What is the recommended treatment for a patient with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) using Selexipag?

Selexipag for Connective Tissue Disease-Associated Pulmonary Arterial Hypertension (CTD-PAH)

Selexipag should be used in patients with CTD-PAH to reduce morbidity and mortality, either as monotherapy in treatment-naïve patients or added to existing PDE-5 inhibitors and/or endothelin receptor antagonists, with dose titration to the highest tolerated level up to 1600 mcg twice daily. 1, 2

FDA-Approved Indication and Evidence Base

• Selexipag is FDA-approved specifically for PAH (WHO Group I) to delay disease progression and reduce hospitalization risk, with established effectiveness in patients with CTD-PAH who comprised 29% of the pivotal trial population 2
• The drug demonstrated a 44% risk reduction (HR 0.56; 95% CI 0.34 to 0.91) for the composite morbidity/mortality endpoint in the PAH-SSc subgroup (n=170 patients) compared to placebo 1
• This benefit was consistent whether patients were treatment-naïve or on stable doses of PDE-5 inhibitors, ERAs, or both 1

Dosing and Titration Protocol

Starting dose: 200 mcg twice daily, taken with food to improve tolerability 2

Titration schedule:

• Increase by 200 mcg twice daily increments at weekly intervals (per FDA label) or every other week in clinical practice 2, 3
• Target the highest tolerated dose up to maximum 1600 mcg twice daily 2
• If a dose is not tolerated, reduce to the previous tolerated dose 2

Maintenance dosing: The median maintenance dose in real-world practice is 1200 mcg twice daily (range 800-1600 mcg), with clinical benefit demonstrated across all dose ranges from low (200-400 mcg) to high (1200-1600 mcg) 4, 3

Treatment Algorithm by WHO Functional Class

WHO FC II patients (treatment-naïve):

• Initiate combination therapy with ambrisentan and tadalafil as first-line, with selexipag as an alternative or add-on option 5

WHO FC III patients:

• Add selexipag to existing dual therapy (PDE-5i + ERA) as triple oral combination therapy 5, 6
• In real-world CTD-PAH cohorts, 80% of patients initiated selexipag as triple oral therapy, with 62% remaining on triple therapy at 6 months 6

WHO FC IV or high-risk patients:

• Intravenous epoprostenol remains first-line therapy with proven survival benefit 5
• Selexipag is not the preferred initial agent in this population 5

Mechanism and Clinical Rationale

• Selexipag is a selective prostacyclin IP receptor agonist—the first non-prostanoid compound targeting this pathway—which addresses one of three established pathogenic pathways in PAH alongside endothelin and nitric oxide pathways 7
• The GRIPHON trial demonstrated a 40% reduction in the composite morbidity/mortality endpoint in 1,156 PAH patients, primarily driven by reductions in disease progression and PAH-related hospitalization 7, 8

Special Dosing Considerations

Hepatic impairment:

• Mild (Child-Pugh A): No adjustment needed 2
• Moderate (Child-Pugh B): Start at 200 mcg once daily, titrate weekly by 200 mcg once daily 2
• Severe (Child-Pugh C): Avoid use 2

Drug interactions:

• When co-administered with moderate CYP2C8 inhibitors (clopidogrel, deferasirox, teriflunomide), reduce dosing frequency to once daily 2

Missed doses:

• If treatment is interrupted for 3 or more days, restart at a lower dose and retitrate 2

Real-World Outcomes in CTD-PAH

• In the EXPOSURE study of 178 CTD-PAH patients, 1-year survival was 85% and 2-year survival was 71% 6
• Most patients (63%) had WHO FC III symptoms at baseline, with 30% at high risk and 40% at intermediate-high risk of 1-year mortality 6
• Discontinuation due to tolerability/adverse events occurred in 20% of patients over a median exposure of 8.6 months 6

Critical Pitfalls to Avoid

Do not use calcium channel blockers empirically in CTD-PAH—they have not shown effectiveness in this population, unlike idiopathic PAH 5

Do not routinely anticoagulate CTD-PAH patients—unlike idiopathic PAH where anticoagulation may be beneficial, recent meta-analysis in SSc-PAH showed increased mortality with anticoagulation (HR 1.58,95% CI 1.08 to 2.31) 1, 5

Do not delay escalation—real-world data suggest an opportunity to optimize outcomes by escalating therapy sooner to prevent clinical deterioration rather than waiting years for deterioration to occur 6

Tolerability Profile

• Adverse events are consistent with prostacyclin pathway therapies, including headache, jaw pain, diarrhea, nausea, and flushing 8
• In real-world practice, 72.2% of patients experienced at least one adverse event, with 37.6% reporting serious adverse events 4
• Tolerability improves when taken with food 2

Monitoring and Treatment Goals

• Reassess every 3-6 months using multiparametric risk stratification 5
• Target low-risk status: WHO FC I-II, 6-minute walk distance >440 meters, preserved right ventricular function, normal/near-normal BNP/NT-proBNP 5
• In real-world cohorts, risk scores remained stable in ~55% and improved in ~20% of patients 4