Assessment of the REPLACE study composite endpoint in riociguat-treated patients in the PATENT study.

The goal of treatment in patients with pulmonary arterial hypertension is to achieve a low risk status, indicating a favorable long-term outcome. The REPLACE study investigated the efficacy of switching to riociguat in patients with pulmonary arterial hypertension and an insufficient response to phosphodiesterase-5 inhibitors. In this post hoc analysis, we applied the REPLACE composite endpoint of clinical improvement to the placebo-controlled PATENT-1 study of riociguat in pulmonary arterial hypertension and its long-term extension, PATENT-2. Clinical improvement was defined as ≥2 of the following in patients who completed the study without clinical worsening: ≥10% or ≥30 m improvement in 6-minute walking distance; World Health Organization functional class I or II; ≥30% decrease in N-terminal prohormone of brain natriuretic peptide. At PATENT-1 Week 12, patients treated with riociguat were more likely to achieve the composite endpoint vs. placebo (P < 0.0001), with similar results in pretreated (P = 0.0189) and treatment-naïve (P < 0.0001) patients. Achievement of the composite endpoint at Week 12 was associated with a 45% reduction in relative risk of death and a 19% reduction in relative risk of clinical worsening in PATENT-2. Overall, these data suggest that use of the REPLACE composite endpoint in patients with pulmonary arterial hypertension is a valid assessment of response to treatment.

A probabilistic model for the carry-over of PCDD/Fs from feed to growing pigs.

When food producing animals are contaminated with PCDD/F congeners, information on the contaminant's concentration in the bodies of the animals at time of slaughter is needed for risk management purposes. We have developed a mathematical model for the kinetics of PCDD/Fs in growing pigs in case of contaminated feed fed for a limited duration of time. This model allows the prediction of concentrations in body fat. It considers absorption fractions of PCDD/Fs, clearance by metabolism, dilution by growth and excretion through fecal fat. The model parameters were calibrated by fitting the model to experimental data. On the basis of this toxicokinetic model a probabilistic model has been constructed. The probabilistic model handles the parameters with appropriate probability distributions and Monte-Carlo simulation technique, providing for realistic situations with many animals and a range of contaminations and feeding intervals. We applied the new model to describe the German dioxin incident of winter 2010/2011 and discuss its viability as decision tool. The approach demonstrated here is a showcase how a risk assessment in the case of contaminated feeding can be performed.