P ulmonary hypertension (PH) caused by systolic left ventricular dysfunction (sLVD) is associated with high levels of morbidity and mortality in patients with heart failure (HF).
1Established HF therapies such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, and diuretics may be effective by improving left ventricular (LV) function and reducing LV filling pressure, but currently available agents do not affect the pulmonary circulation. 1 To date, randomized trials of agents targeted at the pulmonary vasculature either have failed to demonstrate benefit in patients with PH-sLVD or have not been adequately powered to detect changes in morbidity or mortality, 2-5 highlighting an urgent unmet medical need.
Editorial see p 475 Clinical Perspective on p 511Background-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. Methods and Results-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 ; 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
Bonderman et al
Riociguat for PH-sLVD 503Riociguat is a novel soluble guanylate cyclase (sGC) stimulator that is under investigation as a new approach to treat PH. 6 HF-and PH-related diseases are characterized by endothelial dysfunction with a concomitant decrease in availability of nitric oxide. 1,7,8 Riociguat has a dual mode of action: It sensitizes sGC to endogenous nitric oxide and directly stimulates sGC independently of nitric oxide.9 Riociguat induces vasodilation, and results from animal studies have demonstrated additional antifibrotic, antiproliferative, and anti-inflammatory effects.6,9,10 In a hemodynamic study in patients with reduced LV ejection fraction (≤45%) and mean pulmonary artery pressure (mPAP) ≥25 mm Hg, single doses of the sGC stimulator BAY 60-4552 reduced mPAP, pulmonary capillary wedge pressure, systemic vascular resistance (SVR), and pulmonary vascular resistance (PVR) and decreased systemic arterial blood pressure (BP).10,11 Thus, riociguat may be a promising novel treatment for PH-sLVD in patients with HF.To characterize the ...