Riociguat in pulmonary hypertension and heart failure with preserved ejection fraction: the haemoDYNAMIC trial

Abstract

Aims The presence of pulmonary hypertension (PH) severely aggravates the clinical course of heart failure with preserved ejection fraction (HFpEF). To date, neither established heart failure therapies nor pulmonary vasodilators proved beneficial. This study investigated the efficacy of chronic treatment with the oral soluble guanylate cyclase stimulator riociguat in patients with PH-HFpEF. Methods and Results The phase IIb, randomized, double-blind, placebo-controlled, parallel-group, multicentre DYNAMIC trial assessed riociguat in PH-HFpEF. Patients were recruited at five hospitals across Austria and Germany. Key eligibility criteria were mean pulmonary artery pressure ≥25 mmHg, pulmonary arterial wedge pressure >15 mmHg, and left ventricular ejection fraction ≥50%. Patients were randomized to oral treatment with riociguat or placebo (1:1). Patients started at 0.5 mg three times daily (TID) and were up-titrated to 1.5 mg TID. The primary efficacy endpoint was change from baseline to week 26 in cardiac output (CO) at rest, measured by right heart catheterization. Primary efficacy analyses were performed on the full analysis set. Fifty-eight patients received riociguat and 56 patients placebo. After 26 weeks, CO increased by 0.37 ± 1.263 L/min in the riociguat group and decreased by −0.11 ± 0.921 L/min in the placebo group (least-squares mean difference: 0.54 L/min, 95% confidence interval 0.112, 0.971; P = 0.0142). Five patients dropped out due to riociguat-related adverse events but no riociguat-related serious adverse event or death occurred. Conclusion The vasodilator riociguat improved haemodynamics in PH-HFpEF. Riociguat was safe in most patients but led to more dropouts as compared to placebo and did not change clinical symptoms within the study period.

β3 adrenergic agonist treatment in chronic pulmonary hypertension associated with heart failure (SPHERE‐HF): a double blind, placebo‐controlled, randomized clinical trial

“…At inclusion, PVR severity was lower than in the trial by Guazzi et al 30 . in HFpEF (significant reduction of mean PAP using sildenafil), and slightly higher compared to the SIOVAC trial 33 in PH associated with corrected valve disease (negative results using sildenafil) and the recently published DYNAMIC trial in HFpEF 36 (significant improvement of cardiac output with vericiguat). We decided to use the change in PVR as the primary outcome as the most robust haemodynamic parameter in this population 39,40 .…”

The thromboxane receptor antagonist NTP42 promotes beneficial adaptation and preserves cardiac function in experimental models of right heart overload

“…Treatment with NTP42:KVA4 (1 mg/kg PO BID) or Riociguat (5 mg/kg PO, BID) was initiated 2 days after PAB surgery, where Riociguat was chosen as an appropriate comparator compound as, in previous preclinical investigations, it has been shown to prevent deterioration of RV function induced by PAB ( 31 ). In addition, Riociguat is the only PAH SOC which has demonstrated potential clinical uses in heart failure settings, ( 32 ) where other SOC compounds have demonstrated conflicting findings, often with adverse outcomes ( 33 , 34 ). Pre-treatment echocardiogram (ECHO) showed robust and comparable pulmonary arterial (PA) pressure gradients across the randomized PAB animal groups ( Supplementary Figures 2A,B ).…”

The β3‐adrenoreceptor agonist mirabegron for the treatment of combined pre‐ and post‐capillary pulmonary hypertension: new pathway or dead end?

“…Presence of CpcPH is particularly relevant for patients with HF with preserved ejection fraction (HFpEF), because in contrast to HF with reduced ejection fraction (HFrEF) there are still very limited options to treat HFpEF and thereby to lower mPAWP and potentially also PVR 1,2 . Several trials evaluating the impact of drugs specifically targeting the pulmonary vasculature (drugs approved for the treatment of pulmonary arterial hypertension) have been conducted in patients with HFpEF and PH with overall mixed results 3–7 …”

“…1,2 Several trials evaluating the impact of drugs specifically targeting the pulmonary vasculature (drugs approved for the treatment of pulmonary arterial hypertension) have been conducted in patients with HFpEF and PH with overall mixed results. [3][4][5][6][7] On this background, researchers have made efforts to develop innovative treatments for CpcPH. In the present issue of the Journal, Garcia-Alvarez et al 8 controlled double-blind multicentre SPHERE-HF study evaluating the effects of the oral β3-adrenoreceptor (β3AR) agonist mirabegron in CpcPH patients.…”