Evaluating Efficacy of Initial Combination Therapy on Pulmonary Vascular Resistance

An ongoing study is aiming to clarify if macitentan plus riociguat or macitentan plus selexipag are equally effective in reducing pulmonary vascular resistance (PVR) 8 months after initiating the combination therapy in pulmonary arterial hypertension (PAH). The study protocol was published in Circulation Reports.

Long-term survival in patients with PAH can be attributed to reduction in pulmonary artery pressure and PVR and combination early in therapy “is thought to lead to good hemodynamic responses,” the authors wrote.

The SETOUCHI-PH study will evaluate reductions in PVR 8 months after initial combination therapy with macitentan plus riociguat or macitentan plus selexipag. The multicenter, prospective, open-label, randomized control trial will take place in 9 hospitals in Japan and will include patients who meet any of the following:

• A mean pulmonary artery pressure of ≥ 25 mmHg, pulmonary artery wedge pressure ≤ 15 mmHg, and PVR ≥ wood units by right heart catheterization
• World Health Organization functional class (WHO-FC) II or III

When the study started recruiting in April 2019, there had been no interventional studies on the effects of these combination therapies on hemodynamics in PAH. The final enrollment for the SETOUCHI-PH has been set at 76 patients.

“Previously, riociguat was reported to reduce PVR by a mean (±SD) of 223±260 dyn/s/cm5, whereas selexipag was reported to reduce PVR by a mean (±SD) of 130±310 dyn/s/cm5,” the authors explained.

Enrolled patients will be randomized 1:1 to receive macitentan 10 mg once a day plus riociguat 0.5 three times a day or macitentan 10 mg once a day plus selexipag 0.2 mg twice a day. The patients will start with macitentan on Day 1 and will then have a blood examination on Day 3 to identify any side effects. In the absence of side effects, riociguat or selexipag will be added to the regimen.

Patients will undergo chest radiography, laboratory tests, electrocardiography, a 6-minute walk distance (6MWD) tests, and echocardiography on Day 7. These will be performed at 12 weeks and at 32 weeks. At 32 weeks, patients will also undergo lung function tests and right heart catheterization.

The full treatment period is 32 weeks because the riociguat dose can be increased at least every 2 weeks and the selexipag dose can be increased at least once a week, and the researchers are looking to evaluate the effects of the maximum doses of the drugs.

The primary outcome is the difference in the change ratio of PVR from baseline between the 2 treatment regimens. The key secondary outcomes are differences from baseline to follow-up between the 2 regimens in B-type natriuretic peptide, echocardiographic parameters, pulmonary function parameters, hemodynamic parameters and 6MWDs.

“We designed the SETOUCHI-PH study to evaluate equivalence because we speculate that initial combination therapy will contribute to good hemodynamic outcomes regardless of the PAH-specific drugs used,” the authors wrote.

Reference

Akagi S, Dohi Y, Ishikawa K, et al. Effects of dual initial combination therapy with macitentan plus riociguat or macitentan plus selexipag on hemodynamics in patients with pulmonary arterial hypertension (SETOUCHI-PH Study): protocol of a multicenter randomized control trial. Circ Rep. 2021;3(2):105-109. doi:10.1253/circrep.CR-20-0133