Evaluation of the pharmacoDYNAMIC effects of riociguat in subjects with pulmonary hypertension and heart failure with preserved ejection fraction

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Summary

Background

The presence of pulmonary hypertension (PH) severely aggravates the clinical course of heart failure with preserved ejection fraction (HFPEF) resulting in substantial morbidity and mortality. So far, neither established heart failure therapies nor pulmonary vasodilators have proven to be effective for this condition. Riociguat (Adempas®, BAY 63-2521), a stimulator of soluble guanylate cyclase, is a novel pulmonary and systemic vasodilator that has been approved for the treatment of precapillary forms of PH. With regard to postcapillary PH, the DILATE-1 study was a multicenter, double-blind, randomized, placebo-controlled single-dose study in subjects with PH associated with HFPEF. Although there was no significant change in the primary outcome measure, peak decrease in mean pulmonary artery pressure with riociguat versus placebo, riociguat significantly increased stroke volume without changing heart rate, pulmonary artery wedge pressure, transpulmonary pressure gradient or pulmonary vascular resistance. The present study is designed to test the efficacy of long-term treatment with riociguat in patients with PH associated with HFPEF.

Methods/study design

The DYNAMIC study is a randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical phase IIb trial evaluating the efficacy, safety and kinetics of riociguat in PH-HFPEF patients. The drug will be given over 26 weeks to evaluate the effects of riociguat versus placebo. The primary efficacy variable will be the change from baseline in cardiac output at rest, measured by right heart catheter after 26 weeks of study drug treatment. Additional efficacy variables will be changes from baseline in further hemodynamic parameters, changes in left and right atrial area, right ventricular volume, as well as right ventricular ejection fraction measured by cardiac magnetic resonance imaging, and changes from baseline in World Health Organization (WHO) class and N‑terminal prohormone B‑type natriuretic peptide (NT-proBNP).

The trial was registered on 25 August 2014 (EudraCT Number: 2014-003055-60; www.clinicaltrialsregister.eu).

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Most cited references 10

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Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial.

Margaret M. Redfield, Horng Chen, Barry Borlaug … (2013)

Studies in experimental and human heart failure suggest that phosphodiesterase-5 inhibitors may enhance cardiovascular function and thus exercise capacity in heart failure with preserved ejection fraction (HFPEF). To determine the effect of the phosphodiesterase-5 inhibitor sildenafil compared with placebo on exercise capacity and clinical status in HFPEF. Multicenter, double-blind, placebo-controlled, parallel-group, randomized clinical trial of 216 stable outpatients with HF, ejection fraction ≥50%, elevated N-terminal brain-type natriuretic peptide or elevated invasively measured filling pressures, and reduced exercise capacity. Participants were randomized from October 2008 through February 2012 at 26 centers in North America. Follow-up was through August 30, 2012. Sildenafil (n = 113) or placebo (n = 103) administered orally at 20 mg, 3 times daily for 12 weeks, followed by 60 mg, 3 times daily for 12 weeks. Primary end point was change in peak oxygen consumption after 24 weeks of therapy. Secondary end points included change in 6-minute walk distance and a hierarchical composite clinical status score (range, 1-n, a higher value indicates better status; expected value with no treatment effect, 95) based on time to death, time to cardiovascular or cardiorenal hospitalization, and change in quality of life for participants without cardiovascular or cardiorenal hospitalization at 24 weeks. Median age was 69 years, and 48% of patients were women. At baseline, median peak oxygen consumption (11.7 mL/kg/min) and 6-minute walk distance (308 m) were reduced. The median E/e' (16), left atrial volume index (44 mL/m2), and pulmonary artery systolic pressure (41 mm Hg) were consistent with chronically elevated left ventricular filling pressures. At 24 weeks, median (IQR) changes in peak oxygen consumption (mL/kg/min) in patients who received placebo (-0.20 [IQR, -0.70 to 1.00]) or sildenafil (-0.20 [IQR, -1.70 to 1.11]) were not significantly different (P = .90) in analyses in which patients with missing week-24 data were excluded, and in sensitivity analysis based on intention to treat with multiple imputation for missing values (mean between-group difference, 0.01 mL/kg/min, [95% CI, -0.60 to 0.61]). The mean clinical status rank score was not significantly different at 24 weeks between placebo (95.8) and sildenafil (94.2) (P = .85). Changes in 6-minute walk distance at 24 weeks in patients who received placebo (15.0 m [IQR, -26.0 to 45.0]) or sildenafil (5.0 m [IQR, -37.0 to 55.0]; P = .92) were also not significantly different. Adverse events occurred in 78 placebo patients (76%) and 90 sildenafil patients (80%). Serious adverse events occurred in 16 placebo patients (16%) and 25 sildenafil patients (22%). Among patients with HFPEF, phosphodiesterase-5 inhibition with administration of sildenafil for 24 weeks, compared with placebo, did not result in significant improvement in exercise capacity or clinical status. clinicaltrials.gov Identifier: NCT00763867.

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Pulmonary hypertension in heart failure with preserved ejection fraction: a community-based study.

Carolyn S.P. Lam, Véronique L Roger, Richard Rodeheffer … (2009)

This study sought to define the prevalence, severity, and significance of pulmonary hypertension (PH) in heart failure with preserved ejection fraction (HFpEF) in the general community. Although HFpEF is known to cause PH, its development is highly variable. Community-based data are lacking, and the relative contribution of pulmonary venous versus pulmonary arterial hypertension (HTN) to PH in HFpEF is unknown. We hypothesized that PH would be a marker of symptomatic pulmonary congestion, distinguishing HFpEF from pre-clinical hypertensive heart disease. This community-based study of 244 HFpEF patients (age 76 +/- 13 years; 45% male) was followed up using Doppler echocardiography over 3 years. Control subjects were 719 adults with HTN without HF (age 66 +/- 10 years; 44% male). Pulmonary artery systolic pressure (PASP) was derived from the tricuspid regurgitation velocity and PH defined as PASP >35 mm Hg. Pulmonary capillary wedge pressure (PCWP) was estimated from the ratio of early transmitral flow velocity to early mitral annular diastolic velocity. In HFpEF, PH was present in 83% and the median (25th, 75th percentile) PASP was 48 (37, 56) mm Hg. PASP increased with PCWP (r = 0.21; p < 0.007). Adjusting for PCWP, PASP was higher in HFpEF than HTN (p < 0.001). The PASP distinguished HFpEF from HTN with an area under the receiver-operating characteristic curve of 0.91 (p < 0.001) and strongly predicted mortality in HFpEF (hazard ratio: 1.3 per 10 mm Hg; p < 0.001). PH is highly prevalent and often severe in HFpEF. Although pulmonary venous HTN contributes to PH, it does not fully account for the severity of PH in HFpEF, suggesting that a component of pulmonary arterial HTN also contributes. The potent effect of PASP on mortality lends support for therapies aimed at pulmonary arterial HTN in HFpEF.

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Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group.

M. Packer, J R Carver, R J Rodeheffer … (1991)

Milrinone, a phosphodiesterase inhibitor, enhances cardiac contractility by increasing intracellular levels of cyclic AMP, but the long-term effect of this type of positive inotropic agent on the survival of patients with chronic heart failure has not been determined. We randomly assigned 1,088 patients with severe chronic heart failure (New York Heart Association class III or IV) and advanced left ventricular dysfunction to double-blind treatment with (40 mg of oral milrinone daily (561 patients) or placebo (527 patients). In addition, all patients received conventional therapy with digoxin, diuretics, and a converting-enzyme inhibitor throughout the trial. The median period of follow-up was 6.1 months (range, 1 day to 20 months). As compared with placebo, milrinone therapy was associated with a 28 percent increase in mortality from all causes (95 percent confidence interval, 1 to 61 percent; P = 0.038) and a 34 percent increase in cardiovascular mortality (95 percent confidence interval, 6 to 69 percent; P = 0.016). The adverse effect of milrinone was greatest in patients with the most severe symptoms (New York Heart Association class IV), who had a 53 percent increase in mortality (95 percent confidence interval, 13 to 107 percent; P = 0.006). Milrinone did not have a beneficial effect on the survival of any subgroup. Patients treated with milrinone had more hospitalizations (44 vs. 39 percent, P = 0.041), were withdrawn from double-blind therapy more frequently (12.7 vs. 8.7 percent, P = 0.041), and had serious adverse cardiovascular reactions, including hypotension (P = 0.006) and syncope (P = 0.002), more often than the patients given placebo. Our findings indicate that despite its beneficial hemodynamic actions, long-term therapy with oral milrinone increases the morbidity and mortality of patients with severe chronic heart failure. The mechanism by which the drug exerts its deleterious effects is unknown.

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Author and article information

Contributors

Julia Mascherbauer: +43-1-4040046140 , +43-1-4040042160 , julia.mascherbauer@meduniwien.ac.at

Ekkehard Grünig: ekkehard.gruenig@med.uni-heidelberg.de

Michael Halank: michael.halank@uniklinikum-dresden.de

Wolfgang Hohenforst-Schmidt: w.h-s@gmx.de

Andreas A. Kammerlander: andreas.kammerlander@meduniwien.ac.at

Ingrid Pretsch: i.pretsch@salk.at

Regina Steringer-Mascherbauer: regina.mascherbauer@elisabethinen.or.at

Silvia Ulrich: silvia.ulrich@usz.ch

Irene M. Lang: irene.lang@meduniwien.ac.at

Manfred Wargenau: manfred.wargenau@marco-institut.de

Reiner Frey: frey_reiner@t-online.de

Diana Bonderman: +43-1-4040046140 , +43-1-4040042160 , diana.bonderman@meduniwien.ac.at

Journal

Journal ID (nlm-ta): Wien Klin Wochenschr

Journal ID (iso-abbrev): Wien. Klin. Wochenschr

Title: Wiener Klinische Wochenschrift

Publisher: Springer Vienna (Vienna )

ISSN (Print): 0043-5325

ISSN (Electronic): 1613-7671

Publication date (Electronic): 2 September 2016

Publication date PMC-release: 2 September 2016

Publication date (Print): 2016

Volume: 128

Issue: 23

Pages: 882-889

Affiliations

[1 ]Department of Cardiology, Medical University of Vienna, Waehringer Guertel 18–20, 0190 Vienna, Austria

[2 ]Centre for Pulmonary Hypertension, Thoraxclinic, University Hospital of Heidelberg, Heidelberg, Germany

[3 ]Department of Internal Medicine I, University Hospital Carl Gustav Carus Dresden, Dresden, Germany

[4 ]Medical Clinic II, Coburg Hospital, Coburg, Germany

[5 ]Department of Cardiology, Paracelsus Medial University Salzburg, Salzburg, Austria

[6 ]Department of Cardiology, Public Hospital Elisabethinen Linz, Linz, Austria

[7 ]Pulmonary Clinic, Department of Cardiovascular and Thoracic Medicine, University Hospital Zurich, Zurich, Switzerland

[8 ]M.A.R.C.O. GmbH & Co. KG, Düsseldorf, Germany

[9 ]Am Eckbusch 75, 42113 Wuppertal, Germany

Article

Publisher ID: 1068

DOI: 10.1007/s00508-016-1068-8

PMC ID: 5161763

PubMed ID: 27590259

SO-VID: 43be781e-dec3-4c48-8165-6fed65beaa93

License:

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 18 January 2016

Date accepted : 29 July 2016

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100005788, Medizinische Universität Wien;

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ScienceOpen disciplines: Medicine

Keywords: heart failure with preserved ejection fraction,pulmonary hypertension,medical treatment

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ScienceOpen disciplines: Medicine

Keywords: heart failure with preserved ejection fraction, pulmonary hypertension, medical treatment

Evaluation of the pharmacoDYNAMIC effects of riociguat in subjects with pulmonary hypertension and heart failure with preserved ejection fraction : Study protocol for a randomized controlled trial

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Summary

Background

Methods/study design

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The International Journal of Person Centered Medicine

Most cited references 10

Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial.

Pulmonary hypertension in heart failure with preserved ejection fraction: a community-based study.

Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group.

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