Background Dronedarone is a new multichannel blocker for atrial fibrillation (AF) previously demonstrated to have both rhythm and rate control properties in paroxysmal and persistent AF. The Efficacy ...and safety of dRonedArone for The cOntrol of ventricular rate during atrial fibrillation (ERATO) trial assessed the efficacy of dronedarone in the control of ventricular rate in patients with permanent AF, when added to standard therapy. Methods In this randomized, double-blind, multinational trial, dronedarone, 400 mg twice a day (n = 85), or matching placebo (n = 89) was administered for 6 months to adult patients with permanent AF, in addition to standard therapy. The primary end point was the change in mean ventricular rate between baseline and day 14, as assessed by 24-hour Holter. Ventricular rate was also assessed during submaximal and maximal exercise. Results Dronedarone significantly decreased mean 24-hour ventricular rate. Compared with placebo, the mean treatment effect at day 14 was a reduction of 11.7 beats per minute (beat/min; P < .0001). Comparable reductions were sustained throughout the 6-month trial. During maximal exercise and compared to placebo, there was a mean reduction of 24.5 beat/min ( P < .0001), without any reduction in exercise tolerance as measured by maximal exercise duration. The effects of dronedarone were additive to those of other rate-control agents, including β-blockers, calcium antagonists, and digoxin. Dronedarone was well tolerated, with no organ toxicities or proarrhythmia. Conclusion In addition to its reported rhythm-targeting and rate-targeting therapeutic actions in paroxysmal and persistent AF, dronedarone improves ventricular rate control in patients with permanent AF. Dronedarone was well tolerated with no evidence of organ toxicities or proarrhythmias in this short-term study.
Amiodarone is effective in maintaining sinus rhythm in atrial fibrillation but is associated with potentially serious toxic effects. Dronedarone is a new antiarrhythmic agent pharmacologically ...related to amiodarone but developed to reduce the risk of side effects.
In two identical multicenter, double-blind, randomized trials, one conducted in Europe (ClinicalTrials.gov number, NCT00259428 ClinicalTrials.gov ) and one conducted in the United States, Canada, Australia, South Africa, and Argentina (termed the non-European trial, NCT00259376 ClinicalTrials.gov ), we evaluated the efficacy of dronedarone, with 828 patients receiving 400 mg of the drug twice daily and 409 patients receiving placebo. Rhythm was monitored transtelephonically on days 2, 3, and 5; at 3, 5, 7, and 10 months; during recurrence of arrhythmia; and at nine scheduled visits during a 12-month period. The primary end point was the time to the first recurrence of atrial fibrillation or flutter.
In the European trial, the median times to the recurrence of arrhythmia were 41 days in the placebo group and 96 days in the dronedarone group (P=0.01). The corresponding durations in the non-European trial were 59 and 158 days (P=0.002). At the recurrence of arrhythmia in the European trial, the mean (+/-SD) ventricular rate was 117.5+/-29.1 beats per minute in the placebo group and 102.3+/-24.7 beats per minute in the dronedarone group (P<0.001); the corresponding rates in the non-European trial were 116.6+/-31.9 and 104.6+/-27.1 beats per minute (P<0.001). Rates of pulmonary toxic effects and of thyroid and liver dysfunction were not significantly increased in the dronedarone group.
Dronedarone was significantly more effective than placebo in maintaining sinus rhythm and in reducing the ventricular rate during recurrence of arrhythmia.
Aims
SAR247799 is a selective G‐protein‐biased sphingosine‐1 phosphate receptor‐1 (S1P1) agonist with potential to restore endothelial function in vascular pathologies. SAR247799, a first‐in‐class ...molecule differentiated from previous S1P1‐desensitizing molecules developed for multiple sclerosis, can activate S1P1 without desensitization and consequent lymphopenia. The aim was to characterize SAR247799 for its safety, tolerability, pharmacokinetics and pharmacodynamics (activation and desensitization).
Methods
SAR247799 was administered orally to healthy subjects in a double‐blind, randomized, placebo‐controlled study with single (2.5–37.5 mg) or 2‐week once‐daily (0.5–15 mg) doses. An open‐label single dose pilot food‐interaction arm with 10 mg SAR247799 in cross‐over design was also performed.
Results
SAR247799 was well tolerated and, at the higher end of the dose ranges, caused the expected dose‐dependent pharmacodynamics associated with S1P1 activation (heart rate reduction) and S1P1 desensitization (lymphocyte count reduction). SAR247799 demonstrated dose‐proportional increases in exposure and was eliminated with an apparent terminal half‐life of 31.2–33.1 hours. Food had a small effect on the pharmacokinetics of SAR247799. SAR247799 had a low volume of distribution (7–23 L), indicating a potential to achieve dose separation for endothelial vs cardiac S1P1 activation pharmacology. A supratherapeutic dose (10 mg) of SAR247799 produced sustained heart rate reduction over 14 days, demonstrating cardiac S1P1 activation without tachyphylaxis. Sub‐lymphocyte‐reducing doses (≤5 mg) of SAR247799, which, based on preclinical data, are projected to activate S1P1 and exhibit endothelial‐protective properties, had minimal‐to‐no heart rate reduction and displayed no marked safety findings.
Conclusion
SAR247799 is suitable for exploring the biological role of endothelial S1P1 activation without causing receptor desensitization.
Celivarone in Atrial Fibrillation/Atrial Flutter. Introduction: Celivarone, a new noniodinated benzofuran derivative pharmacologically related to dronedarone and amiodarone, has been shown to have ...antiarrhythmic properties at a molecular level. The purpose of the 2 trials presented here (MAIA and CORYFEE) was to assess celivarone efficacy in the maintenance of sinus rhythm postcardioversion and for the conversion of atrial fibrillation (AF)/atrial flutter (AFL).
Methods and Results: In the MAIA trial, 673 patients with AF/AFL recently converted to sinus rhythm were randomly assigned to receive 50, 100, 200, or 300 mg once‐daily dosing of celivarone; 200 mg daily of amiodarone preceded by a loading dose of 600 mg for 10 days; or placebo. At 3 months’ follow up, no significant difference was observed in time to AF/AFL relapse among the various celivarone groups and placebo. However, fewer symptomatic AF/AFL recurrences were observed in the lower‐dose celivarone groups (26.6% for celivarone 50 mg P = 0.022 and 25.2% for celivarone 100 mg P = 0.018 vs 40.5% for placebo at 90 days). Fewer adverse events were observed with the use of celivarone and placebo than amiodarone. In the CORYFEE study, 150 patients with AF/AFL were randomly assigned to once‐daily celivarone dosing of 300 or 600 mg, or placebo, for a 2‐day treatment period. There was no significant difference in the rate of spontaneous conversion to sinus rhythm between the treatment and control groups.
Conclusions: In these studies, celivarone does not appear to be efficacious in the maintenance of sinus rhythm in AF/AFL patients or for the conversion of AF/AFL patients. (J Cardiovasc Electrophysiol, Vol. 23, pp. 462‐472, May 2012)
Dronedarone versus Amiodarone in Patients with AF. Introduction: We compared the efficacy and safety of amiodarone and dronedarone in patients with persistent atrial fibrillation (AF).
Methods: Five ...hundred and four amiodarone‐naïve patients were randomized to receive dronedarone 400 mg bid (n = 249) or amiodarone 600 mg qd for 28 days then 200 mg qd (n = 255) for at least 6 months. Primary composite endpoint was recurrence of AF (including unsuccessful electrical cardioversion, no spontaneous conversion and no electrical cardioversion) or premature study discontinuation. Main safety endpoint (MSE) was occurrence of thyroid‐, hepatic‐, pulmonary‐, neurologic‐, skin‐, eye‐, or gastrointestinal‐specific events, or premature study drug discontinuation following an adverse event.
Results: Median treatment duration was 7 months. The primary composite endpoint was 75.1 and 58.8% with dronedarone and amiodarone, respectively, at 12 months (hazard ratio HR 1.59; 95% confidence interval CI 1.28–1.98; P < 0.0001), mainly driven by AF recurrence with dronedarone compared with amiodarone (63.5 vs 42.0%). AF recurrence after successful cardioversion was 36.5 and 24.3% with dronedarone and amiodarone, respectively. Premature drug discontinuation tended to be less frequent with dronedarone (10.4 vs 13.3%). MSE was 39.3 and 44.5% with dronedarone and amiodarone, respectively, at 12 months (HR = 0.80; 95% CI 0.60–1.07; P = 0.129), and mainly driven by fewer thyroid, neurologic, skin, and ocular events in the dronedarone group.
Conclusion: In this short‐term study, dronedarone was less effective than amiodarone in decreasing AF recurrence, but had a better safety profile, specifically with regard to thyroid and neurologic events and a lack of interaction with oral anticoagulants. (J Cardiovasc Electrophysiol, Vol. 21, pp. 597‐605, June 2010)
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.
Objectives. To establish the rate of spontaneous closure of atrial septal defects diagnosed before age 3 months, 101 infants (mean age 26 days) with an interatrial shunt confirmed by Doppler ...echocardiography were followed up for an average of 265 ± 190 days,
Background. Even if interatrial shunts in the newborn are frequently encountered, little is known about their natural history.
Methods. Defect diameter on two-dimensional echocardiography and width of color flow jet were measured in the subcostal view. Right and left ventricular diameters and atrial septal curvature were also studied. Kaplan-Meier curves were obtained to predict age of spontaneous closure in relation to initial defect diameter.
Results. There was no significant correlation between the diameter of the atrial septal defect and right ventricular/left ventricular ratio or type of septal curvature (vertical or concave toward the left atrium). The classic predominance of girls over boys was observed only for defects >5 mm. An overall rate of spontaneous closure of 87% was observed. Frequency and timing of closure were inversely correlated to atrial septal defect diameter: closure occurred in 100% (32 of 32) of defects in group 1 (diameter <3 mm), 87% of defects (39 of 45) in group 2 (diameter 3 to 5 mm), 80% of defects (16 of 20) in group 3 (diameter 5 to 8 mm). Spontaneous closure did not occur in four patients of group 4 (defect ≥8 mm) during an average follow-up interval of 417 days (range 294 to 597 days).
Conclusions. These results suggest that infants with an atrial septal defect <3 mm need not be followed up as 100% of these defects will be closed by age 18 months; those with a defect 3 to 5 or 5 to 8 mm should be evaluated by the end of the 12th and the 15th month, respectively, when >80% of these defects will be closed. An atrial septal defect with a diameter ≥8 mm may have little chance of closing spontaneously and the possibility of surgical correction should be considered. Defects <3 mm probably do not constitute a cardiac malformation in light of their natural evolution and gender distribution.
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