Introduction: The appreciable growth in pharmaceutical expenditure has resulted in multiple initiatives across Europe to lower generic prices and enhance their utilization. However, considerable variation in their use and prices.Objective: Assess the influence of multiple supply and demand-side initiatives across Europe for established medicines to enhance prescribing efficiency before a decision to prescribe a particular medicine. Subsequently utilize the findings to suggest potential future initiatives that countries could consider.Method: An analysis of different methodologies involving cross national and single country retrospective observational studies on reimbursed use and expenditure of PPIs, statins, and renin-angiotensin inhibitor drugs among European countries.Results: Nature and intensity of the various initiatives appreciably influenced prescribing behavior and expenditure, e.g., multiple measures resulted in reimbursed expenditure for PPIs in Scotland in 2010 56% below 2001 levels despite a 3-fold increase in utilization and in the Netherlands, PPI expenditure fell by 58% in 2010 vs. 2000 despite a 3-fold increase in utilization. A similar picture was seen with prescribing restrictions, i.e., (i) more aggressive follow-up of prescribing restrictions for patented statins and ARBs resulted in a greater reduction in the utilization of patented statins in Austria vs. Norway and lower utilization of patented ARBs vs. generic ACEIs in Croatia than Austria. However, limited impact of restrictions on esomeprazole in Norway with the first prescription or recommendation in hospital where restrictions do not apply. Similar findings when generic losartan became available in Western Europe.Conclusions: Multiple demand-side measures are needed to influence prescribing patterns. When combined with supply-side measures, activities can realize appreciable savings. Health authorities cannot rely on a “spill over” effect between classes to affect changes in prescribing.

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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.

T he corticosteroid hormones cortisol and aldosterone are important determinants of blood pressure and cardiovascular risk. Excess cortisol results in Cushing syndrome, associated with hypertension and accelerated atherogenesis, 1 whereas excess aldosterone, in primary aldosteronism, leads to severe hypertension with markedly increased risk of myocardial infarction, stroke, and left ventricular hypertrophy. 2 The frequency of primary aldosteronism in hypertensive patients is now accepted to be ≈5% to 10% 3,4 ; recent studies show that aldosterone is an important predictor of cardiovascular risk and outcome, with levels toward the high end of the normal range predicting blood pressure and development of hypertension. 5 Controlled release of corticosteroids from the adrenal cortex is achieved, in part, by strictly regulated expression of genes encoding the steroidogenic enzymes that catalyze their biosynthetic pathways. The final enzymes in this process are particularly important: 11β-hydroxylase (CYP11B1) is responsible for the terminal conversion that produces cortisol, whereas aldosterone synthase (CYP11B2) fulfills the equivalent role in aldosterone production. The CYP11B1 and CYP11B2 genes lie in tandem on human chromosome 8 and have ≈93% sequence similarity within their coding regions. 6 Changes in the expression of these genes have been observed in cases of aldosterone-producing adenoma (APA). 7,8 In addition, the rate of aldosterone production is known to be heritable, 9 and several polymorphisms in the CYP11B1 and CYP11B2 genes associate with altered 11β-hydroxylation, aldosterone production, or hypertension. 10 Although it is relatively straightforward to propose mechanisms by which polymorphisms in the 5′ regulatory regions of these genes, such as rs1799998, 11 could affect transcription, it is not immediately apparent how polymorphisms located in introns or the 3′ untranslated region (3′ UTR) of these genes could alter expression. However, in recent years, microRNAs (miRNAs) have emerged as key regulatory molecules that regulate ≈30% of human genes.12 They are endogenous, single-stranded noncoding RNA molecules of ≈22 nucleotides, produced through a series of maturation reactions mediated by the RNase III enzymes, Drosha and Dicer.13 These post-transcriptional regulatory molecules exert their effects by targeting the 3′ UTR of specific mRNAs. Through mRNA destabilization Abstract-Dysregulation of aldosterone or cortisol production can predispose to hypertension, as seen in aldosteroneproducing adenoma, a form of primary aldosteronism. We investigated the role of microRNA (miRNA) in their production, with particular emphasis on the CYP11B1 (11β-hydroxylase) and CYP11B2 (aldosterone synthase) genes, which produce the enzymes responsible for the final stages of cortisol and aldosterone biosynthesis, respectively. Knockdown of Dicer1, a key enzyme in miRNA maturation, significantly altered CYP11B1 and CYP11B2 expression in a human adrenocortical cell line. Screening of nondiseased human adrenal and aldost...