Riociguat
Fuentes regulatorias consultadas
Indicaciones aprobadas
- España: tratamiento de adultos en clase funcional II a III de la OMS con hipertensión pulmonar tromboembólica crónica inoperable, o persistente o recidivante después de tratamiento quirúrgico, para mejorar la capacidad de ejercicio.
- España: tratamiento de adultos con hipertensión arterial pulmonar en clase funcional II a III de la OMS, en monoterapia o en combinación con antagonistas de los receptores de endotelina, para mejorar la capacidad de ejercicio.
- España: tratamiento de la hipertensión arterial pulmonar en pacientes pediátricos de 6 a menos de 18 años con clase funcional II a III de la OMS, en combinación con antagonistas de los receptores de endotelina.
Contraindicaciones
Absolutas
- Embarazo; nitratos o donadores de óxido nítrico; inhibidores de PDE5; otros estimuladores de guanilato ciclasa soluble; hipertensión pulmonar asociada a neumonías intersticiales idiopáticas.
- Presión arterial sistólica antes del inicio menor de 95 mmHg en adultos y pacientes de 12 a menos de 18 años, o menor de 90 mmHg en pacientes de 6 a menos de 12 años.
- Hipersensibilidad a riociguat o a sus excipientes, o insuficiencia hepática grave Child-Pugh C.
Advertencias clínicas
- Advertencia destacada (boxed warning) · Puede causar daño fetal; excluir embarazo antes del inicio, mensualmente durante el tratamiento y durante un mes después, y usar anticoncepción eficaz. — DailyMed label; AEMPS CIMA registro 113907004
- Advertencia mayor · Riesgo de hipotensión, hemorragia respiratoria grave o mortal y edema pulmonar en enfermedad venooclusiva pulmonar; suspender y evaluar si aparece edema pulmonar. — AEMPS CIMA registro 113907004
Interacciones medicamentosas
- SeveraNitratos o donadores de óxido nítrico
Mecanismo: Potencian el efecto hipotensor de riociguat.
Recomendación: Contraindicado: no usar conjuntamente.
https://cima.aemps.es/cima/dochtml/ft/113907004/FT_113907004.html
- SeveraInhibidores de PDE5
Mecanismo: Aumentan el efecto hipotensor sistémico de riociguat.
Recomendación: Contraindicado el uso simultáneo. Suspender sildenafilo al menos 24 horas antes de riociguat; suspender tadalafilo al menos 48 horas antes en adultos y 72 horas antes en niños; suspender riociguat al menos 24 horas antes de iniciar un inhibidor de PDE5. Vigilar hipotensión tras la transición.
https://cima.aemps.es/cima/dochtml/ft/113907004/FT_113907004.html
- SeveraInhibidores potentes de múltiples vías CYP y P-gp/BCRP
Mecanismo: Pueden aumentar significativamente la exposición a riociguat y el riesgo de hipotensión.
Recomendación: Considerar una dosis inicial de 0,5 mg tres veces al día y vigilar signos y síntomas de hipotensión.
https://cima.aemps.es/cima/dochtml/ft/113907004/FT_113907004.htmlhttps://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8092c64b-e240-43c3-9d2e-e0dd7708d96f
- ModeradaAntiácidos
Mecanismo: Los antiácidos reducen la absorción de riociguat.
Recomendación: Separar su administración al menos 1 hora.
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8092c64b-e240-43c3-9d2e-e0dd7708d96f
Eventos adversos
Comunes (≥1%)
Cefalea · Mareo · Dispepsia · Edema periférico · Náuseas · Diarrea · Vómitos
Raros pero graves
Hemoptisis grave · Hemorragia pulmonar · Hipotensión grave
Embarazo y lactancia
Categoría FDA: Contraindicado en el embarazo
Riociguat está contraindicado en embarazo; interrumpir la lactancia durante el tratamiento y usar anticoncepción eficaz.
Bibliografía reciente (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