title: [Hepatotoxicity in patients treated with endothelin receptor antagonists: systematic review and meta-analysis of randomized clinical trials].
abstract: OBJECTIVE
  We evaluated the risk of hepatotoxicity associated to endothelin receptor antagonists.
  
  
  METHODS
  Systematic searches in PubMed/MEDLINE, the Cochrane Library as well as regulatory agencies websites were performed. Randomized controlled trials in patients receiving endothelin receptor antagonists (bosentan, sitaxentan or ambrisentan) in at least one treatment group were included. Prior to data extraction, definitions of hepatotoxicity were established. Effect sizes with 95% confidence intervals were calculated using random effects models. Heterogeneity was analysed using Cochran's Q and I(2) tests. Publication bias was assessed using Egger's method and funnel plots were generated.
  
  
  RESULTS
  Twenty-one trials met the inclusion criteria (3,644 patients). Bosentan was the evaluated drug in 1,689 (74%) patients who received endothelin receptor antagonists. Compared with controls, relative risk for any hepatic adverse reaction was 2.92 (1.85-4.62; I(2)=30.6%). When hepatotoxicity was defined as elevations of liver alanine or aspartate aminotransferases equal or greater than 3 times the upper limit of normal, relative risk was 2.98 (1.69-5.25; I(2) = 40.9%). No evidence of publication bias was found (Egger's method: p = 0.68).
  
  
  CONCLUSIONS
  Our results suggest an increased risk of hepatotoxicity in patients receiving endothelin receptor antagonists. Given the limited data available for endothelin receptor antagonists other than bosentan, it is not possible to draw firm conclusions about the individual risk associated for the remaining endothelin receptor antagonists.
authors.affiliation: División de Farmacoepidemiología y Farmacovigilancia, Agencia Española de Medicamentos y Productos Sanitarios (AEMPS), Madrid, España. Electronic address: dmacias.sg@gmail.com.
authors.forename: Diego
authors.initials: D
authors.lastname: Macías Saint-Gerons
authors.affiliation: División de Farmacoepidemiología y Farmacovigilancia, Agencia Española de Medicamentos y Productos Sanitarios (AEMPS), Madrid, España.
authors.forename: César
authors.initials: C
authors.lastname: de la Fuente Honrubia
authors.affiliation: División de Farmacoepidemiología y Farmacovigilancia, Agencia Española de Medicamentos y Productos Sanitarios (AEMPS), Madrid, España.
authors.forename: Dolores
authors.initials: D
authors.lastname: Montero Corominas
authors.affiliation: División de Farmacoepidemiología y Farmacovigilancia, Agencia Española de Medicamentos y Productos Sanitarios (AEMPS), Madrid, España; Centro Superior de Investigación en Salud Pública (CSISP), Red de Investigación en Servicios de Salud en Enfermedades Crónicas (REDISSEC), Valencia, España; Fundación Instituto de Investigación en Servicios de Salud, Valencia, España.
authors.forename: Ferrán
authors.initials: F
authors.lastname: Catalá-López
mesh_terms: D000959:Antihypertensive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D000077300:Bosentan; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000453:epidemiology / Q000209:etiology*; D065128:Endothelin Receptor Antagonists / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D007555:Isoxazoles / Q000009:adverse effects / Q000627:therapeutic use; D010666:Phenylpropionates / Q000009:adverse effects / Q000627:therapeutic use; D011724:Pyridazines / Q000009:adverse effects / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D056737:Safety-Based Drug Withdrawals; D013449:Sulfonamides / Q000009:adverse effects / Q000627:therapeutic use; D013876:Thiophenes / Q000009:adverse effects / Q000627:therapeutic use; D000637:Transaminases / Q000097:blood
chemical_list: D000959:Antihypertensive Agents; D015415:Biomarkers; D065128:Endothelin Receptor Antagonists; D007555:Isoxazoles; D010666:Phenylpropionates; D011724:Pyridazines; D013449:Sulfonamides; D013876:Thiophenes; D000637:Transaminases; C467894:ambrisentan; C106276:sitaxsentan; D000077300:Bosentan
keywords: Ambrisentan; Ambrisentán; Bosentan; Bosentán; Daño hepático; Ensayo clínico aleatorizado y controlado; Hepatic event; Hepatotoxicidad; Hepatotoxicity; Liver injury; Meta-analysis; Metaanálisis; Randomized controlled trial; Reacción hepática; Sitaxentan; Sitaxentán; Sitaxsentan; Sitaxsentán