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.

Risk assessment in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.

BACKGROUND: Current pulmonary hypertension treatment guidelines recommend use of a risk stratification model encompassing a range of parameters, allowing patients to be categorised as low, intermediate or high risk. Three abbreviated versions of this risk stratification model were previously evaluated in patients with pulmonary arterial hypertension (PAH) in the French, Swedish and COMPERA registries. Our objective was to investigate the three abbreviated risk stratification methods for patients with mostly prevalent PAH and chronic thromboembolic pulmonary hypertension (CTEPH), in patients from the PATENT-1/2 and CHEST-1/2 studies of riociguat. METHODS: Risk was assessed at baseline and at follow-up in PATENT-1 and CHEST-1. Survival and clinical worsening-free survival were assessed in patients in each risk group/strata. RESULTS: With all three methods, riociguat improved risk group/strata in patients with PAH after 12 weeks. The French non-invasive and Swedish/COMPERA methods discriminated prognosis for survival and clinical worsening-free survival at both baseline and follow-up. Furthermore, patients achieving one or more low-risk criteria or a low-risk stratum at follow-up had a significantly reduced risk of death and clinical worsening compared with patients achieving no low-risk criteria or an intermediate-risk stratum. Similar results were obtained in patients with inoperable or persistent/recurrent CTEPH. CONCLUSIONS: This analysis confirms and extends the results of the registry analyses, supporting the value of goal-oriented treatment in PAH. Further assessment of these methods in patients with CTEPH is warranted.

[Osteoporosis: diagnostic assessment]. / Osteoporose: Diagnostische Aspekte und Frakturrisikoevaluation.

Osteoporosis is a generalized disease of bone that increases the fracture risk. Among the multiple factors involved in osteoporosis, some, but not all, are related to bone mass. Although bone mineral density (BMD) measurement is specific for detecting high-risk individuals, it misses a notable proportion of individuals who have clinical or epidemiological risk factors for osteoporotic fractures. Therefore, composite scores that rely both on BMD and on validated clinical risk factors have been developed. The Fracture Risk Assessment Tool (FRAX) was designed to predict the 10-year probabilities of sustaining a major osteoporotic fractures or a hip fracture. The cutoff value beyond which treatment should be initiated needs to be determined, based not only on clinical criteria, but also on economic considerations.

Diffusion in compartmental systems. I. A comparison of an analytical model with simulations.

This article examines the way in which microscopic tissue parameters affect the signal attenuation of diffusion-weighted MR experiments. The influence of transmembrane water flux on the signal decay is emphasized using the Kärger equations, which are modified with respect to the cellular boundary restrictions for intra- and extracellular diffusion. This analytical approach is extensively compared to Monte-Carlo simulations for a tissue model consisting of two compartments. It is shown that diffusion-weighted MR methods provide a unique tool for estimation of the intracellular exchange time. Restrictions of applicability to in vivo data are examined. It is shown that the intracellular exchange time strongly depends on the size of a cell, leading to an apparent diffusion time dependence for in vivo data. Hence, an analytical model of a two-compartment system with an averaged exchange time is inadequate for the interpretation of signal curves measured in vivo over large ranges of b-values. Furthermore, differences of multiexponential signal curves, as obtained by different methods of diffusion weighting, can be explained by the influence of transmembrane water flux.