Riociguat could improve the exercise capacity and residual symptoms in patients with chronic thromboembolic pulmonary hypertension (CTEPH) even after normalization of pulmonary arterial pressure by balloon pulmonary angioplasty (BPA). This randomized controlled trial study aimed to clarify whether the improvement of peak cardiac index (CI) during exercise maintains or not between the riociguat continued group and the riociguat discontinued group.

CTEPH is a disease that causes progressive pulmonary hypertension due to stenoses or occlusions in the pulmonary artery due to an organized thrombus. And this is a disease that results in right heart failure and death unless early diagnosis and appropriate treatment are performed. Pulmonary endarterectomy (PEA), which surgically removes the intimal thrombus, has been established as the treatment of choice for CTEPH. In the AHA/ACC guideline and ESC guideline, PEA for CTEPH is class IC (1). In 2014, a soluble guanylate cyclase stimulant (generic name: riociguat), which is one of the therapeutic agents for pulmonary hypertension, was approved for patients with CTEPH who are ineligible for PEA, and residual pulmonary hypertension after PEA (2). In addition, it has been reported that BPA, which is a catheter interventional treatment, is also effective to improve hemodynamics in inoperable patients with CTEPH (3, 4). However, some patients have residual symptoms such as dyspnea on exertion even after normalization in hemodynamics by BPA. A randomized control study should be done to confirm the necessary of continuation of riociguat for such patients.

Inclusion Criteria:

1. Patients who meet CTEPH diagnostic criteria (complying with 2017 Japanese Cardiovascular Society Guidelines diagnostic criteria)
2. Patients with diagnosed as a contraindication of pulmonary endarterectomy by an experienced surgeon in the central diagnosis
3. Patients who were adjusted to reach the appropriate dose of riociguat within 8 weeks and were able to continue riociguat thereafter
4. Patients who underwent BPA once or more after the dose adjustment of riociguat
5. Patients who have been able to continue taking the same dose of riociguat for more than 3 months
6. Patients who can obtain written informed consent from the patients and legal representatives
7. Patients with WHO functional class II or III at the time of the allocation
8. Over the age of 18 and under 85 at the time of obtaining informed consent
9. Patients with the resting CI value of less than 3.0 L/min/m2 in the right heart catheterization test immediately before the allocation
10. Patients with the mean pulmonary artery pressure less than 25 mmHg in a right heart catheterization test immediately before the allocation

Exclusion Criteria:

1. Patients who are eligible for pulmonary endarterectomy (PEA)
2. Patients with pulmonary hypertension other than class 4 by NICE classification
3. Patients having difficulty in performing cardiopulmonary exercise test (CPET)
4. Patients with severe right heart failure requiring cardiotonic drugs
5. Patients with severe heart disease
6. Patients with severe liver damage
7. Patients with systolic blood pressure less than 90 mmHg at the screening
8. Patients with shunt disease
9. Patients with severe renal dysfunction (CCr < 15 mL/min) requiring hemodialysis
10. Patients with life expectancy less than 2 years
11. Being pregnant or lactating
12. Patients who are contraindicated for riociguat
13. Patients using other unlicensed drugs
14. Patients who used pulmonary vasodilators within 4 weeks after obtaining the informed consent of the right heart catheterization test.
15. Patients whom the investigator determines that the participation in this study is inappropriate

A double-blind, placebo-controlled study