Impact of dronedarone in atrial fibrillation and flutter on stroke reduction

Christine Benn Christiansen1, Christian Torp-Pedersen1, Lars Køber21Department of Cardiology, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; 2Department of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, DenmarkBackground: Dronedarone has been developed for treatment of atrial fibrillation (AF) or atrial flutter (AFL). It is an amiodarone analogue but noniodinized and without the same adverse effects as amiodarone.Objective and methods: This is a review of 7 studies (DAFNE, ADONIS, EURIDIS, ATHENA, ANDROMEDA, ERATO and DIONYSOS) on dronedarone focusing on efficacy, safety and prevention of stroke. There was a dose-finding study (DAFNE), 3 studies focusing on maintenance of sinus rhythm (ADONIS, EURIDIS and DIONYSOS), 1 study focusing on rate control (ERATO) and 2 studies investigating mortality and morbidity (ANDROMEDA and ATHENA).Results: The target dose for dronedarone was established in the DAFNE study to be 400 mg twice daily. Both EURIDIS and ADONIS studies demonstrated that dronedarone was superior to placebo for maintaining sinus rhythm. However, DIONYSOS found that dronedarone is less efficient at maintaining sinus rhythm than amiodarone. ERATO concluded that dronedarone reduces ventricular rate in patients with chronic AF. The ANDROMEDA study in patients with severe heart failure was discontinued because of increased mortality in dronedarone group. Dronedarone reduced cardiovascular hospitalizations and mortality in patients with AF or AFL in the ATHENA trial. Secondly, according to a post hoc analysis a significant reduction in stroke was observed (annual rate 1.2% on dronedarone vs 1.8% on placebo, respectively [hazard ratio 0.66, confidence interval 0.46 to 0.96, P = 0.027]). In total, 54 cases of stroke occurred in 3439 patients (crude rate 1.6%) receiving dronedarone compared to 76 strokes in 3048 patients on placebo (crude rate 2.5%), respectively.Conclusion: Dronedarone can be used for maintenance of sinus rhythm and can reduce stroke in patients with AF who receive usual care, which includes antithrombotic therapy and heart rate control.Keywords: atrial fibrillation, stroke, dronedaron

Intra-articular treatment of hip osteoarthritis: a randomized trial of hyaluronic acid, corticosteroid, and isotonic saline

SummaryObjectiveHyaluronic acid (HA) and corticosteroids are both widely used for intra-articular treatment of knee osteoarthritis (OA). We examined the effect of both drugs in intra-articular treatment for hip OA.MethodsOne hundred and one patients with hip OA were included in a prospective double blind study, using a randomized controlled trial with a three-armed parallel-group design. Three ultrasound-guided, intra-articular injections were given at 14 days interval. The primary outcome measure was ‘pain on walking’, registered on a visual analogue scale (VAS). Evaluation was performed at baseline and after 14, 28 and 90 days. The study adhered to the Consolidated Standards of Reporting Trials. All analyses were based on intention-to-treat analyses, and used ‘mixed-procedures’ with the baseline-observation as covariate.ResultsThere were no significant interactions with respect to Treatment×Time for any of the analyzed outcome measures. There was a significant treatment effect for ‘pain on walking’ (P=0.044) due to a significant improvement following corticosteroid compared to saline with an effect-size of 0.6 (95% confidence interval: 0.1–1.1, P=0.021). By contrast, HA compared to saline had an effect size of 0.4 (−0.1 to 0.9; P=0.13). The peak-effect was obtained after 2 weeks. There was no difference between the treatment groups at endpoint. No significant side effects of the injections were observed.ConclusionsPatients treated with corticosteroids experienced significant improvement during the 3 months of intervention, with an effect size indicating a moderate clinical effect. Although a similar significant result following treatment with HA could not be shown, the effect size indicated a small clinical improvement. A higher number of patients in future HA studies would serve to clarify this point

Oral tranexamic acid and thrombosis risk in women

BACKGROUND: Oral tranexamic acid is effective for heavy menstrual bleeding, but the thrombosis risk with this treatment is largely not studied. METHODS: Using nationwide registries, we assessed associations between use of oral tranexamic acid and risk of deep-vein thrombosis or pulmonary embolism and arterial thrombosis in heart or brain in a nationwide historical prospective cohort of Danish women aged 15 to 49 years in the period 1996–2017. Exclusion criteria included potential confounding factors such as history of thromboembolism, anticoagulation therapy, thrombophilia, and cancer. FINDINGS: Among 2·0 million women followed for 13·8 million person-years, 3,392 venous thromboembolisms and 4,198 arterial thromboses occurred. A total of 63,896 women (3·2%) filled 146,729 prescriptions of oral tranexamic acid during follow-up with median filled prescription per user being one of 15 g. The age-standardised incidence rate of venous thromboembolism was 11·8 (95% CI 4·6 to 30·2) per 10,000 person-years in oral tranexamic acid use compared to 2·5 (2·4 to 2·6) per 10,000 person-years in non-use. For arterial thrombosis, the age-standardised incidence rate per 10,000 person-years was 3·4 (1·1 to 10·7) among exposed compared to 3·0 (2·9 to 3·1) in non-exposed. Comparing oral tranexamic acid use with non-use, the adjusted incidence rate ratio was 4·0 (1·8 to 8·8) for venous thromboembolism and 1·3 (0·4 to 4·2) for arterial thrombosis. Number needed to harm per five days of treatment was 78,549 women for venous thromboembolism. INTERPRETATION: We found use of oral tranexamic acid to be positively associated with venous thromboembolism. However, number needed to harm per five days of treatment was high

Risk of stroke, myocardial infarction, and death among patients with retinal artery occlusion and the effect of antithrombotic treatment

PURPOSE: To evaluate the risk of future stroke, myocardial infarction (MI), and death of patients with retinal artery occlusion (RAO) and the effect of various antithrombotic treatments as secondary prevention. METHODS: This cohort study was based on nationwide health registries and included the entire Danish population from 2000 to 2018. All patients with RAO were identified and their adjusted risks of stroke, MI, or death in time periods since RAO were compared with those of the Danish population. Furthermore, antithrombotic treatment of patients with RAO was determined by prescription claims, and the association with the risk of stroke, MI, or death was assessed using multivariate Poisson regression models and expressed as rate ratios (RR) with 95% confidence intervals (95% CIs). RESULTS: After inclusion, 6628 individuals experienced a first-time RAO, of whom 391 had a stroke, 66 had a MI, and 402 died within the first year after RAO. RAO was associated with an increased risk of stroke, MI, or death which persisted for more than 1 year for all three outcomes but was highest on days 3 to 14 after RAO for stroke, with an adjusted RR of 50.71 (95% CI, 41.55–61.87), and on days 14 to 90 after RAO for MI and death, with adjusted RRs of 1.98 (95% CI, 1.25–3.15) and 1.64 (95% CI, 1.28–189), respectively. Overall, antithrombotic treatment was not associated with any protective effect the first year. CONCLUSIONS: Patients with RAO had an increased risk of stroke, MI, or death. No protective effect of antithrombotic treatment was shown. TRANSLATIONAL RELEVANCE: These findings are relevant to the management of patients with RAO

Calcium/sodium exchange in purified secretory vesicles from bovine neurohypophyses

Purified secretory vesicles isolated from bovine neurohypophyses take up Na+ under the same circumstances where an efflux of Ca2+ takes place, suggesting a Na+/Ca2+ exchange. Potassium cannot substitute for Na+ in this process. Also, a Ca2+/Ca2+ exchange can occur. Inhibiting the latter process by Mg2+ allowed to estimate an apparent KM of 0.7 μM free Ca2+ and a maximal uptake of 1.5 nmol × mg protein−1 × min−1 Ca2+ in exchange for Na+. The vesicles did not contain plasma membrane marker (Na+/K+ ATPase) as shown by distribution analyses on the density gradients on which they were purified. Similarly, distribution studies also showed that no other ATPase activity could be detected in the purified vesicle fraction. It is concluded that a Na+/Ca2+ exchange is operating across the secretory vesicle membrane and that it is not directly dependent on ATP hydrolysis