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: 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.

Figure 1 –

Patient disposition. ^an = 1 invalid for the PP population because of noncompliance with the protocol (laboratory parameters/ECG assessed before informed consent provided). All patients who completed the hemodynamic assessments underwent a valid pharmacokinetic analysis. One patient in the placebo group withdrew because of an AE of pain in the left shoulder. AE = adverse event; PP = per protocol.

Figure 2 –

Peak decrease in mPAP from baseline up to 6 h after administration of study drug in the riociguat 2 mg group vs placebo group (primary end point). The difference between treatment groups was analyzed by a two-group, two-sided t test. The treatment difference (95% CI) and P value are also shown. mPAP = mean pulmonary artery pressure.

Figure 3 –

Mean change (± SD) from baseline in selected hemodynamic parameters in the 6 h following administration of study drug. A, Cardiac index. B, PAWP. C, SVR. D, MAP. MAP = mean arterial pressure; PAWP = pulmonary arterial wedge pressure; SVR = systemic vascular resistance.