomly sample individual index dates. We include the last prescription redemption prior to the index date in the analysis. Only redemptions within distance δ of the index date are included. In a simulation study with varying types and degrees of stockpiling at the end of the year, we investigated bias and precision of the reverse WTD with fixed and random index dates, respectively. In addition, we applied the new method to estimate durations of Norwegian warfarin prescriptions in 2014. Results In simulation settings with stockpiling, the reverse WTD with random index dates had low relative biases (−0.65% to 6.64%) and high coverage probabilities (92.0% to 95.3%), although when stockpiling was pronounced, coverage probabilities decreased (2.7% to 85.8%). Using a fixed index date was inferior. The estimated duration of warfarin prescriptions in Norway using random index dates was 131 (130; 132) days. Conclusions In the presence of seasonal stockpiling, the WTD with random index dates provides estimates of prescription durations, which are more stable, less biased and with better coverage when compared to using a fixed index date.

It is necessary to carry out large observational studies to generate robust evidence about the safety of drugs used during pregnancy. In the Nordic countries, nationwide population-based health registers that document all births and dispensed prescribed drugs are valuable resources for such studies. A common data model (CDM) is a data harmonization and structuring tool that enables a unified and streamlined analytic approach for studies including data from multiple countries or databases. We describe a CDM developed for the Nordic Pregnancy Drug Safety Studies (NorPreSS), including details on data sources and structure of the data tables. We also provide an overview of the advantages and disadvantages of the approach (e.g. sharing of data analysis programs versus extra initial work to create CDM datasets from raw data).

The uptake of DOACs was rapid and spurred an increase in new users of oral anticoagulants for atrial fibrillation from 2010 to 2015 in Norway. The mean CHADS-VASc score did not change substantially during this period. Vascular disease, heart failure, and diabetes were associated with initiation of warfarin, and previous stroke, age 65-74 and female sex with initiation of DOACs.