Background and Objectives: Appropriate dosing of direct oral anticoagulants (DOACs) is required to avoid under- and overdosing that may precipitate strokes or thromboembolic events and bleedings, respectively. Our objective was to analyze the appropriateness of DOAC dosing according to the summaries of product characteristics (SmPC). Furthermore, determinants for inappropriate prescribing were investigated.Methodology: Retrospective cohort study of hospitalized patients aged ≥60 years with at least one DOAC intake during hospital stay. Descriptive analyses were used to summarize the characteristics of the study population. Chi-square test was used to evaluate differences between DOACs. Binary logistic regression analysis was performed to assess determinants for inappropriate prescribing.Results: For the 772 included patients, inappropriate dosing occurred in 25.0% of hospitalizations with 23.4, 21.9, and 29.7% for dabigatran, rivaroxaban, and apixaban, respectively (p = 0.084). Underdosing was most prevalent for apixaban (24.5%) compared to dabigatran (14.0%) and rivaroxaban (12.8%), p < 0.001. In 67.1% (apixaban), 26.7% (dabigatran), and 51.2% (rivaroxaban) of underdosed DOAC cases according to the SmPC, the dose would be considered appropriate according to the European Heart Rhytm Association (EHRA) guidelines. Overdosing was observed in 4.5% (apixaban), 4.7% (dabigatran), and 7.7% (rivaroxaban) of patients. For all DOACs, our analysis showed an age ≥80 years (p = 0.036), use of apixaban (p = 0.026), DOAC use before hospitalization (p = 0.001), intermediate renal function (p = 0.014), and use of narcotic analgesics (p = 0.019) to be associated with a higher rate of inappropriate prescribing. Undergoing surgery was associated with a lower odds of inappropriate prescribing (p = 0.012). For rivaroxaban, use of medication for hypothyroidism (p = 0.027) and the reduced dose (p < 0.001) were determinants for inappropriate prescribing. Treatment of venous thromboembolism was associated with less errors (p = 0.002). For apixaban, severe renal insufficiency (p < 0.001) and initiation in hospital (p = 0.016) were associated with less and the reduced dose (p < 0.001) with more inappropriate prescribing. No determinants were found in the dabigatran subgroup.Conclusions: Inappropriate DOAC prescribing is frequent with underdosing being the most common drug related problem when using the SmPC as reference. More appropriate prescriptions were found when taking the EHRA guidelines into account. Analysis of determinants of inappropriate prescribing yielded insights in the risk factors associated with inappropriate DOAC prescriptions.
For decades, angiotensin (Ang) II was considered as the end product and the only bioactive peptide of the renin-angiotensin system (RAS). However, later studies revealed biological activity for other Ang fragments. Amongst those, Ang IV has drawn a lot of attention since it exerts a wide range of central and peripheral effects including the ability to enhance learning and memory recall, anticonvulsant and anti-epileptogenic properties, protection against cerebral ischemia, activity at the vascular level and an involvement in atherogenesis. Some of these effects are AT(1) receptor dependent but others most likely result from the binding of Ang IV to insulin-regulated aminopeptidase (IRAP) although the exact mechanism(s) of action that mediate the Ang IV-induced effects following this binding are until now not fully known. Nevertheless, three hypotheses have been put forward: since Ang IV is an inhibitor of the catalytic activity of IRAP, its in vivo effects might result from a build-up of IRAP's neuropeptide substrates. Second, IRAP is co-localized with the glucose transporter GLUT4 in several tissue types and therefore, Ang IV might interact with the uptake of glucose. A final and more intriguing hypothesis ascribes a receptor function to IRAP and hence an agonist role to Ang IV. Taken together, it is clear that further work is required to clarify the mechanism of action of Ang IV. On the other hand, a wide range of studies have made it clear that IRAP might become an important target for drug development against different pathologies such as Alzheimer's disease, epilepsy and ischemia.
Brain angiotensin II (Ang II) induces tonic sympathoexcitatory effects through AT1 receptor stimulation of glutamatergic neurons and sympathoinhibitory effects via GABAergic neurons in the rostral ventrolateral medulla, the brainstem 'pressor area'. NADPH-derived superoxide production and reactive oxygen species signalling is critical in these actions, and AT2 receptors in the rostral ventrolateral medulla appear to mediate opposing effects on sympathetic outflow. In the hypothalamic paraventricular nucleus, Ang II has AT1 receptor-mediated sympathoexcitatory effects and enhances nitric oxide formation, which in turn inhibits the Ang II effects through a GABAergic mechanism. Ang II also decreases the tonic sympathoinhibitory effect of gamma amino butyric acid within the paraventricular nucleus. Angiotensin III and Angiotensin IV increase blood pressure via brain AT1 receptor stimulation. Angiotensin (1-7) influences cardiovascular function through a specific Mas-receptor. This review examines the evidence that brain angiotensin peptides, glutamate, gamma amino butyric acid and nitric oxide interact within the rostral ventrolateral medulla and paraventricular nucleus to control sympathetic tone and blood pressure.
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