Riociguat Should Be Continued When Adding Selexipag
In a patient with WHO Group 1 PAH on riociguat (Adempas) with suboptimal response, you should continue riociguat when adding selexipag (Uptravi) to achieve triple oral combination therapy. This approach is supported by both FDA labeling and recent clinical evidence demonstrating safety and efficacy of this specific combination.
Rationale for Continuing Riociguat
The FDA label for Uptravi explicitly indicates it is approved "as combination therapy in patients insufficiently controlled with an endothelin receptor antagonist and/or a phosphodiesterase type 5 inhibitor" 1. While riociguat is not specifically mentioned in this indication, it functions as an alternative to PDE5 inhibitors in the nitric oxide pathway, and recent evidence strongly supports triple therapy including riociguat.
Multiple recent studies demonstrate that the ERA + riociguat + selexipag combination is both effective and well-tolerated:
A 2024 multicenter study of 192 PAH patients showed that oral sequential triple combination therapy (including 37 patients on ERA + riociguat + selexipag) improved WHO functional class, increased 6-minute walk distance, reduced NT-proBNP levels, and achieved 88% event-free survival at 6 months 2, 3.
A 2021 Japanese study specifically evaluated macitentan + riociguat + selexipag triple therapy in 26 patients, demonstrating 29% reduction in mean PAH pressure, 65% reduction in pulmonary vascular resistance, and 93.3% survival at 3 years 4. Importantly, 65.4% of patients reached maximum doses of all three drugs, indicating good tolerability.
Critical Contraindication to Note
You cannot combine riociguat with PDE5 inhibitors (sildenafil or tadalafil). The Adempas FDA label explicitly states: "Discontinue sildenafil at least 24 hours prior to administering Adempas" and "Discontinue tadalafil at least 48 hours prior to administering Adempas" 5. This is a contraindication due to hypotension risk. Therefore, if your patient were on a PDE5 inhibitor instead of riociguat, you would need to discontinue it before starting selexipag.
Practical Implementation
When adding selexipag to existing riociguat therapy:
- Start selexipag at 200 mcg twice daily (standard FDA-approved starting dose) 1
- Continue riociguat at current dose initially, but monitor closely for hypotension
- Titrate selexipag weekly by 200 mcg increments to maximum tolerated dose (up to 1,600 mcg twice daily)
- Monitor blood pressure carefully during titration, as both drugs can cause hypotension
- Consider reducing riociguat by 0.5 mg three times daily if symptomatic hypotension occurs, rather than stopping it entirely
Risk Stratification Matters
The 2024 studies showed differential responses based on baseline risk 2:
- Low/intermediate-risk patients: 92.9% prostacyclin-free rate at 3 years with triple therapy
- High-risk patients: 55% prostacyclin-free rate at 3 years
This suggests triple oral therapy is particularly effective in preventing escalation to parenteral prostacyclins in lower-risk patients, but even high-risk patients benefit.
Common Pitfall to Avoid
Do not discontinue riociguat simply because you're adding selexipag. The evidence supports additive benefit from triple combination therapy. The only scenario requiring riociguat discontinuation would be if you needed to switch to a PDE5 inhibitor instead (which would require stopping riociguat 24 hours before starting the PDE5 inhibitor) 5.