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.

Keywords: Heart failure with preserved ejection fraction; Pulmonary hypertension; Randomized controlled trial; Riociguat; Soluble guanylate cyclase stimulation.

Structured Graphical Abstract

A total of 114 consecutive patients with pulmonary hypertension associated with heart failure and preserved ejection fraction were randomized to receive riociguat (Rio) or placebo. Riociguat is an orally administered drug that stimulates soluble guanylate cyclase (sGC) directly, independent of nitric oxide, and also sensitizes sGC to endogenous nitric oxide. Stimulation of sGC results in an increase of the cyclic guanosine monophosphate (cGMP) concentration which leads to vasorelaxation. After 26 weeks, the primary efficacy endpoint—cardiac output (CO) at rest measured by right heart catheterization—improved significantly in response to riociguat, along with other haemodynamic parameters.

Figure 1

Trial profile. *Valid for safety analysis set. ‡Multiple reasons per patient possible. AEs, adverse events; SAE, serious adverse event.

Figure 2

Change in cardiac output after 26 weeks of treatment (full analysis set). Individual changes in cardiac output after 26 weeks of treatment were plotted for each treatment group (excluding the implausible value) and are presented by open circles. The box presents the interquartile range and the whiskers the minimum and maximum values. The median is presented by the line and the mean by the black diamond.

Figure 3

Change in secondary haemodynamic parameters after 26 weeks of treatment (full analysis set). Individual changes in transpulmonary pressure gradient (A), pulmonary vascular resistance (B), pulmonary arterial wedge pressure (C), and systemic vascular resistance (D) after 26 weeks of treatment were plotted for each treatment group and are presented by open circles. The box presents the interquartile range and the whiskers the minimum and maximum values. The median is presented by the line and the mean by the black diamond.