Riociguat in Pulmonary Hypertension and Heart Failure With Preserved Ejection Fraction haemoDYNAMIC trial - DYNAMIC
Contribution To Literature:
Among patients with HFpEF with pulmonary hypertension in the DYNAMIC trial, riociguat led to improved cardiac output at rest after 26 weeks of therapy as compared to placebo.
The goal of the trial was to characterize the hemodynamic and clinical effects, safety, and tolerability of riociguat therapy among patients with heart failure with preserved ejection fraction (HFpEF) and pulmonary hypertension (PH).
The DYNAMIC trial was a multicenter, randomized, double-blind, placebo-controlled phase IIb trial among five hospitals across Austria and Germany. Patients were randomized in a 1:1 fashion to riociguat (n = 58) or placebo (n = 56) therapy. The study phase consisted of an 8-week up-titration phase followed by 18 weeks of fixed-dose treatment. Riociguat was up-titrated to doses of 1.0-1.5 mg TID. Cardiac output was determined by follow-up right heart catheterization at 26 weeks based on the thermodilution method.
- Total screened participants: 118
- Total randomized participants: 114
- Mean duration of follow-up: 186 days
- Mean patient age: 71 years
- Percentage female: 72.8%
- White race: 99.1%
- Age 18-80 years
- PH-HFpEF defined as left ventricular ejection fraction (LVEF) ≥50%, mean pulmonary artery pressure (PAPmean) ≥25 mm Hg at rest, and pulmonary arterial wedge pressure (PAWP) >15 mm Hg at rest, measured by right heart catheterization
- Unchanged medical treatment >30 days (>7 days of no change in diuretic) prior to enrollment
- HF with reduced EF, amyloidosis, chronic thromboembolic pulmonary hypertension, pulmonary arterial hypertension, or significant pulmonary disease
- Significant coronary artery disease
Other salient features/characteristics:
- Mean LVEF: 60%
- PAPmean: 36 mm Hg
- Mean PAWP: 20.9 mm Hg
The primary outcome, change in cardiac output at rest from baseline to week 26 of treatment, measured by right heart catheterization, for riociguat vs. placebo, was 0.37 L/min vs. –0.11 L/min, mean difference of 0.54 L/min (p = 0.0142).
Secondary outcomes for riociguat vs. placebo:
- Mean transpulmonary gradient: –2.5 mm Hg vs. 0.0 mm Hg (p = 0.0023)
- Mean pulmonary vascular resistance: –38.1 dyn·s·cm−5 vs. 6.6 dyn·s·cm−5 (p = 0.0068)
- Mean change in PAWP: –0.2 mm Hg vs. –0.4 mm Hg (p = 0.9601)
- Median change in N-terminal pro–B-type natriuretic peptide (NT-proBNP): 60.4 pg/mL vs. 76 pg/mL
- 6-minute walk test: 21.3 meters vs. 10.3 meters
- 18 patients in riociguat arm vs. 8 patients in placebo arm discontinued the study prematurely
- 32.8% adverse event rate in riociguat arm vs. 21.4% adverse event rate in placebo arm
- 1 death in riociguat arm vs. 2 deaths in placebo arm
The results of this trial show that, among patients with HFpEF and PH, riociguat improved cardiac output at rest compared to placebo. Additionally, adverse event rates were greater in the riociguat versus placebo arm; however, documented adverse events were mostly mild. There was substantially greater dropout in the riociguat versus placebo arm, which will require further investigation. There were no significant differences observed in NT-proBNP or functional outcomes. The study is limited as the majority of patients were enrolled at one study center, and the patient population was not diverse.
Previous investigations into soluble guanyl-cyclase stimulators for patients with HFpEF have not shown any clinical benefit. However, the present study investigated treatment among patients with comorbid PH. The study findings are reassuring with regard to safety. However, further study is required to investigate whether this improvement in cardiac output will lead to improved clinical outcomes.
Clinical Topics: Diabetes and Cardiometabolic Disease, Geriatric Cardiology, Heart Failure and Cardiomyopathies, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Pulmonary Hypertension, Hypertension
Keywords: Cardiac Catheterization, Cardiac Output, Geriatrics, Heart Failure, Hypertension, Pulmonary, Natriuretic Peptide, Brain, Pulmonary Wedge Pressure, Stroke Volume, Thermodilution, Vascular Resistance, Ventricular Function, Left
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