Catheter Ablation Versus Antiarrhythmic Medication in Patients with Atrial Fibrillation: a Propensity-Matched Analysis Based on a German Claims Data Set

Several lines of evidence indicate that improving fibrinolysis by valproic acid may be a fruitful strategy for thrombosis prevention.This study investigated the safety, pharmacokinetics, and effect on biomarkers for thrombosis of CS1, a new advanced controlled release formulation of sodium valproate designed to produce optimum valproic acid concentrations during the early morning hours, when concentrations of plasminogen activator inhibitor (PAI)-1 and the risk of thrombotic events is highest.Healthy volunteers (n=17) aged 40-65 years were randomized to receive single doses of one of three formulations of CS1 (FI, FII, and FIII).The CS1 FII formulation showed the most favorable pharmacokinetics and was chosen for multiple dosing.Thirteen healthy volunteers received CS1 FII 276 mg once daily for 14 days, and 552 mg for a further 14 days.The mean (SD) peak plasma concentration (Cmax) of valproic acid at day 28 was 312.5 (70.0) µmol/L, and the median time to Cmax was 12 hours (range 9-16 hours).CS1 was safe well tolerated.Plasma PAI-1 concentrations decreased significantly from baseline to the end of the 28-day treatment period.Peak valproic acid concentrations were attained slightly later than peak PAI-1 levels.There was a close association (R 2 =0.65) between plasma PAI-1 concentrations and clot lysis time.In conclusion, this study showed that CS1 was safe and well-tolerated, showed favorable pharmacokinetics, as well as a significant reduction in PAI-1 and evidence of improved fibrinolysis.Further studies are warranted to further characterize the safety, tolerability and antithrombotic (fibrinolytic activity) of CS1.