Acute hemoDynamic effects of rIociguat in patients with puLmonary hypertension Associated with diasTolic heart failurE (DILATE-1): A randomized, double-blind, placebo-controlled, single-dose study

Abstract

BACKGROUND: Defi cient nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate signaling results from endothelial dysfunction and may underlie impaired cardiac relaxation in patients with heart failure with preserved left ventricular ejection fraction (HFpEF) and pulmonary hypertension (PH). Th e acute hemodynamic eff ects of riociguat, a novel soluble guanylate cyclase stimulator, were characterized in patients with PH and HFpEF. METHODS: Clinically stable patients receiving standard HF therapy with a left ventricular ejection fraction. 50%, mean pulmonary artery pressure (mPAP) Ն 25 mm Hg, and pulmonary arterial wedge pressure (PAWP). 15 mm Hg at rest were randomized to single oral doses of placebo or riociguat (0.5, 1, or 2 mg). Th e primary effi cacy variable was the peak decrease in mPAP from baseline up to 6 h. Secondary outcomes included hemodynamic and echocardiographic parameters, safety, and pharmacokinetics. RESULTS: Th ere was no signifi cant change in peak decrease in mPAP with riociguat 2 mg (n 5 10) vs placebo (n 5 11, P 5 .6). However, riociguat 2 mg signifi cantly increased stroke volume (1 9 mL [95% CI, 0.4-17]; P 5 .04) and decreased systolic BP (2 12 mm Hg [95% CI, 2 22 to 2 1]; P 5 .03) and right ventricular end-diastolic area (2 5.6 cm 2 [95% CI, 2 11 to 2 0.3]; P 5 .04), without signifi cantly changing heart rate, PAWP, transpulmonary pressure gradient, or pulmonary vascular resistance. Riociguat was well tolerated. CONCLUSIONS: In patients with HFpEF and PH, riociguat was well tolerated, had no signifi cant eff ect on mPAP, and improved exploratory hemodynamic and echocardiographic parameters.

Soluble Guanylate Cyclase Stimulators: a Novel Treatment Option for Heart Failure Associated with Cardiorenal Syndromes?

“…While the primary endpoint (reduction in mean pulmonary artery pressure) was not achieved, riociguat did result in higher stroke volume, lower right ventricular end-diastolic volume, and a decrease in systolic blood pressure by 12 mmHg [43]. In the Left Ventricular Systolic Dysfunction Associated with Pulmonary Hypertension Riociguat Trial (LEPHT), 200 patients with pulmonary hypertension due to heart failure with reduced ejection fraction (HFrEF) already on optimal therapy were randomized to placebo or target doses of riociguat 0.5, 1, or 2 mg three times daily over 16 weeks.…”

“…As in DILATE-1, the primary endpoint, reduction in mean pulmonary artery pressure, was not achieved; however, patients treated in the 2 mg target dose arm had reduced pulmonary and systemic vascular resistance, increased cardiac index, and improved quality of life, without reduction of systolic blood pressure [44]. Notably, DILATE-1 [43] and LEPHT [44] were the only studies to include patients with reduced renal function, and none included patients with eGFR < 30 ml/min/1.73 m2 ( Table 1). The parallel-group Soluble Guanylate Cyclase Stimulator in Heart Failure Studies (SOCRATES) trials aimed to study the effects of a once-daily sGC stimulator, vericiguat, in patients recently hospitalized for HFrEF (SOCRATES-Reduced) or HFpEF (SOCRATES-Preserved) [45].…”

Pulmonary Hypertension Secondary to Heart Failure With Preserved Ejection Fraction

“…61 DILATE-1 compared varying doses of riociguat: 0.5 mg in 8 patients, 1 mg in 7 patients, and 2 mg in 10 patients compared to placebo (in 11 patients) to determine the short-term effects on invasive hemodynamics 6 hours after administration of the study drug. 61 There was no difference in the change in mean PAP between baseline and 6 hours time points in the riociguate 2 mg (n=10) vs. placebo (n=11) groups (difference in the delta mean PAP between the two groups: 1.2 [95% CI: -2.9 to 5.2] mm Hg).…”

Impact of Pharmacologic Interventions—Treating Endothelial Dysfunction and Group 2 Pulmonary Hypertension

“…Nonetheless, the validity of this conclusion has been recently questioned by the availability of newer selective agents that may optimally target endothelial pathways involved in the control of pulmonary vascular tone and permeability whose hemodynamic effects are described in the next sections. Table 1 outlines major study findings of trials testing pulmonary vasodilator therapies in LHD-PH [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24].…”