Acute Hemodynamic Effects of Riociguat in Patients With Pulmonary Hypertension Associated With Diastolic Heart Failure (DILATE-1)

Abstract

BACKGROUND:Deficient 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). The acute hemodynamic effects 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) ≥ 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). The primary efficacy variable was the peak decrease in mPAP from baseline up to 6 h. Secondary outcomes included hemodynamic and echocardiographic parameters, safety, and pharmacokinetics.RESULTS:There was no significant change in peak decrease in mPAP with riociguat 2 mg (n = 10) vs placebo (n = 11, P = .6). However, riociguat 2 mg significantly increased stroke volume (+9 mL [95% CI, 0.4-17]; P = .04) and decreased systolic BP (−12 mm Hg [95% CI, −22 to −1]; P = .03) and right ventricular end-diastolic area (−5.6 cm2 [95% CI, −11 to −0.3]; P = .04), without significantly 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 significant effect on mPAP, and improved exploratory hemodynamic and echocardiographic parameters.TRIAL REGISTRY:ClinicalTrials.gov; No.: NCT01172756; URL: www.clinicaltrials.gov

Clinical Phenotypes in Heart Failure With Preserved Ejection Fraction

“…In the absence of evidence‐based data, PDE5‐I cannot be recommended for the treatment of PH in HFpEF 185, 186, 187. Riociguat, a soluble guanylate cyclase stimulator that sensitizes guanylate cyclase through nitric oxide–dependent and –independent pathways, has been evaluated for the treatment of PH in HFpEF 188, 189. Riociguat increases stroke volume and cardiac output without changes in pulmonary vascular resistance and TPG 188, 189.…”

“…Riociguat, a soluble guanylate cyclase stimulator that sensitizes guanylate cyclase through nitric oxide–dependent and –independent pathways, has been evaluated for the treatment of PH in HFpEF 188, 189. Riociguat increases stroke volume and cardiac output without changes in pulmonary vascular resistance and TPG 188, 189. The lack of US Food and Drug Administration–approved therapy makes the management of HFpEF patients with PH and particularly out of proportion PH extremely challenging.…”

Pulmonary Hypertension in Heart Failure Preserved Ejection Fraction

“…65 Riociguat is currently undergoing regulatory review for the indications of PAH and inoperable chronic thromboembolic pulmonary hypertension and is being investigated as a treatment for PH-HFpEF in a Phase 2b study (Effects of Riociguat in Patients With Pulmonary Hypertension Associated With Left Ventricular Diastolic Dysfunction, DILATE trial; ClinicalTrials.gov Identifier: NCT01172756) whose primary end point was the mPAP response up to 6 hours after active drug and whose results have been recently presented at the ESC 2013 Congress. 66 Other than some preliminary data on the hemodynamic effects, the DILATE trial has provided safety and pharmacokinetics information of single different doses of riociguat in patients with PH-HFpEF. Study findings showed a good safety and tolerability profile with nonsignificant changes in mPAP and PCWP compared with placebo.…”

Endothelial Dysfunction and Lung Capillary Injury in Cardiovascular Diseases

“…Both the LEPTH [patients with HF-reduced ejection fraction (HFrEF)] 65 and the DILATE (patients with HFpEF) 66 trials have investigated hemodynamic effects, showing a good safety and tolerability profile, even with riociguat at different doses. However, no data has thus far been reported on endothelial function and gas exchange.…”