What is the role of selexipag (Selexipag) and riociguat (Riociguat) in the treatment of pulmonary arterial hypertension (PAH)?

Role of Selexipag and Riociguat in Pulmonary Arterial Hypertension Treatment

Both selexipag and riociguat are effective treatments for pulmonary arterial hypertension (PAH), with selexipag recommended as add-on therapy to reduce morbidity/mortality events by 44% in patients already on background therapy, and riociguat recommended for patients who need to add or switch from PDE5 inhibitors, particularly in systemic sclerosis-associated PAH. 1

Mechanism of Action and Indications

Selexipag

• Oral prostacyclin receptor agonist (IP receptor agonist)
• FDA-approved for PAH (WHO Group I) to delay disease progression and reduce hospitalization risk 2
• Targets the prostacyclin pathway, one of the three main pathways involved in PAH pathogenesis 3
• Dosing: Starting at 200 mcg twice daily, titrated weekly to maximum tolerated dose up to 1,600 mcg twice daily 2

Riociguat

• Soluble guanylate cyclase stimulator
• Enhances the nitric oxide-cGMP pathway, causing pulmonary vasodilation and anti-proliferative effects 1
• Approved for PAH and chronic thromboembolic pulmonary hypertension (CTEPH) 1
• Dosing: 0.5-1 mg three times daily initially, titrated to maximum of 2.5 mg three times daily 1

Evidence for Efficacy

Selexipag

• In SSc-PAH patients (n=170), selexipag showed a 44% reduction in risk of morbidity/mortality events (HR 0.56,95% CI 0.34-0.91) 1
• The SPHERE registry (real-world data) showed that at 18 months, most patients had stable or improved WHO functional class and risk category 4
• 18-month survival rates were 89.4% overall (84.2% in newly initiated patients) 4
• Efficacy is consistent across different maintenance dose ranges 5

Riociguat

• In SSc-PAH patients (n=66), riociguat improved 6-minute walk distance (6MWD) by 4 meters compared to a 37-meter worsening in the placebo group 1
• Associated with improvements in hemodynamics and WHO functional class 1
• Long-term extension study showed maintained improvements in exercise and functional capacity at 4 years 6
• 3-year survival rate of 91% in a mixed PAH/CTEPH population 6

Treatment Algorithm Based on Patient Characteristics

1. Initial Therapy for PAH:

   • First-line combination therapy with endothelin receptor antagonists (ERAs) and PDE5 inhibitors is recommended 7
   • For patients with positive vasoreactivity testing (10-15% of IPAH patients), calcium channel blockers are recommended 7

2. Add-on Therapy:

   • For patients already on PDE5i and/or ERA therapy with inadequate response:

     • Consider adding selexipag to reduce risk of clinical worsening and hospitalization 1
     • Selexipag showed a 44% reduction in morbidity/mortality events in this population 1

   • For patients on PDE5i with inadequate response or intolerance:

     • Consider switching to or adding riociguat 1
     • Note: Combination of PDE5i and riociguat is contraindicated due to risk of hypotension 7

3. Based on WHO Functional Class:

   • WHO FC III/IV or intermediate/high risk:
     • Consider riociguat or adding prostacyclin agonists like selexipag 1
     • For advanced PAH (WHO FC IV), IV prostacyclin analogs should be considered 7

Safety Considerations

Selexipag

• Most common adverse events: headache, diarrhea, jaw pain, nausea (prostacyclin-associated side effects)
• In the SPHERE registry, 18-month discontinuation rates for adverse events were 22% overall 4
• No new safety signals identified in long-term real-world use 4

Riociguat

• Most common adverse events: headache, dizziness, dyspepsia, peripheral edema
• Contraindicated with PDE5 inhibitors due to risk of severe hypotension
• Contraindicated in pregnancy (teratogenic potential) 1
• Long-term safety profile shows nasopharyngitis (57%) and peripheral edema (37%) as most common adverse events 6

Special Populations

Systemic Sclerosis-Associated PAH

• Both selexipag and riociguat have demonstrated efficacy specifically in SSc-PAH patients 1
• Riociguat showed improvements in 6MWD, hemodynamics, and WHO functional class in SSc-PAH 1
• Selexipag reduced morbidity/mortality events by 44% in SSc-PAH patients 1

Hepatic Impairment

• For selexipag:
  • No dose adjustment needed for mild hepatic impairment
  • For moderate impairment, start at 200 mcg once daily and titrate weekly
  • Avoid in severe hepatic impairment 2

Important Caveats and Pitfalls

1. Drug Interactions:

   • Selexipag dose should be reduced to once daily when co-administered with moderate CYP2C8 inhibitors (e.g., clopidogrel) 2
   • Riociguat should never be combined with PDE5 inhibitors or nitrates due to risk of severe hypotension 7

2. Treatment Monitoring:

   • Regular assessment of WHO functional class, 6MWD, right ventricular function, and BNP/NT-proBNP levels is essential 7
   • Treatment should be managed at specialized centers with expertise in PAH 7

3. Anticoagulation in PAH:

   • Anticoagulants (warfarin) are not recommended for SSc-PAH due to increased mortality risk (HR 1.58) 1
   • This differs from idiopathic PAH where anticoagulation may be considered 1

4. Dosing Considerations:

   • Both medications require careful up-titration to reach effective doses while managing side effects
   • Efficacy of selexipag appears consistent across different maintenance dose ranges, suggesting individualized dosing to maximum tolerated dose is appropriate 5, 4