Pharmacodynamic Effects of Riociguat in Pulmonary Hypertension and Heart Failure With Preserved Ejection Fraction

Exclusion Criteria

• •PH-HF-PEF defined as:
• •* LVEF ≥50%, diagnosed by echocardiography or left heart catheterization (LHC) within 30 days before randomization
• •* PAPmean ≥25 mmHg at rest, measured by RHC
• •* PAWP \>15 mmHg at rest, measured by RHC
• •Optimized therapy for hypertension
• •The dose regimen of the background treatment must have been stable for \>30 days before randomization. Diuretic therapy must have been stable for ≥1 week.
• •RHC results for the definite diagnosis of PH not older than 12 weeks at Visit 1. RHC must have been performed in the participating center under standardized conditions
• •CMRI must be performed at Visit 1 (baseline) or must not be older than 12 weeks with all parameters measured as listed in Section 7.3.3
• •PH in groups other than group 2.2 according to Dana Point classification.(4) In particular, PAH, CTEPH, and HF-REF must have been ruled out according to accepted diagnostic procedures and guidelines.
• •Cardiac decompensation, with hospitalization or visit to the emergency department,
• •≤30 days before randomization
• •Left heart disease because of to ischemic heart disease or dilated cardiomyopathy
• •Resynchronization therapy at any time
• •Need for intravenous (IV) diuretics ≤30 days before randomization
• •Treatment with inotropes or IV vasodilators ≤30 days before randomization
• •Pre-treatment with endothelin receptor antagonists (ERAs), phosphodiesterase type 5 (PDE5) inhibitors, or prostanoids ≤30 days before randomization, or with nitrates ≤7 days before randomization
• •Bronchial asthma or chronic obstructive pulmonary disease (COPD) with forced expiratory volume in 1 second (FEV1) \<60% of predicted
• •Restrictive lung disease with total lung capacity (TLC) \<60% of predicted
• •Subjects on oxygen therapy
• •Severe congenital abnormalities of the lung, thorax, or diaphragm
• •Clinically relevant hepatic dysfunction shown by:
• •Aspartate aminotransferase (AST) ≥3 times the upper limit of normal (ULN) or
• •Child Pugh stage B and C in cirrhotic subjects
• •Severe renal impairment (glomerular filtration rate \[GFR\] \<30mL/min/1.73 m2 calculated by the Modification of Diet in Renal Disease \[MDRD\] formula)
• •Uncontrolled arterial hypertension (SBP \>180 mmHg or diastolic blood pressure \[DBP\] \>110 mmHg)
• •SBP \<110 mmHg at baseline
• •Myocardial disease, such as ischemic or dilative infiltrative myocardial disease (i.e. amyloidosis, hypertrophic cardiomyopathy)
• •Severe aortic or mitral stenosis, or any such stenosis with indication for surgery
• •Coronary artery disease with angina of Canadian Cardiovascular Society (CCS) class III or IV or requiring nitrates, unstable angina, or acute myocardial infarction \<90 days before randomization
• •Reperfusion procedure (percutaneous coronary intervention \[PCI\] or coronary artery bypass graft \[CABG\]) \<90 days before randomization, or \<21 days in case of a negative stress test effect after PCI
• •Stroke with persistent neurological deficit
• •Subjects positive for human immunodeficiency virus (HIV)
• •Resting HR while awake of \<50 beats per minute (BPM) or \>105 BPM (in case of atrial fibrillation \>110 BPM)
• •Participation in another clinical study \<90 days before randomization
• •Subjects with a medical disorder, condition, or history thereof that in the opinion of the investigator would impair the subject's ability to participate or complete the 26-week study
• •Subjects with underlying medical disorders with an anticipated life expectancy below 2 years because of a non-cardiac disease (e.g. active cancer disease with localized and / or metastasized tumor mass)
• •Subjects with a history of multiple drug allergies
• •Subjects with hypersensitivity to the investigational drug or any of the excipients
• •Previous assignment to treatment during this study