Riociguat Improves Clinical Outcomes in Chronic Thromboembolic Pulmonary Hypertension

Table of Content

Introduction

Although pulmonary endarterectomy is the only potentially curative treatment for chronic thromboembolic pulmonary hypertension (CTEPH), not all patients are eligible for surgery and some patients who have undergone surgery may also present persistent or recurrent CTEPH. Riociguat, first in the class of soluble guanylate cyclase (sGC) stimulator has been approved for such CTEPH cases. Riociguat directly stimulates sGC independently of nitric oxide (NO) and in presence of NO, it increases the sensitivity of soluble guanylate cyclase to NO. Riociguat causes vasorelaxation and has antiproliferative and antifibrotic effects. Clinical study in CTEPH patients have shown the improvement in exercise capacity and hemodynamic variables with riociguat.

Aim

Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator Trial 1 (CHEST-1) evaluated the efficacy and safety profile of riociguat in patients with CTEPH who were considered as ineligible for surgery or who had persistent or recurrent PH after pulmonary endarterectomy.

Methods

Study design

  • Double-blind, randomized phase 3 trial
  • Patients aged 18 to 80 years diagnosed with CTEPH
  • Ineligible for surgery or had persistent or recurrent PH after pulmonary endarterectomy
  • Number of patients: 261
  • Patients were randomized 1:2 into placebo (N=88) or riociguat groups (N=173)
  • The dose of riociguat was adjusted for 8 weeks to a final range of 0.5 to 2.5 mg thrice daily
  • Follow up at weeks 2, 4, 6 and 8 (dose-adjustment phase) and at weeks 12 and 16 during the maintenance phase

Endpoints

Primary Endpoint

  • Change from baseline to week 16 in the 6-minute walk distance (6-MWD)

Secondary Endpoints

  • Changes from baseline to week 16 in pulmonary vascular resistance (PVR) and N-terminal pro-brain natriuretic peptide (NT-proBNP) level
  • World Health Organization (WHO) functional class
  • Time to clinical worsening
  • Borg dyspnea score
  • Quality of life variable
  • Safety

Results

  • Out of a total of 261 patients, 173 received riociguat and 88 received placebo
  • The riociguat showed significant improvements in the endpoints at week 16 from baseline as shown in table 1.
Table 1. Changes in endpoints from baseline to week 16

Parameter

Riociguat

Placebo

Least squares mean difference

P value

 

Baseline

Change

Baseline

Change

 

 

6-MWD (m)

342+82

39+79

356+75

-6+84

46

<0.001

PVR (dyn.sec.cm-5)

791+432

-226+248

779+401

23+274

-246

<0.001

NT-pro BNP (pg/ml)

1508+2338

-291+1717

1706+2567

76+1447

-444

<0.001

  • Significant improvement in WHO FC was seen in riociguat group (33% vs 15%; p=0.003)
  • The difference in the incidence of clinically worsening events was insignificant in both the groups (2% vs 6%; p=0.17)
  • Borg dyspnea score decreased by 0.8 points in the study group whereas it increased by 0.2 points in the placebo group; p=0.004
  • Riociguat and placebo groups had similar incidence of serious adverse events
    • Right ventricular failure (3% in both)
    • Syncope (2% vs 3% respectively)
    • Hemoptysis (2% vs 0% respectively)

Conclusion

  • Treatment with riociguat demonstrated improvement in 6-minute walk distance, pulmonary vascular resistance, WHO functional class and other clinical outcomes in patients with chronic thromboembolic pulmonary hypertension

N Engl J Med. 2013 Jul 25;369(4):319-29. Doi: 10.1056/NEJMoa1209657.