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Amarin Pharma, Inc. The REDUCE-IT clinical trial demonstrated significant reductions in cardiovascular events and reported atrial fibrillation (Afib), bleeding, constipation, and peripheral edema as potential adverse events (AEs) with icosapent ethyl (IPE) [Vascepa®/Vazkepa®]. It is unclear how the frequency of these AEs compares with real world IPE experience. To compare the frequency of select AEs with IPE across data sources, including the REDUCE-IT clinical trial, product labels, and estimates derived from real world data (RWD). Data were extracted from the REDUCE-IT publications and branded USA and/or Europe IPE labels to establish the frequency of Afib, bleeding, constipation, and peripheral edema. For comparison, real world data (RWD) estimates were derived from retrospective cohort studies of the MarketScan Commercial Claims data from the USA. New IPE users were followed for up to 4 years to identify AEs based on ICD-10 diagnosis and procedure codes. The percentages of patients experiencing each event were compared descriptively across REDUCE-IT, product labels, and RWD analyses. For each of the events considered, IPE AE rates documented in REDUCE-IT and both the USA and/or Europe labels were higher than the rates of the same events observed in RWD. The percentage of people with each documented event across data sources is as follows: Afib – REDUCE-IT 5.3%, label 5.8%, RWD 1.0%; bleeding – REDUCE-IT 11.8%, label 11.8%, RWD 4.3%; constipation – REDUCE-IT 5.4%, label 5.4%, RWD 1.3%; peripheral edema – REDUCE-IT 6.5%, label 7.8%, RWD 1.9%. Estimates provided by RWD paralleled the trial-based estimates in terms of rank order frequency, but the magnitude of RWD estimates was consistently 3-5 times lower than the REDUCE-IT trial or product label. RWD demonstrated trends in the frequency of IPE-labeled AEs that are consistent with, but 3-5x lower than, trial and labeling data. Potential reasons for consistently lower AE rates in RWD compared with trial data may be related to differences in how AEs are assessed and documented in the real world vs. in trials. [ABSTRACT FROM AUTHOR]

A mathematically linked mercury transport, speciation, kinetic, and simple biotic uptake (BIOTRANSPEC) model has been developed. An extension of the metal transport and speciation (TRANSPEC) model, BIOTRANSPEC estimates the fate and biotic uptake of inorganic (Hg(II)), elemental (Hg(0)) and organic (MeHg) forms of mercury and their species in the dissolved, colloidal (e.g., dissolved organic matter [DOM]), and particulate phases of surface aquatic systems. A pseudo-steady state version of the model was used to describe mercury dynamics in Lahontan Reservoir (near Carson City, NV, USA), where internal loading of the historically deposited mercury is remobilized, thereby maintaining elevated water concentrations. The Carson River is the main source of total mercury (THg), of which more than 90% is tightly bound in a gold-silver-mercury amalgam, to the system through loadings in the spring, with negligible input from the atmospheric deposition. The speciation results suggest that aqueous species are dominated by Hg-DOM, Hg(OH)2, and HgClOH. Sediment-to-water diffusion of MeHg and Hg-DOM accounts for approximately 10% of total loadings to the water column. The water column acts as a net sink for MeHg by reducing its levels through two competitive processes: Uptake by fish, and net MeHg demethylation. Although reservoir sediments produce significant amounts of MeHg (4 g/d), its transport from sediment to water is limited (1.6 g/d), possibly because of its adsorption on metal oxides of iron and manganese at the sediment-water interface. Fish accumulate approximately 45% of the total MeHg mass in the water column, and 9% of total MeHg uptake by fish leaves the system because of fishing. Results from this new model reiterate the previous conclusion that more than 90% of THg input is retained in sediment, which perpetuates elevated water concentrations. [ABSTRACT FROM AUTHOR]