84
Specific Conditions
Table 43. First-Line PAH-Directed Therapy in Patients With
Eisenmenger Syndrome
Medication Class Clinical Trial Evidence
Endothelin receptor
antagonists
Two moderate-size randomized controlled trials of bosentan
(BREATHE 5 trial, 54 patients) and macitentan (MAESTRO
trial, 226 patients) evaluated the effects of endothelin receptor
antagonists in Eisenmenger syndrome. BREATHE 5 showed
improvement in hemodynamics and functional class aer 16
weeks of treatment. e MAESTRO trial design was different
and included a more heterogeneous patient population, including
wider age range, wider spectrum of functional classes, patients
on back-ground therapy with PDE5 inhibitors, and patients
with Down syndrome. e primary end-point, which consisted
of 6MWD, was neutral. Secondary endpoints of functional
class and NT-proBNP levels favored macitentan therapy. In a
subgroup of patients aged ≥18 years who had a follow-up invasive
hemodynamic assessment and did not have Down syndrome,
those in the macitentan group had hemodynamic improvement,
which was also associated with an improvement in 6MWD.
Phosphodiesterase-5
inhibitors
A small randomized controlled trial (28 patients) and a
retrospective observational study showed improvements in
6MWD, functional status, and hemodynamics without a
significant reduction in SVR.
Soluble guanylate
cyclase stimulator
(riociguat)
Data on Eisenmenger syndrome are currently lacking. A
subgroup analysis of the trials that had shown benefit in PAH
(PATENT 1+2) demonstrated that in patients with persistent or
recurrent PAH aer con-genital heart defect correction, riociguat
use was associated with sustained improvement in 6MWD, PVR,
NT-proBNP level, and WHO functional class at 2 years.
Prostacyclin analogs
and receptor
agonists
Data on the effects of inhaled iloprost are conflicting, with 1
small randomized controlled trial (16 patients) showing no
effect on 6MWD, BNP levels, or quality of life, whereas 1 small
single-arm study (11 patients) showed an increase in 6MWD,
subjective quality of life, and RV function. ere are no data on
subcutaneous/intravenous prostacyclin or oral prostacyclin receptor
agonist therapy (selexipag ) as a stand-alone initial treatment.
Activin signaling
inhibitors
No data are currently available on the activin signaling inhibitor
sotatercept in patients with Eisenmenger syndrome.
6MWD indicates 6-minute walk distance; ACC, American College of Cardiolog y; AHA, American
Heart Association; BNP, B-type natriuretic peptide; BREATHE-5, Bosentan Randomized Trial of
Endothelin Antagonist erapy-5; ERS, European Respiratory Society; ESC, European Society of
Cardiolog y; MAESTRO, Macitentan in Eisenmenger Syndrome to Restore Exercise Capacity; NT-
proBNP, N-terminal prohormone of B-type natriuretic peptide; PAH, pulmonary arterial hypertension;
PATENT 1+2, Pulmonary Arterial hypertension sGC-stimulator Trial; PVR, pulmonary vascular
resistance; SVR, systemic vascular resistance; and WHO, World Health Organization.
