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Primary Objective: To determine the effects of pimobendan 2.5 and 5 mg daily on exercise capacity in patients with chronic heart failure.Design: A randomised, double blind, placebo controlled trial of the addition of pimobendan to conventional treatment with a minimum follow up of 24 weeks.Setting: Outpatient cardiology clinics in six European countries.Patients: 317 patients with stable symptomatic heart failure, objectively impaired exercise capacity, and an ejection fraction of 45% or lower who were treated with at least an angiotensin converting enzyme inhibitor and a diuretic and who tolerated a test dose of pimobendan.Results: Compared with placebo, both pimobendan 2.5 and 5 mg daily improved exercise duration (bicycle ergometry) by 6% (P = 0.03 and 0.05) after 24 weeks of treatment. At that time 63% of patients allocated to pimobendan and 59% of those allocated to placebo were alive and able to exercise to at least the same level as at entry (P = 0.5). No significant effects on oxygen consumption (assessed in a subgroup of patients) and on quality of life (assessed by questionnaire) were observed. Pimobendan was well tolerated. Proarrhythmic effects (24-hour electrocardiography) were not observed. In both pimobendan groups combined the hazard of death was 1.8 (95% confidence interval 0.9 to 3.5) times higher than in the placebo group.Conclusions: Pimobendan improves exercise capacity in patients with chronic heart failure who are also on conventional treatment. The balance between benefit and risk of treatment with this compound remains to be established however. [ABSTRACT FROM AUTHOR]

Background: Dabigatran is effective and safe for stroke prevention in patients with atrial fibrillation and for venous thromboembolism prevention and treatment. In Canada, APO-dabigatran, a generic formulation, has been approved based on a bioequivalence study, but its bioavailability in settings of reduced gastric acidity has not been examined., Methods: Treatment With A PO- D abigatran A bsorption (TADA) was an open-label crossover study in 46 healthy male volunteers, comparing the absorption of APO-dabigatran (150 mg) with vs without rabeprazole. The primary outcome was the 24-hour total dabigatran exposure as measured by area under the curve (AUC) and peak concentration (C max )., Results: Compared with no rabeprazole pretreatment, the total dabigatran AUC (geometric mean [gmean] AUC 0-tz : 567.2 vs 804 ngh/mL, and gmean AUC 0-∞ : 609.7 vs 804) and C max (gmean: 64.1 vs 104.4 ng/mL) were significantly reduced with rabeprazole. The percent gmean ratios for AUC 0-tz , AUC 0-∞ , and C max (with rabeprazole vs without) were 70.5% (95% confidence interval [CI]: 51.9% to 95.7%), 71.8% (95% CI: 53.1% to 96.9%), and 61.4% (95% CI: 44.1% to 85.5%), respectively. With rabeprazole, the proportions of participants with > 50% reduction in AUC 0-tz, AUC 0-∞, and C max were 32.6%, 30.4%, and 39.1%, respectively., Conclusions: When APO-dabigatran is administered with rabeprazole, the exposure to dabigatran is reduced by about 30%, which is similar to the level observed with Pradaxa when it was co-administered with a proton pump inhibitor. However, the finding that one-third of participants had a > 50% reduction in exposure is concerning, and it highlights the need for caution in patients who have, or are at risk of, reduced gastric acidity., (© 2022 The Authors.)

Background: Decision on the most appropriate oral anticoagulation therapy for stroke prevention in patients with nonvalvular atrial fibrillation is difficult because multiple treatment options are available, and these vary in their clinical effects and relevant nonclinical characteristics., Objectives: To use a multicriteria decision analysis (MCDA) to compare the oral anticoagulants apixaban, dabigatran, edoxaban, rivaroxaban, and vitamin K antagonist (VKAs; specifically warfarin) in patients with nonvalvular atrial fibrillation., Methods: We identified the evaluation criteria through a targeted literature review and clinical judgment. The final evaluation model included nine clinical events and four other criteria. We ranked possibly fatal clinical event criteria on the basis of the differences in risks of fatal events and the corresponding window of therapeutic opportunity, as observed in clinical trials. Clinical judgment was used to rank other criteria. Full criteria ranking was used to calculate centroid weights, which were combined with individual treatment performances to estimate the overall value score for each treatment., Results: Using such an MCDA, dabigatran yielded the highest overall value, approximately 6% higher than that of the second-best treatment, apixaban. Dabigatran also had the highest first-rank probability (0.72) in the probabilistic sensitivity analysis. Rivaroxaban performed worse than the other non-VKA oral anticoagulants, but better than VKAs (with both having 0.00 first-rank probability). The results were insensitive to changes in model structure., Conclusions: When all key oral anticoagulant value criteria and their relative importance are investigated in an MCDA, dabigatran appears to rank the highest and warfarin the lowest., (Copyright © 2017 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

At least 30 million people worldwide carry a diagnosis of atrial fibrillation (AF), and many more suffer from undiagnosed, subclinical, or 'silent' AF. Atrial fibrillation-related cardiovascular mortality and morbidity, including cardiovascular deaths, heart failure, stroke, and hospitalizations, remain unacceptably high, even when evidence-based therapies such as anticoagulation and rate control are used. Furthermore, it is still necessary to define how best to prevent AF, largely due to a lack of clinical measures that would allow identification of treatable causes of AF in any given patient. Hence, there are important unmet clinical and research needs in the evaluation and management of AF patients. The ensuing needs and opportunities for improving the quality of AF care were discussed during the fifth Atrial Fibrillation Network/European Heart Rhythm Association consensus conference in Nice, France, on 22 and 23 January 2015. Here, we report the outcome of this conference, with a focus on (i) learning from our 'neighbours' to improve AF care, (ii) patient-centred approaches to AF management, (iii) structured care of AF patients, (iv) improving the quality of AF treatment, and (v) personalization of AF management. This report ends with a list of priorities for research in AF patients., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Purpose: Three new oral anticoagulants (NOACs) have recently become available in the United Kingdom as an alternative to warfarin in the prevention of stroke and systemic embolism in atrial fibrillation. This study examines the relative cost-effectiveness of dabigatran (BID dosing of 150 mg or 110 mg based on patient age), rivaroxaban, and apixaban from a UK payer perspective., Methods: A previously published model that follows up patients through treatment of atrial fibrillation during a lifetime was adapted to allow comparison of the 3 NOACs and warfarin. Acute thromboembolic and bleeding events, as well as long-term consequences of stroke, intracranial hemorrhage, and acute myocardial infarction, were tracked. Relative efficacy was calculated from a formal indirect treatment comparison using data from the 3 key trials (Randomized Evaluation of Long-Term Anticoagulation Therapy, Rivaroxaban Once-daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation, and Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation) of the NOACs. Data from the rivaroxaban trial were adjusted for the difference in international normalized ratio control among warfarin patients versus the other 2 trials. Model outputs included total costs, event rates, and quality-adjusted life-years., Findings: Among the patients taking NOACs, those taking dabigatran had the highest total QALYs (7.68 QALYs), followed by apixaban (7.63 QALYs) and rivaroxaban (7.47 QALYs). Patients taking dabigatran had the lowest total lifetime costs (£23,342), followed by apixaban (£24,014) and rivaroxaban (£25,220). The differences between dabigatran and apixaban were modest but consistent in sensitivity analyses, with the directionality only changing at the limits of the CIs for the relative risks of ischemic stroke or intracranial hemorrhage or when assuming that both treatment discontinuation and post-event disability rates differ by drug., Implications: Dabigatran was found to be economically dominant over rivaroxaban and apixaban in the UK setting. These economic findings are based on relative clinical efficacy from an indirect treatment comparison and would benefit from any data of direct comparisons of the NOACs in the future., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: Two extended release (ER) formulations of morphine sulphate (30 mg each), Oramorph SR (test) and a marketed reference formulation (MST Mundipharma Retardtabletten), were investigated for their relative bioavailability at steady-state:, Methods: The study was designed as a single-centre, open-label, two-period crossover, pharmacokinetic comparison in 28 healthy male volunteers and was completed in 23 subjects. The determination of morphine and its metabolite morphine-6-glucuronide in plasma was done by HPLC with electrochemical detection after solid-phase extraction., Results: Under steady-state conditions in the first dosing interval, mean maximum plasma concentrations for morphine were 19.1 ng/ml (CV% 41) for Oramorph SR 30 mg and 19.1 ng/ml (CV% 33) for MST-30 Mundipharma Retardtabletten. Geometric mean AUC(0-12) values were calculated as 108 ngxh/ml (CV% 40) for Oramorph SR 30 mg and as 118 ng x h/ml (CV% 30) for the reference formulation. The plasma concentrations of the major metabolite, morphine-6-glucuronide, were found to be generally in a higher range compared to the parent compound. The 90% confidence intervals of test to reference ratios calculated for all relevant parameters (AUC, C(max), PTF) for both the parent compound and morphine-6-glucuronide were all within the limits of 80 - 125%. The most frequent adverse events (AE > 10%) during Oramorph SR 30 mg treatment were headache (36%), dizziness (18%), nausea (21%), vomiting (21%) and pruritus (11%). During treatment with MST-30 Mundipharma Retardtabletten, the most frequent AEs were headache (29%), dizziness (13%), nausea (29%) and vomiting (29%)., Conclusion: The results demonstrate bioequivalence of Oramorph SR 30 mg and MST-30 Mundipharma Retardtabletten.

Background: Although observations have shown that half a tablet (0.125 mg) of brotizolam develops an adequate sedative effect in patients who cannot get to sleep, confirmatory pharmacodynamic studies are lacking., Method: In a comparative double-blind, randomized, placebo-controlled study, the hypnotic effects of 0.125 mg and 0.250 mg brotizolam, a short-acting benzodiazepine-like hetrazepine, were investigated. The concept underlying the study was that both doses are equally rapid in action onset, but differ in duration of effect. The study included 49 healthy women aged between 23 and 44 years. The nocturnal tests lasted until 2.30 am, and a concluding examination took place after breakfast. The test subjects were asked to estimate their state of well-being on visual analog scales at half-hour intervals, while concentration was tested hourly using the digit symbol substitution test (DSST) tried and tested in numerous studies on benzodiazepines., Results: Both doses proved to be equally effective after 0.5, 1.5 and 2.5 hours. While the hypnotic effect of the lower dose no longer differed from that of placebo after 3.5 hours, the larger dose still had a greater effect than both placebo and the lower dose after 4.5 hours. A hangover effect in the morning was not observed with either dose. The pharmacodynamic results indicate that the effect of the substance is readily controllable, and that half a tablet of brotizolam is an effective treatment of difficulty in getting to sleep initially or after waking prematurely., Conclusion: The results of the present study demonstrate for the first time that a half-tablet of brotizolam is an effective treatment of difficulty in getting to sleep initially or after premature wakening.

The hypnotic activity of acute doses of 0.125 mg and 0.250 mg brotizolam (CAS 57801-81-7, Lendormin) was compared in a double-blind randomised placebo-controlled study. Forty-nine healthy female volunteers aged between 23 and 44 years were enrolled. Trial medication was administered sublingually at 9:15 p.m. and 9:30 p.m., respectively. The nocturnal investigations continued until 2:30 a.m. A final examination was performed in the morning after breakfast. Every 30 min mood was measured by visual analogue scales. A computerised psychometric test (CDT) over 8 min was undertaken in order to measure continuous attention under short-term memory load. The Digit Symbol Substitution Test (DSST) was performed every hour. The CDT was not evaluable due to significant baseline differences. A statistically significant sedative effect in the DSST was already found 30 min after administration of 0.250 mg brotizolam, while the effect of 0.125 mg brotizolam just failed to reach the threshold of significance. Both treatments showed equivalent efficacy at 0.5, 1.5 and 2.5 h after administration. After 3.5 and 4.5 h there was no statistically significant difference between placebo and 0.125 mg brotizolam. After 4.5 h 0.250 mg brotizolam still showed significant hypnotic activity compared to placebo and 0.125 mg brotizolam. No treatment effects on mood were apparent according to the visual analogue scales. Furthermore, no hangover effects were detected for any of the parameters measured. The pharmacodynamic results confirmed the duration of action of more than 4.5 of h 0.250 mg brotizolam found in earlier studies and suggest that 0.125 mg is as effective as 0.250 mg with regard to sleep onset disturbances but has a shorter duration of action.