AimsThe aim of this study was to compare the clinical effectiveness and safety of direct oral anticoagulants (DOACs) in patients with atrial fibrillation (AF) in routine clinical practice.MethodsThis retrospective cohort study used linked administrative data. The study population (n = 14 577) included patients with a diagnosis of AF (confirmed in hospital) who initiated DOAC treatment in Scotland between August 2011 and December 2015. Multivariate Cox proportional hazard models were used to estimate hazard ratios of thromboembolic events, mortality and bleeding events.ResultsNo differences between the DOACs were observed with regard to the risk of stroke, systemic embolism or cardiovascular death. In contrast, the risk of myocardial infarction was higher among patients prescribed apixaban in comparison to those on rivaroxaban (HR 1.67, 95% CI 1.02‐2.71), and all‐cause mortality was higher among rivaroxaban patients in contrast to both apixaban (1.22 [1.01–1.47]) and dabigatran (1.55 [1.16–2.05]) patients; rivaroxaban patients also had a higher risk of pulmonary embolism than apixaban patients (5.27 [1.79–15.53]). The risk of other major bleeds was higher among rivaroxaban patients compared to apixaban (1.50 [1.10–2.03]) and dabigatran (1.58 [1.01–2.48]) patients; the risks of gastrointestinal bleeds and overall bleeding were higher among rivaroxaban patients than among apixaban patients (1.48 [1.01–2.16] and 1.52 [1.21–1.92], respectively).ConclusionsAll DOACs were similarly effective in preventing strokes and systemic embolisms, while patients being treated with rivaroxaban exhibited the highest bleeding risks. Observed differences in the risks of all‐cause mortality, myocardial infarction and pulmonary embolism warrant further research.

PurposeTo report the use of direct oral anticoagulants (DOACs) for stroke prevention in patients with atrial fibrillation in Scotland and advocate the standardisation of drug utilisation research methods.MethodsRetrospective cohort study using linked administrative data. Patients included those with a diagnosis of atrial fibrillation (confirmed in hospital) who received a first prescription for a DOAC (dabigatran, rivaroxaban, or apixaban) from September 2011 to June 2014. Drug utilisation measures included discontinuation, persistence, and adherence.ResultsA total of 5398 patients (mean CHA2DS2‐VASc score 2.98 [SD 1.71], 89.7% with ≥5 concomitant medicines) were treated with DOACs for a median of 228 days (interquartile range 105‐425). Of 35.6% who discontinued DOAC treatment, 11.0% switched to warfarin, and 48.3% reinitiated DOACs. Persistence after 12 and 18 months was 75.9% and 69.8%, respectively. Differences between individual DOACs were observed: Discontinuation rates ranged from 20.4% (apixaban) to 60.6% (dabigatran) and 12 months persistence from 60.1% (dabigatran) to 85.5% (apixaban). Adherence to treatment with all DOACs was good: Overall DOAC median medication refill adherence was 102.9% (interquartile range 88.9%‐115.5%), and 82.3% of patients had a medication refill adherence > 80%.ConclusionsIn Scotland, adherence to DOAC treatment was good, and switching from DOAC to warfarin was low. However, discontinuation and persistence rates were variable—although treatment interruptions were often temporary.To decrease the inconsistencies in drug utilisation methods and facilitate meaningful study comparison, the use of a coherent framework—using a combination of discontinuation, persistence, and adherence—and the standardisation of measurements is advocated.

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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.

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Background/Methods: Melatonin, the neurohormone for darkness, mediates photoperiod-dependent changes in physiology and behavior by targeting specific membrane-bound receptors (MT1 and MT2). In the present study, we investigated the impact of MT1 receptor deficiency on feeding behavior, locomotor activity and mRNA expression levels encoding for the polypeptide pro-opiomelanocortin (Pomc) and neuropeptide Y (Npy) in the hypothalamic arcuate nucleus (ARC) and the adenohypophysis [pars distalis (PD) and pars intermedia (PI)] in a comparison between wild-type (WT) and MT1-deficient (MT1-/-) mice. Results: The MT1-/- mice spent significantly more time feeding than the WT mice, while the general locomotor behavior, body weight and the total amount of food consumed did not differ between both genotypes. The nocturnal expression levels of Pomc in the ARC and PD were significantly higher in WT as compared to MT1-/- mice and exogenous melatonin administered during the light phase stimulated Pomc expression in WT mice only. No differences were found between WT and MT1-/- mice with regard to Pomc expression levels in the PI. Conclusion: Thus, the MT1-mediated signaling stimulates Pomc expression in a region-specific pattern. Since the MT1-mediated changes in Pomc expression do not elicit direct orexigenic or anorexigenic effects, such effects are obviously mediated by regulatory systems downstream of the Pomc mRNA (e.g. cleavage and release of POMC derivatives), which are independent of MT1 signaling.

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Purpose New treatments are introduced into standard care based on clinical trial results. However, it is not clear if these benefits are reflected in the broader population. This study analysed the clinical outcomes of patients with metastatic castration‐resistant prostate cancer, treated with abiraterone and enzalutamide, within the Scottish National Health Service. Methods Retrospective cohort study using record linkage of routinely collected healthcare data (study period: February 2012 to February 2017). Overall survival (OS) was analysed using Kaplan‐Meier methods and Cox Proportional Hazard models; a subgroup analysis comprised potentially trial‐eligible patients. Results Overall, 271 patients were included and 73.8% died during the study period. Median OS was poorer than in the pivotal trials, regardless of medication and indication: 10.8 months (95% confidence interval [CI] 8.6‐15.1) and 20.9 months (95% CI 14.9‐29.0) for abiraterone, and 12.6 months (95% CI 10.5‐18.2) and 16.0 months (95% CI 9.8—not reached) for enzalutamide, post and pre chemotherapy, respectively. Only 46% of patients were potentially “trial eligible” and in this subgroup OS improved. Factors influencing survival included baseline performance status, and baseline prostate‐specific antigen, alkaline phosphatase, and albumin levels. Conclusions Poorer prognostic features of non‐trial eligible patients impact real‐world outcomes of cancer medicines. Electronic record linkage of routinely collected healthcare data offers an opportunity to report outcomes on cancer medicines at scale and describe population demographics. The availability of such observational data to supplement clinical trial results enables patients and clinicians to make more informed treatment decisions, and policymakers to contextualise trial findings.