Riociguat Clinical Effects Studied in Patients With Insufficient Treatment Response to Phosphodiesterase-5 Inhibitor

6MWD test was used to measure the subjects functional exercise capacity. Subjects were instructed to walk alone, not run, from one end to the other end of the walking course, at their own pace, while attempting to cover as much ground as possible in 6 minutes. No "warm-up" period was performed before the test. Investigators have not walked with the subjects. This was an encouraged test (the person conducting the test encouraged subjects to walk farther or faster by using only standardized phrases).

The cardiac output was measured by using the thermodilution methodology and a respective electronic device. The cardiac index was assessed by dividing the cardiac output by the person's BSA.

NT-proBNP cardiac biomarker was used to detect, diagnose, and evaluate the severity of heart failure. A higher level of the marker was indicative of heart failure.

WHO FC assessment of PAH ranged from functional class I (subjects with PH but without resulting limitation of physical activity); class II (subjects with PH resulting in slight limitation of physical activity); class III (subjects with PH resulting in marked limitation of physical activity); class IV (subjects with PH with inability to carry out any physical activity without symptoms); and class V death. Changes to a lower WHO FC resemble improvement; changes to a higher functional class resemble deterioration of PAH.

Clinical worsening was defined as death (all-cause mortality); atrial septostomy; lung transplantation; non-planned PAH-related hospitalisation; start of new PAH treatment (ERA, inhaled or oral prostanoid) or modification of pre-existing treatment, initiation of intravenous or subcutaneous prostanoids; persistent decrease of greater than (>) 15% from baseline or >30% from last measurement in 6MWD; persistent worsening of WHO FC; or appearance or worsening of signs/symptoms of right heart failure not responding to optimised oral diuretic therapy. All identified and suspected clinical worsening events were confirmed by independent central adjudication.

EQ-5D was a standardized instrument which was used to measure the health outcome. The EQ-5D was a selfreport questionnaire and needed to be completed by the subject. After the subject filled in the questionnaire, the questionnaire was transferred into the electronic case report form (eCRF). EQ-5D was calculated by two types of questionnaires Part A (descriptive health profile) and Part B (visual analogue scale). Part A, EQ-5D comprised 5-item questionnaires to measure own health profile status (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Each measure has three levels (1. no problems, 2. some problems, 3. extreme problems). In Part B, visual analogue rating scale to measure how good or bad a health state was. Scale was drawn by using thermometer-like scale, on which the best state imagine was marked as 100 and worst state imagine was marked as 0.

Percentage of subjects without clinical worsening who achieve at least who FC II and an improvement in 6 MWD of >= 30 meters were reported.