Randomized Study of Triple Therapy vs Sildenafil Dose Optimization in Pulmonary Arterial Hypertension

This is a prospective, randomized, open-label, parallel-group clinical trial designed to evaluate therapeutic escalation strategies in adults with pulmonary arterial hypertension (PAH, Group 1) who remain at intermediate-low, intermediate-high, or high risk according to the COMPERA 2.0 four-stratum model despite stable dual therapy.

Eligible participants must be receiving an endothelin receptor antagonist in combination with sildenafil and have a clinical indication for treatment escalation. After confirmation of eligibility and baseline assessments, participants will be randomized in a 1:1 ratio to one of two strategies:

Escalation to triple therapy through addition of a prostacyclin pathway agent (inhaled iloprost or selexipag), according to clinical judgment and availability.

Optimization of dual therapy by increasing the dose of sildenafil according to clinical practice.

Baseline assessments may include WHO functional class, 6-minute walk distance, and BNP or NT-proBNP levels obtained within 90 days prior to randomization. Follow-up evaluation will occur between 3 and 6 months after randomization, with the primary analysis based on the assessment closest to 6 months within that window.

The primary endpoint is the proportion of patients who achieve improvement in risk stratification, defined as a decrease of at least one risk category according to the COMPERA 2.0 four-stratum model. Secondary endpoints include composite clinical improvement and worsening, change in individual clinical parameters, time to clinical worsening, safety outcomes, need for additional therapeutic escalation, and treatment persistence.

The study is powered to detect a clinically meaningful absolute difference of 20 percentage points in risk improvement between groups, with planned enrollment of approximately 196 participants to account for potential losses to follow-up

Inclusion criteria

• Age ≥18 years
• Diagnosis of pulmonary arterial hypertension (PAH, Group 1) confirmed according to accepted clinical and hemodynamic criteria
• Stable treatment with an endothelin receptor antagonist in combination with sildenafil prior to randomization
• Classified as intermediate-low, intermediate-high, or high risk according to the COMPERA 2.0 four-stratum model
• Clinical indication for therapeutic escalation
• Availability for follow-up assessment between 3 and 6 months after randomization
• Ability to provide written informed consent

Exclusion criteria

• Participation in another interventional clinical trial that mandates treatment modification
• Known contraindication to prostacyclin pathway agents (including iloprost or selexipag)
• Known contraindication to sildenafil dose escalation
• Pregnancy or breastfeeding
• Women of childbearing potential not using effective contraception
• Any clinical condition that, in the investigator's judgment, would interfere with study participation or outcome assessment