Role of Riociguat in Chronic Thromboembolic Pulmonary Hypertension (CTEPH)
Riociguat is strongly recommended for symptomatic patients with inoperable CTEPH or persistent/recurrent CTEPH after pulmonary endarterectomy (PEA) to improve exercise capacity and WHO functional class. 1
Treatment Algorithm for CTEPH
- All patients with CTEPH should be evaluated by a multidisciplinary team including at least one experienced PEA surgeon to determine operability 1
- Surgical PEA in deep hypothermia circulatory arrest is the first-line treatment for operable CTEPH patients 1
- Lifelong anticoagulation is recommended in all CTEPH patients, including after successful PEA or balloon pulmonary angioplasty (BPA) 1
- For patients with inoperable CTEPH or persistent/recurrent CTEPH after PEA, riociguat is the only approved targeted therapy 1
- BPA may be considered in patients who are technically non-operable or have unfavorable risk-benefit ratio for PEA 1
Evidence Supporting Riociguat in CTEPH
Efficacy
- Riociguat significantly increases 6-minute walking distance (6MWD) by 39 meters compared to placebo (primary endpoint) 1
- Riociguat significantly reduces pulmonary vascular resistance (PVR) by 246 dyn.cm.s⁻⁵ compared to placebo (secondary endpoint) 1
- Long-term data shows sustained benefits in exercise and functional capacity for up to 1 year 2
- 10-year observational data demonstrates sustained improvement in PVR and cardiac index, with survival estimates of 97%, 86%, 72%, and 61% at 1,3,5, and 8 years, respectively 3
Mechanism of Action
- Riociguat is an oral stimulator of soluble guanylate cyclase that works within the nitric oxide pathway in pulmonary vasculature 1, 4
- This mechanism addresses the pulmonary microvascular disease component of CTEPH 1
Dosing and Administration
- Riociguat is administered three times daily, starting at 1 mg and titrating up to a maximum of 2.5 mg three times daily based on systemic blood pressure tolerance 5, 4
- Careful dose adjustment is required, with monitoring for hypotension 4
Safety Profile
- The most common serious adverse events include syncope (6%), right ventricular failure (3%), and pneumonia (2%) 5
- Hypotension and bleeding are the two most serious adverse effects 4
- Riociguat is contraindicated in pregnancy (category X) 4
Comparative Efficacy
- Unlike the dual endothelin antagonist bosentan, which failed to meet its primary endpoint in CTEPH patients, riociguat demonstrated significant improvements in both 6MWD and PVR 1
- Macitentan (another endothelin antagonist) has shown improvements in PVR and 6MWD in phase II trials but is not yet approved for CTEPH 1
Sequential and Combination Therapy
- Sequential treatment with riociguat followed by BPA provides additional benefits in improving pulmonary hemodynamics and WHO functional class 6
- In patients with severe hemodynamic compromise, off-label combination of drugs approved for pulmonary arterial hypertension has been proposed, but limited prospective data are available 1
Important Caveats
- Riociguat should only be prescribed after a thorough assessment by a multidisciplinary CTEPH team 1
- Riociguat is not indicated for CTEPH patients who are candidates for PEA, as surgery remains the treatment of choice 1
- Medical therapy is not indicated in symptomatic survivors of acute PE with documented post-thrombotic obstructions but without PH at right heart catheterization (CTED) 1
- Patients should be followed at specialized CTEPH centers, with at least one hemodynamic assessment 6-12 months after treatment initiation 1