Role of Riociguat in Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

Treatment Algorithm for CTEPH

The European Respiratory Society recommends that all patients with CTEPH should be evaluated by a multidisciplinary team including at least one experienced PEA surgeon to determine operability 1, 2
Surgical PEA in deep hypothermia circulatory arrest is the first-line treatment for operable CTEPH patients, as recommended by the European Respiratory Society 1, 3
The European Heart Society recommends lifelong anticoagulation in all CTEPH patients, including after successful PEA or balloon pulmonary angioplasty (BPA) 1, 4
For patients with inoperable CTEPH or persistent/recurrent CTEPH after PEA, riociguat is the only approved targeted therapy, according to the European Heart Society 4, 5
BPA may be considered in patients who are technically non-operable or have unfavorable risk-benefit ratio for PEA, as suggested by the European Respiratory Society 1, 5

Riociguat significantly increases 6-minute walking distance (6MWD) by 39 meters compared to placebo, as reported in the European Heart Journal 6, 3
Riociguat significantly reduces pulmonary vascular resistance (PVR) by 246 dyn.cm.s⁻⁵ compared to placebo, according to the European Heart Journal 6, 3

Riociguat is an oral stimulator of soluble guanylate cyclase that works within the nitric oxide pathway in pulmonary vasculature, as described in the European Heart Journal 4, 7
This mechanism addresses the pulmonary microvascular disease component of CTEPH, as reported in the European Heart Journal and European Respiratory Journal 5, 7

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, as reported in the European Heart Journal and European Respiratory Journal 6, 7
Macitentan (another endothelin antagonist) has shown improvements in PVR and 6MWD in phase II trials but is not yet approved for CTEPH, according to the European Heart Journal 5

Riociguat should only be prescribed after a thorough assessment by a multidisciplinary CTEPH team, as recommended by the European Respiratory Society 1, 2
Riociguat is not indicated for CTEPH patients who are candidates for PEA, as surgery remains the treatment of choice, according to the European Respiratory Society and European Heart Journal 1, 3
Medical therapy is not indicated in symptomatic survivors of acute PE with documented post-thrombotic obstructions but without PH at right heart catheterization (CTED), as stated in the European Heart Journal 5
Patients should be followed at specialized CTEPH centers, with at least one hemodynamic assessment 6-12 months after treatment initiation, as recommended by the European Respiratory Society 7

The American Thoracic Society recommends riociguat for treatment-naive PAH patients with WHO functional class II or III symptoms who are not candidates for or have failed calcium channel blocker therapy 8
Riociguat improves 6-minute walk distance by approximately 30-40 meters, WHO functional class, and delays time to clinical worsening in PAH patients 8, 9
Riociguat reduces pulmonary vascular resistance by 223 dyn/s/cm⁵ compared to placebo in PAH patients 9
The European Respiratory Society recommends riociguat as the only approved targeted therapy for patients with inoperable CTEPH or persistent/recurrent CTEPH after pulmonary endarterectomy (PEA) 10

The American College of Chest Physicians recommends starting riociguat at 1 mg three times daily and titrating upward by 0.5 mg increments every 2 weeks to a maximum of 2.5 mg three times daily, with dose adjustments based on systolic blood pressure and absence of hypotensive symptoms 8, 9
The dose should only be increased if trough systolic blood pressure is >95 mmHg AND patient has no signs or symptoms of hypotension 9

The American Heart Association recommends monitoring systolic blood pressure at trough during the 8-week titration period and assessing for signs and symptoms of hypotension at each dose adjustment 9
The European Society of Cardiology recommends assessing WHO functional class at baseline and during follow-up, and performing 6-minute walk distance testing to evaluate treatment response 8, 9

The American College of Cardiology recommends avoiding concomitant use with PDE5 inhibitors (sildenafil, tadalafil, vardenafil) due to severe systemic hypotension 8

Syncope occurs in 1% of PAH patients on riociguat compared to 4% on placebo 9
Worsening pulmonary hypertension occurs in less than 1% of PAH patients on riociguat compared to 2% on placebo 9

The European Respiratory Society recommends following patients at specialized pulmonary hypertension centers with expertise in PAH/CTEPH management and access to right heart catheterization, echocardiography, CT scanning, and exercise testing 10
Lifelong anticoagulation is required for all CTEPH patients, including those on riociguat 10

All patients with chronic thromboembolic pulmonary hypertension require lifelong anticoagulation, including those treated with riociguat, as recommended by the European Heart Society 11
The American College of Chest Physicians recommends extended anticoagulation in all CTEPH patients 12, 13, 14

Traditional guidelines emphasized vitamin K antagonists for CTEPH anticoagulation, but more recent evidence demonstrates that DOACs, including apixaban, appear safe and effective in this population, with the American College of Chest Physicians providing guidelines 12, 13, 14