Risk of Major Bleeding in Patients With Atrial Fibrillation Taking Dronedarone in Combination With a Direct Acting Oral Anticoagulant (From a U.S. Claims Database).

Dronedarone may increase exposure and the risk of major bleeding when prescribed with a direct oral anticoagulant (DOAC). This retrospective cohort study examined the risk of the first occurrence of major bleeding (hospitalization or emergency room visit for gastrointestinal [GI] bleeding, intracranial hemorrhage [ICH], or bleeding at other sites) among new users of apixaban, dabigatran, and rivaroxaban in patients with AF ≥18 years (January 1, 2007 to September 30, 2017) from the United States Truven Health MarketScan claims, comparing concomitant users of dronedarone to DOAC alone users in patients with atrial fibrillation (AF). No increased risk of major bleeding was associated with use of dronedarone and apixaban (adjusted Hazard Ratio [aHR]: 0.69 [95% confidence interval [CI]: 0.40, 1.17], p = 0.16), a modestly increased risk of GI bleeding but not overall bleeding was associated with use of dronedarone and dabigatran (aHR bleeding: 1.18 [95% CI: 0.89, 1.56], p = 0.26; aHR GI bleeding: 1.40 [95% CI: 1.01, 1.93]; p = 0.04) and an increased risk of overall bleeding, driven by GI bleeding, was associated with use of dronedarone and rivaroxaban (aHR bleeding: 1.31 [95% CI: 1.01, 1.69]; p = 0.04; aHR GI bleeding: 1.39 [95% CI: 0.98, 1.95]; p = 0.06), compared to each DOAC respectively. There was no increased risk of ICH associated with combined use of dronedarone and any DOAC. Prospective analyses, preferably randomized controlled studies, are needed to further explore the risk of major bleeding with concomitant use of DOACs and CYP3A4/P-gp inhibitors such as dronedarone.

Evaluating the Risk of Digitalis Intoxication Associated With Concomitant Use of Dronedarone and Digoxin Using Real-World Data.

PURPOSE: Dronedarone may increase digoxin plasma levels through inhibition of P-glycoprotein. Using real-world data, we evaluated the risk of digitalis intoxication in concomitant users of dronedarone and digoxin compared digoxin-alone users. METHODS: We used the Clinformatics DataMart, a US claims database, to identify adult patients with atrial fibrillation (AF) or atrial flutter (AFL) who concomitantly used dronedarone and digoxin and those who used digoxin alone between July 2009 and March 2016. Digitalis intoxication during follow-up until March 2016 was ascertained using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) and International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM). Adjusted hazard ratios (HR) for digitalis intoxication in concomitant users versus users of digoxin alone were estimated, controlling for age, sex, cohort entry year, number of medical encounters for AF or AFL, history of congestive heart failure, diabetes, hypertension, stroke, myocardial infarction, renal failure, use of drugs interacting with digoxin, and digoxin dose. FINDINGS: Overall, 524 concomitant users and 32,459 users of digoxin alone were identified, among which 3 and 301 events of digitalis intoxication occurred during follow-up, respectively. Incidence rates were 17.25 and 9.17 cases per 1000 person-years, respectively. The adjusted HR for digitalis intoxication in concomitant users versus users of digoxin alone was 1.56 (95% CI, 0.50-4.88; P = 0.45). When digitalis intoxication was defined by ICD-9-CM and ICD-10-CM codes accompanied by laboratory testing for digoxin/digitoxin or hospitalization within 30 days, no events occurred in the concomitant users and 40 events occurred in the users of digoxin alone (incidence rate of 1.22 cases per 1000 person-years). IMPLICATIONS: Concomitant use of dronedarone and digoxin was uncommon in this study, and no significant increase in the risk of digitalis intoxication with concomitant use was found.

Endothelial-protective effects of a G-protein-biased sphingosine-1 phosphate receptor-1 agonist, SAR247799, in type-2 diabetes rats and a randomized placebo-controlled patient trial.

AIMS: SAR247799 is a G-protein-biased sphingosine-1 phosphate receptor-1 (S1P1 ) agonist designed to activate endothelial S1P1 and provide endothelial-protective properties, while limiting S1P1 desensitization and consequent lymphocyte-count reduction associated with higher doses. The aim was to show whether S1P1 activation can promote endothelial effects in patients and, if so, select SAR247799 doses for further clinical investigation. METHODS: Type-2 diabetes patients, enriched for endothelial dysfunction (flow-mediated dilation, FMD <7%; n = 54), were randomized, in 2 sequential cohorts, to 28-day once-daily treatment with SAR247799 (1 or 5 mg in ascending cohorts), placebo or 50 mg sildenafil (positive control) in a 5:2:2 ratio per cohort. Endothelial function was assessed by brachial artery FMD. Renal function, biomarkers and lymphocytes were measured following 5-week SAR247799 treatment (3 doses) to Zucker diabetic fatty rats and the data used to select the doses for human testing. RESULTS: The maximum FMD change from baseline vs placebo for all treatments was reached on day 35; mean differences vs placebo were 0.60% (95% confidence interval [CI] -0.34 to 1.53%; P = .203) for 1 mg SAR247799, 1.07% (95% CI 0.13 to 2.01%; P = .026) for 5 mg SAR247799 and 0.88% (95% CI -0.15 to 1.91%; P = .093) for 50 mg sildenafil. Both doses of SAR247799 were well tolerated, did not affect blood pressure, and were associated with minimal-to-no lymphocyte reduction and small-to-moderate heart rate decrease. CONCLUSION: These data provide the first human evidence suggesting endothelial-protective properties of S1P1 activation, with SAR247799 being as effective as the clinical benchmark, sildenafil. Further clinical testing of SAR247799, at sub-lymphocyte-reducing doses (≤5 mg), is warranted in vascular diseases associated with endothelial dysfunction.