Riociguat
Sources réglementaires consultées
Indications approuvées
- Espagne : traitement des adultes en classe fonctionnelle OMS II a III atteints d hypertension pulmonaire thromboembolique chronique inoperable, ou persistante ou recidivante apres traitement chirurgical, afin d ameliorer la capacite d exercice.
- Espagne : traitement des adultes atteints d hypertension arterielle pulmonaire en classe fonctionnelle OMS II a III, en monotherapie ou en association avec des antagonistes des recepteurs de l endothelin, afin d ameliorer la capacite d exercice.
- Espagne : traitement de l hypertension arterielle pulmonaire chez les patients pediatriques de 6 ans a moins de 18 ans en classe fonctionnelle OMS II a III, en association avec des antagonistes des recepteurs de l endothelin.
Contre-indications
Absolues
- Grossesse; nitrates ou donneurs d oxyde nitrique; inhibiteurs de la PDE5; autres stimulateurs de la guanylate cyclase soluble; hypertension pulmonaire associee aux pneumopathies interstitielles idiopathiques.
- Avant le debut, pression arterielle systolique inferieure a 95 mmHg chez l adulte et les patients de 12 ans a moins de 18 ans, ou inferieure a 90 mmHg chez les patients de 6 ans a moins de 12 ans.
- Hypersensibilite au riociguat ou a ses excipients, ou insuffisance hepatique severe, Child-Pugh C.
Mises en garde cliniques
- Mise en garde encadrée · Peut causer des dommages foetaux; exclure une grossesse avant le debut, chaque mois pendant le traitement et durant un mois apres, et utiliser une contraception efficace. — DailyMed label; AEMPS CIMA registro 113907004
- Mise en garde majeure · Risque d hypotension, d hemorragie respiratoire grave ou mortelle et d oedeme pulmonaire dans la maladie veino-occlusive pulmonaire; arreter et evaluer si un oedeme pulmonaire apparait. — AEMPS CIMA registro 113907004
Interactions médicamenteuses
- SévèreNitrates ou donneurs d oxyde nitrique
Mécanisme: Ils potentialisent l effet hypotenseur du riociguat.
Recommandation: Contre-indique : ne pas utiliser ensemble.
https://cima.aemps.es/cima/dochtml/ft/113907004/FT_113907004.html
- SévèreInhibiteurs de la PDE5
Mécanisme: Ils augmentent l effet hypotenseur systemique du riociguat.
Recommandation: L utilisation concomitante est contre-indiquee. Arreter le sildenafil au moins 24 heures avant le riociguat; arreter le tadalafil au moins 48 heures avant chez l adulte et 72 heures avant chez l enfant; arreter le riociguat au moins 24 heures avant un inhibiteur de la PDE5. Surveiller l hypotension apres la transition.
https://cima.aemps.es/cima/dochtml/ft/113907004/FT_113907004.html
- SévèreInhibiteurs puissants de plusieurs voies CYP et de la P-gp/BCRP
Mécanisme: Ils peuvent augmenter significativement l exposition au riociguat et le risque d hypotension.
Recommandation: Envisager une dose initiale de 0,5 mg trois fois par jour et surveiller les signes et symptomes d hypotension.
https://cima.aemps.es/cima/dochtml/ft/113907004/FT_113907004.htmlhttps://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8092c64b-e240-43c3-9d2e-e0dd7708d96f
- ModéréeAntiacides
Mécanisme: Les antiacides reduisent l absorption du riociguat.
Recommandation: Espacer l administration d au moins 1 heure.
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8092c64b-e240-43c3-9d2e-e0dd7708d96f
Effets indésirables
Communs (≥1%)
Cefalee · Vertiges · Dyspepsie · Oedeme peripherique · Nausees · Diarrhee · Vomissements
Rares mais graves
Hemoptysie severe · Hemorragie pulmonaire · Hypotension severe
Grossesse et allaitement
Catégorie FDA: Contraindicado en el embarazo
Le riociguat est contre-indique pendant la grossesse; interrompre l allaitement pendant le traitement et utiliser une contraception efficace.
Bibliographie récente (PubMed)
Pulmonary arterial hypertension (PAH) is a subtype of pulmonary hypertension (PH), characterized by pulmonary arterial remodeling. The prevalence of PAH is approximately 10.6 cases per 1 million adults in the US. Untreated, PAH progresses to right heart failure and death. Pulmonary hypertension is defined by a mean pulmonary artery pressure greater than 20 mm Hg and is classified into 5 clinical groups based on etiology, pathophysiology, and treatment. Pulmonary arterial hypertension is 1 of the 5 groups of PH and is hemodynamically defined by right heart catheterization demonstrating a mean pulmonary artery pressure greater than 20 mm Hg, a pulmonary artery wedge pressure of 15 mm Hg or lower, and a pulmonary vascular resistance of 3 Wood units or greater. Pulmonary arterial hypertension is further divided into subgroups based on underlying etiology, consisting of idiopathic PAH, heritable PAH, drug- and toxin-associated PAH, pulmonary veno-occlusive disease, PAH in long-term responders to calcium channel blockers, and persistent PH of the newborn, as well as PAH associated with other medical conditions including connective tissue disease, HIV, and congenital heart disease. Early presenting symptoms are nonspecific and typically consist of dyspnea on exertion and fatigue. Currently approved therapy for PAH consists of drugs that enhance the nitric oxide-cyclic guanosine monophosphate biological pathway (sildenafil, tadalafil, or riociguat), prostacyclin pathway agonists (epoprostenol or treprostinil), and endothelin pathway antagonists (bosentan and ambrisentan). With these PAH-specific therapies, 5-year survival has improved from 34% in 1991 to more than 60% in 2015. Current treatment consists of combination drug therapy that targets more than 1 biological pathway, such as the nitric oxide-cyclic guanosine monophosphate and endothelin pathways (eg, ambrisentan and tadalafil), and has shown demonstrable improvement in morbidity and mortality compared with the previ
Chronic thromboembolic pulmonary hypertension (CTEPH) is a treatable form of pulmonary hypertension and right heart failure. CTEPH (group 4 pulmonary hypertension) is caused by persistent organized thromboembolic obstruction of the pulmonary arteries from incompletely resolved acute pulmonary embolism. CTEPH also may present without prior VTE history, which can contribute to its underrecognition. The true incidence of CTEPH is unclear, but is estimated to be approximately 3% after acute pulmonary embolism. V˙/Q˙ scintigraphy is the best screening test for CTEPH, with CT scan imaging and other advanced imaging methods now playing a larger role in disease detection and confirmation. Perfusion defects on V˙/Q˙ scintigraphy in the setting of pulmonary hypertension are suggestive of CTEPH, but pulmonary angiography and right heart catheterization are required for confirmation and treatment planning. CTEPH potentially is curative with pulmonary thromboendarterectomy surgery, with mortality rates of approximately 2% at expert centers. Advances in operative techniques are allowing more distal endarterectomies to be performed successfully with favorable outcomes. However, more than one-third of patients may be considered inoperable. Although these patients previously had minimal therapeutic options, effective treatments now are available with pharmacotherapy and balloon pulmonary angioplasty. Diagnosis of CTEPH should be considered in all patients with suspicion of pulmonary hypertension. Treatments for CTEPH have advanced with improvements in outcomes for both operable and inoperable patients. Therapy should be tailored based on multidisciplinary team evaluation to ensure optimal treatment response.
The evidence for the treatment of connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) mostly depends on subgroup or post hoc analysis of randomized controlled trials (RCTs). Thus, we performed a meta-analysis of RCTs that reported outcomes for CTD-PAH. PubMed and EMBASE were searched for CTD-PAH treatment. The selected outcomes were functional class (FC) change, survival rates, 6-min walk distance (6-MWD), clinical worsening (CW), N-terminal prohormone BNP (NT-proBNP), pulmonary vascular resistance (PVR), mean pulmonary arterial pressure (mPAP), right atrial pressure (RAP), and cardiac index (CI). The meta-analysis was conducted according to the PRISMA guidelines and registered in PROSPERO (CRD42020153560). Twelve RCTs conducted with 1837 patients were included. The diagnoses were systemic sclerosis in 59%, SLE in 20%, and other CTDs in 21%. The pharmacological interventions were epoprostenol, treprostinil, sildenafil, tadalafil, bosentan, macitentan, ambrisentan, riociguat, and selexipag. There was a significant difference between interventions and placebo in FC, 6MWD, CW, PVR, RAP, and CI that favored intervention. Our analysis showed a 39% reduction in the CW risk with PAH treatment. The short-term survival rates and mean serum NT-proBNP changes were similar between the study and control groups. Treatment for CTD-PAH had favorable effects on clinical and hemodynamic outcomes but not on survival and NT-proBNP levels. Different from the previous meta-analyses that focused on 6-MWD, time to clinical worsening, and CW as outcomes, this meta-analysis additionally reports the pooled analysis of change in FC, hemodynamic measurements (RAP, PVR, CI), and NT-proBNP, some of which have prognostic value for PAH.
Riociguat and balloon pulmonary angioplasty (BPA) are treatment options for inoperable chronic thromboembolic pulmonary hypertension (CTEPH). However, randomised controlled trials comparing these treatments are lacking. We aimed to evaluate the efficacy and safety of BPA versus riociguat in patients with inoperable CTEPH. In this phase 3, multicentre, open-label, parallel-group, randomised controlled trial done in 23 French centres of expertise for pulmonary hypertension, we enrolled treatment-naive patients aged 18-80 years with newly diagnosed, inoperable CTEPH and pulmonary vascular resistance of more than 320 dyn·s/cm5. Patients were randomly assigned (1:1) to BPA or riociguat via a web-based randomisation system, with block randomisation (block sizes of two or four patients) without stratification. The primary endpoint was change in pulmonary vascular resistance at week 26, expressed as percentage of baseline pulmonary vascular resistance in the intention-to-treat population. Safety analyses were done in all patients who received at least one dose of riociguat or had at least one BPA session. Patients who completed the RACE trial continued into an ancillary 26-week follow-up during which symptomatic patients with pulmonary vascular resistance of more than 320 dyn·s/cm5 benefited from add-on riociguat after BPA or add-on BPA after riociguat. This trial is registered at ClinicalTrials.gov, NCT02634203, and is completed. Between Jan 19, 2016, and Jan 18, 2019, 105 patients were randomly assigned to riociguat (n=53) or BPA (n=52). At week 26, the geometric mean pulmonary vascular resistance decreased to 39·9% (95% CI 36·2-44·0) of baseline pulmonary vascular resistance in the BPA group and 66·7% (60·5-73·5) of baseline pulmonary vascular resistance in the riociguat group (ratio of geometric means 0·60, 95% CI 0·52-0·69; p<0·0001). Treatment-related serious adverse events occurred in 22 (42%) of 52 patients in the BPA group and five (9%) of 53 patients in the riocig