What is the recommended use and dosing of Selexipag (selective IP receptor agonist) for a patient with pulmonary arterial hypertension (PAH) who is not responding to other treatments?

Selexipag for Pulmonary Arterial Hypertension

Selexipag is FDA-approved to delay disease progression and reduce hospitalization risk in PAH patients, but current evidence shows it does not significantly reduce mortality, and the 2019 CHEST guidelines concluded there is insufficient evidence to make a recommendation for or against its use due to lack of clinically meaningful improvement in functional capacity. 1, 2

FDA-Approved Indication and Dosing

Selexipag is indicated for PAH (WHO Group I) to delay disease progression and reduce the risk of hospitalization for PAH. 2

Standard Dosing Protocol

• Starting dose: 200 mcg twice daily 2
• Titration: Increase by 200 mcg twice daily at weekly intervals to the highest tolerated dose up to a maximum of 1,600 mcg twice daily 2
• Maintenance dose is determined by tolerability, not by a fixed target 2
• In the GRIPHON trial, patients achieved doses distributed as: 200-400 mcg (23%), 600-1,000 mcg (31%), and 1,200-1,600 mcg (43%) 2

Special Population Dosing

• Moderate hepatic impairment: Start at 200 mcg once daily, increase by 200 mcg once daily at weekly intervals to the highest tolerated dose up to 1,600 mcg once daily 2
• Severe hepatic impairment: Avoid use 2
• Severe renal impairment: No dose adjustment required, though exposure increases 40-70% 2

Evidence Base and Clinical Outcomes

The GRIPHON Trial Results

The pivotal GRIPHON trial enrolled 1,156 PAH patients (WHO FC I-IV, predominantly FC II-III) and demonstrated: 2, 3

• 40% reduction in the composite primary endpoint (HR 0.60,99% CI 0.46-0.78, p<0.0001) of death or PAH-related complications 2, 3
• The benefit was primarily driven by reductions in hospitalization for PAH and disease progression, not mortality 1, 2
• No significant difference in PAH mortality (HR 0.86,95% CI 0.63-1.18, p=0.18) 1
• No significant difference in all-cause mortality (HR 0.97,95% CI 0.74-1.28, p=0.42) 1
• Change in 6-minute walk distance was only 12 meters (99% CI 1-24), which did not meet the clinically meaningful threshold of 33 meters 1

Critical Limitation in the Evidence

The 2019 CHEST guidelines panel concluded there is insufficient evidence to recommend for or against selexipag because the primary endpoint was a composite score and the 6-minute walk distance improvement did not reach the minimally important difference of 33 meters. 1 This represents a significant divergence between FDA approval (based on composite endpoints) and guideline recommendations (which prioritize functional capacity).

European Guidelines Perspective

The 2015 ESC/ERS guidelines noted that selexipag reduced the composite morbidity-mortality endpoint by 40% (HR 0.60, p<0.001) when used alone or added to mono- or double therapy with ERAs and/or PDE-5 inhibitors. 1 However, these guidelines preceded the full CHEST analysis that highlighted the lack of clinically meaningful functional improvement.

Clinical Use in Practice

Background Therapy Considerations

• 80% of GRIPHON patients were already on PAH-specific therapy at baseline: ERA alone (15%), PDE-5 inhibitor alone (32%), or both (33%) 2
• Treatment effect was consistent regardless of background therapy, including monotherapy, dual therapy, or no background therapy 2
• Real-world data from SPHERE showed 55% of patients on double therapy and 30.6% on monotherapy at selexipag initiation 4

Patient Selection

Based on trial enrollment, selexipag has been studied in: 2

• WHO Functional Class II (46%) and III (53%) patients predominantly
• Idiopathic or heritable PAH (58%), CTD-associated PAH (29%), congenital heart disease with repaired shunts (10%)
• Patients at intermediate or high risk despite existing PAH therapy

Drug Interactions and Contraindications

Absolute Contraindications

• Concomitant use with strong CYP2C8 inhibitors (e.g., gemfibrozil) 2
• Hypersensitivity to selexipag or excipients 2

Dose Adjustments for Drug Interactions

• Moderate CYP2C8 inhibitors (clopidogrel, deferasirox, teriflunomide): Reduce dosing to once daily 2
• CYP2C8 inducers (rifampin): May increase dose up to twice the usual dose 2

Adverse Effects

The most common adverse effects (≥5% more frequent than placebo) are headache, diarrhea, jaw pain, nausea, myalgia, vomiting, pain in extremity, and flushing. 2 These are consistent with prostacyclin pathway effects. 5

• 14.3% of selexipag patients discontinued due to adverse events compared to 7.1% on placebo 3
• In real-world practice (SPHERE), 72.2% had at least one adverse event and 37.6% had a serious adverse event 4

Special Warnings

Pulmonary edema may occur in patients with pulmonary veno-occlusive disease; if confirmed, discontinue treatment. 2

Clinical Decision-Making Algorithm

Given the conflicting evidence between FDA approval and guideline recommendations:

1. For treatment-naïve WHO FC II-III PAH patients: Prioritize initial combination therapy with ambrisentan and tadalafil over selexipag monotherapy, as this has stronger evidence for functional improvement 1, 6

2. For patients inadequately controlled on ERA and/or PDE-5 inhibitor therapy: Consider selexipag as add-on therapy if the goal is to reduce hospitalization risk and delay disease progression, acknowledging it may not improve functional capacity 2

3. For patients who cannot tolerate or have contraindications to other PAH therapies: Selexipag represents an alternative prostacyclin pathway option with oral administration 2, 5

4. Titrate to the highest tolerated dose rather than targeting a specific dose, as benefit in GRIPHON was similar across all dose ranges 2

Real-World Considerations

• Median maintenance dose in real-world practice is 1,200 mcg twice daily (IQR 800-1,600 mcg) 4
• 72.4% of patients achieving low doses (200-400 mcg) required subsequent dose adjustments compared to 34.5% of those achieving high doses (1,200-1,600 mcg) 7
• Survival at 1 year was 85% and at 2 years was 71% in PAH-CTD patients treated with selexipag in the EXPOSURE study 8