Riociguat for Patients with Pulmonary Hypertension due to Systolic Left Ventricular Dysfunction: A Phase IIb Double-Blind, Randomized, Placebo-Controlled, Dose-Ranging Hemodynamic Study
Background—Pulmonary hypertension due to systolic left ventricular dysfunction (PH-sLVD) 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 PH-sLVD.
Methods and Results—Overall, 201 patients with heart failure due to PH-sLVD were randomized to double-blind treatment with oral placebo or riociguat (0.5, 1, or 2 mg three-times daily) for 16 weeks in four parallel arms. The primary outcome was the placebo-corrected change from baseline at Week 16 in mean pulmonary artery pressure (mPAP). Although the decrease in mPAP in the riociguat 2 mg group (-6.1±1.3 mmHg; P<0.0001 vs baseline) was not significantly different from placebo (P=0.10), cardiac index (+0.4 L•min-1•m-2 [95% CI 0.2 to 0.5]; P=0.0001) and stroke volume index (+5.2 mL•m-2 [95% CI 2.0 to 8.4]; P=0.0018) were significantly increased, without changes in heart rate, or systemic blood pressure versus placebo. Both pulmonary (-46.6 dyn•s-1•cm-5 [95% CI -89.4 to -3.8]; P=0.03) and systemic vascular resistance (-239.3 dyn•s-1•cm-5 [95% CI -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.
Conclusions—Although the primary endpoint of the study was not met, riociguat was well tolerated in patients with PH-sLVD and improved cardiac index, and pulmonary and systemic vascular resistance.
Clinical Trial Registration Information—www.clinicaltrials.gov. Identifier: NCT01065454.
- systolic heart failure
- soluble guanylate cyclase stimulator
- pulmonary hypertension
- clinical trial
- Received January 22, 2013.
- Revision received May 24, 2013.
- Accepted May 31, 2013.