bay-63-2521 and Ventricular-Dysfunction--Left

Topics: Animals; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Pyrazoles; Pyrimidines; Thromboembolism; Ventricular Dysfunction, Left

Pulmonary hypertension caused by systolic left ventricular dysfunction is associated with significant morbidity and mortality; however, no treatment is approved for this indication. We hypothesized that riociguat, a novel soluble guanylate cyclase stimulator, would have beneficial hemodynamic effects in patients with pulmonary hypertension caused by systolic left ventricular dysfunction.. Overall, 201 patients with heart failure resulting from pulmonary hypertension caused by systolic left ventricular dysfunction were randomized to double-blind treatment with oral placebo or riociguat (0.5, 1, or 2 mg 3 times daily) for 16 weeks in 4 parallel arms. The primary outcome was the placebo-corrected change from baseline at week 16 in mean pulmonary artery pressure. Although the decrease in mean pulmonary artery pressure in the riociguat 2 mg group (-6.1±1.3 mm Hg; P<0.0001 versus baseline) was not significantly different from placebo (P=0.10), cardiac index (0.4 L·min(-1)·m(-2); 95% confidence interval, 0.2-0.5; P=0.0001) and stroke volume index (5.2 mL·m(-2); 95% confidence interval, 2.0-8.4; P=0.0018) were significantly increased without changes in heart rate or systemic blood pressure compared with placebo. Both pulmonary (-46.6 dynes·s(-1)·cm(-5); 95% confidence interval, -89.4 to -3.8; P=0.03) and systemic vascular resistance (-239.3 dynes·s(-1)·cm(-5); 95% confidence interval, -363.4 to -115.3; P=0.0002) were significantly reduced with riociguat 2 mg. Riociguat reduced the Minnesota Living With Heart Failure score (P=0.0002). Discontinuation of treatment was similar between treatment groups.. Although the primary end point of the study was not met, riociguat was well tolerated in patients with pulmonary hypertension caused by systolic left ventricular dysfunction and improved cardiac index and pulmonary and systemic vascular resistance.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01065454.

Topics: Adult; Aged; Dose-Response Relationship, Drug; Double-Blind Method; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pyrazoles; Pyrimidines; Ventricular Dysfunction, Left

Pulmonary hypertension (PH) due to systolic left ventricular dysfunction (PH-sLVD) frequently complicates heart failure (HF), and greatly worsens the prognosis of patients with sLVD, but as yet has no approved treatment. The LEPHT study aims to characterize the haemodynamic profile, safety, tolerability, and pharmacokinetic profile of riociguat (BAY 63-2521), an oral stimulator of soluble guanylate cyclase, in patients with PH-sLVD.. This 16-week, phase IIb, randomized, placebo-controlled, double-blind study enrols patients with PH-sLVD, defined as left ventricular ejection fraction (LVEF) ≤40% and mean pulmonary arterial pressure (PAP(mean)) ≥25 mmHg at rest. Patients using optimized HF medication will receive placebo or riociguat 0.5 mg, 1 mg, or up to 2 mg three times daily. The dose will be titrated for 8 weeks, based on systolic blood pressure and well-being, followed by 8 weeks of treatment at a stable dose. The primary efficacy variable is PAP(mean), while secondary efficacy endpoints include LVEF, exercise capacity, quality of life, and other haemodynamic and echocardiographic measurements. Safety and pharmacokinetics will also be assessed. After the 16-week study, patients will have the opportunity to be treated with riociguat in a long-term extension phase.. The LEPHT study will provide valuable information on the haemodynamic, echocardiographic, and preliminary clinical effects of riociguat in patients with PH-sLVD. Trial registration NCT01065454.

Topics: Dose-Response Relationship, Drug; Double-Blind Method; Exercise Tolerance; Guanylate Cyclase; Heart Failure, Systolic; Hemodynamics; Humans; Hypertension, Pulmonary; Prognosis; Pyrazoles; Pyrimidines; Quality of Life; Research Design; Stroke Volume; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Function, Left

Topics: Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Pyrazoles; Pyrimidines; Ventricular Dysfunction, Left