Riociguat for pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD): A subgroup analysis from the PATENT studies

  • Rosenkranz Stephan
  • Hossein-Ardeschir Ghofrani
  • Maurice Beghetti
  • Dunbar Ivy
  • Arno Fritsch
  • Gerrit Weimann
  • Soundos Saleh
  • Christian Apitz
  • Reiner Frey
Open Access
Meeting abstract
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Keywords

Congenital Heart Disease Pulmonary Arterial Hypertension Guanylate Cyclase Placebo Patient Soluble Guanylate Cyclase 

Background

Pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) is a common associated form of PAH [1]. Riociguat, a soluble guanylate cyclase stimulator, was shown to be a safe and effective treatment for patients with PAH in the Phase III PATENT-1 study and the PATENT-2 long-term extension [2, 3]. Here we report data for the subgroup of patients with PAH-CHD in PATENT-1 and PATENT-2.

Materials and methods

In PATENT-1, adults with symptomatic PAH were randomized to receive placebo, riociguat up to 2.5 mg three times daily (tid) or riociguat up to 1.5 mg tid (exploratory) for 12 weeks. Patients completing PATENT-1 without ongoing riociguat-related serious adverse events (AEs) were eligible to enter the PATENT-2 long-term extension, during which all patients received open-label riociguat up to 2.5 mg tid.

Results

There were 35 patients with PAH-CHD in PATENT-1. All had persistent/recurrent PAH following complete surgical repair of CHD. Mean time since last corrective surgery was 16.8 years. At baseline, 57% of patients were treatment-naïve and all were in WHO FC II (60%) or III (40%). At Week 12, 6MWD (primary endpoint) had increased from baseline by mean±SD 39±60 m in the riociguat 2.5 mg–maximum group and by 43±54 m in the 1.5 mg–maximum group and was unchanged with placebo (Figure 1). Several secondary endpoint, including PVR, NT-proBNP and WHO FC, also improved from baseline in both riociguat groups (Table 1). Of 35 patients with PAH-CHD in PATENT-1, 33 entered PATENT-2. The improvements in 6MWD with riociguat seen in PATENT-1 were sustained for up to 2 years; 6MWD also increased in the former placebo group after transition to riociguat (Figure 2). At 2 years the overall mean±SD change from PATENT-1 baseline in 6MWD in PATENT-2 was +68±97 m and WHO FC had improved/stabilized/worsened in 32/60/8% of patients (n=25). In PATENT-1, the most commonly reported AEs (occurring in ≥15% of PAH-CHD patients in any treatment group) were dyspepsia, headache, dizziness, palpitations, back pain, nausea, vomiting, chest discomfort, dyspnea and pain in extremity. Six serious AEs were reported in these patients in PATENT-1: intra-abdominal hemorrhage (one riociguat 2.5 mg–maximum patient); right ventricular failure and worsening PAH (separate events in one 1.5 mg–maximum patient); loss of consciousness (one placebo patient); pneumothorax and supraventricular tachycardia (separate events in one placebo patient). None of these events were considered related to study drug. No new or unexpected safety signals were observed in PAH-CHD patients in PATENT-2.
Table 1

Changes from baseline to end of Week 12 in secondary endpoints in patients with PAH-CHD in PATENT-1 (observed values):

 

Placebo

Riociguat 2.5 mg–maximum

Riociguat 1.5 mg–maximum

 

n

Baseline

Change from baseline

n

Baseline

Change from baseline

n

Baseline

Change from baseline

PVR (dyn·s·cm–5)

11

1312±763

-66±632

13

1130±664

-250±410

7

1047±564

-126±368

NT-proBNP (pg/mL)

12

1573±1775

-46±697

13

761±1172

-164±317a

7

1352±1350

-872±1147a

WHO FC (%)

12

II – 58%

Improved 8%

15

II – 67%

Improved 21%

8

II – 50%

Improved 29%

  

III – 42%

Stabilized 83%

 

III – 33%

Stabilized 79%

 

III – 50%

Stabilized 71%

   

Worsened 8%

  

Worsened 0%a

  

Worsened 0%a

Borg dyspnea score

12

4.3±2.7

-0.1±2.4

15

2.5±1.4

-0.3±1.3b

8

3.2±1.6

-0.8±0.8a

EQ-5D score

12

0.74±0.16

-0.05±0.22

15

0.78±0.15

0.03±0.18a

8

0.74±0.08

+0.09±0.14a

LPH score

12

40.4±20.0

-0.1±15.8

15

34.9±26.0

-8.0±15.9a

8

40.0±15.3

-13.7±13.2a

Data are mean±SD unless otherwise indicated.

a Data missing for one patient.

b Data missing for two patients. EQ-5D, EuroQol Group 5-Dimension Self-report Questionnaire; Living with Pulmonary Hypertension questionnaire NT-proBNP, N-terminal prohormone of brain natriuretic peptide; PVR, pulmonary vascular resistance; WHO FC, World Health Organization functional class

Figure 1.

Change from baseline in 6MWD in patients with PAH-CHD in PATENT-1

Data are observed values (mean±SEM)

6MWD, 6-minute walking distance; SEM, standard error of the mean

Figure 2.

Change from baseline in 6MWD in patients with PAH-CHD in PATENT-1 and PATENT-2

Data are observed values (mean±SEM)

Data from PATENT-1 are shown for patients who subsequently entered PATENT-2

6MWD, 6-minute walking distance; SEM, standard error of the mean

Conclusion

This exploratory subgroup analysis showed that riociguat improved clinical outcomes and was well tolerated in patients with persistent/recurrent PAH following complete surgical repair of CHD.

References

  1. 1.
    D'Alto M, Mahadevan VS: Pulmonary arterial hypertension associated with congenital heart disease. Eur Respir Rev. 2012, 21 (126): 328-337. 10.1183/09059180.00004712.CrossRefPubMedGoogle Scholar
  2. 2.
    Ghofrani HA, Galiè N, Grimminger F, Grünig E, Humbert M, Jing ZC, et al: Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013, 369: 330-340. 10.1056/NEJMoa1209655.CrossRefPubMedGoogle Scholar
  3. 3.
    Rubin LJ, Galie N, Grimminger F, Grunig E, Humbert M, Jing Z-C, et al: Riociguat for the treatment of pulmonary arterial hypertension (PAH): a long-term extension study (PATENT-2). Eur Respir J. 2015, 45 (5): 1303-1313. 10.1183/09031936.00090614.CrossRefPubMedGoogle Scholar

Copyright information

© Stephan et al. 2015

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors and Affiliations

  • Rosenkranz Stephan
    • 1
  • Hossein-Ardeschir Ghofrani
    • 2
  • Maurice Beghetti
    • 3
  • Dunbar Ivy
    • 4
  • Arno Fritsch
    • 5
  • Gerrit Weimann
    • 5
  • Soundos Saleh
    • 5
  • Christian Apitz
    • 6
  • Reiner Frey
    • 5
  1. 1.Department III of Internal Medicine and Cologne Cardiovascular Research Center (CCRC)Cologne University Heart CenterCologneGermany
  2. 2.Department of Internal MedicineUniversity Hospital Giessen and MarburgGiessenGermany
  3. 3.Paediatric Cardiology Unit, Children's HospitalUniversity Hospital of GenevaGenevaSwitzerland
  4. 4.Department of PediatricsUniversity of Colorado School of Medicine, Children's Hospital ColoradoAuroraUS
  5. 5.Bayer Pharma AGWuppertalGermany
  6. 6.Pediatric Heart CentreUniversity Children's HospitalGiessenGermany

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