Chronic thromboembolic pulmonary hypertension (CTEPH) results from the obstruction of the
pulmonary arteries by organised fibrotic thrombi and the associated microvasculopathy,
leading to increased pulmonary vascular resistance and progressive right-sided heart
failure. CTEPH is associated with significant mortality and morbidity, so prompt
initiation of treatments are necessary to improve the prognosis.
For those with accessible pulmonary arteries occlusions, surgical pulmonary
endarterectomy (PEA) is the treatment of choice. Nevertheless, about 40% of CTEPH
patients are not considered to be operable due to occlusion of distal pulmonary vessels.
For patients with inoperative CTEPH, current treatment options include balloon pulmonary
angioplasty (BPA) and medical therapies.
Several medical therapies that target microvascular components of CTEPH, such as
phosphodiesterase type 5 inhibitor (PDE5i) and endothelin receptor antagonist (ERA), have
been used off-label, as the efficacy of those medications in inoperable CTEPH has not
been proven in randomised controlled trials or registry data. The CHEST-1 randomised
controlled trial demonstrated that the soluble guanylate cyclase stimulator (sGCs),
riociguat, significantly reduced pulmonary vascular resistance and improved exercise
capacity in patients with inoperative CTEPH or persistent or recurrent pulmonary
hypertension after PEA. Based on the finding of this study, riociguat has been approved
for treatment for symptomatic inoperable patients with CTEPH.
Both PDE5i and sGCs act via the same nitric oxide (NO)-soluble guanylate cyclase
(sGC)-cyclic guanosine monophosphate (cGMP) pathway, but these two classes of medications
target different molecular targets in the same pathway. PDE5i inhibits the degradation of
cGMP, so its efficacy is dependent on a functioning NO-sGC-cGMP axis and the presence of
intracellular cGMP. In contrast, riociguat stimulates sGC directly, thus it increases
intracellular cGMP level regardless the presence of NO. Therefore, based on this
biological rationale, it is postulated that riociguat may be more effective in increasing
intracellular cGMP compared to PDE5i. Currently there is no head-to-head trials comparing
the efficacy of PDE5i and riociguat in treating pulmonary hypertension. Nevertheless, 2
clinical trials have demonstrated improvement in the clinical and biochemical parameters
after switching from PDE5i to sGCs in selected patients with pulmonary arterial
hypertension (PAH) with insufficient response to PDE5i. It is currently unknown whether
this switching will also apply to patients with CTEPH as those 2 clinical trials do not
include patients with CTEPH.
In addition to medical therapies, BPA, an endovascular procedure to dilate the occlusions
and stricture in segmental or subsegmental pulmonary arteries, has emerged as a treatment
for patients with inoperable CTEPH or persistent or recurrent pulmonary hypertension
after PEA. Two randomised controlled trials comparing BPA and riociguat have demonstrated
that BPA was associated with a greater improvement in mean pulmonary artery pressure and
reduction in pulmonary vascular resistance in inoperable CTEPH patients.
Currently, the data of safety and efficacy of switching PDE5i to sGCs after BPA is
lacking. Therefore, this study was designed to investigate the safety and efficacy of
replacing PDE5i with riociguat in patients with CTEPH who have undergone BPA and remains
symptomatic despite treatments with PDE5i.