title: Early Experience of Macitentan for Pulmonary Arterial Hypertension in Adult Congenital Heart Disease.
abstract: BACKGROUND
  Endothelin receptor antagonists (ERA) have been recognised as effective therapy for pulmonary arterial hypertension in congenital heart disease (CHD-PH), and Eisenmenger syndrome (ES) since The Bosentan Randomized Trial of Endothelin Antagonist Therapy-5 (Breathe 5) study. A new dual receptor antagonist - Macitentan - is currently undergoing trials to determine its efficacy in simple ES. To date there is little information on this therapy in CHD and we report our first experience, some with more complex diseases.
  
  
  METHODS
  Data was collected prospectively from September 2014. Patients with CHD-PH were started on or converted to macitentan if they required therapy with phosphodiesterase 5 inhibitor (PDE5i) or if there was insufficient response or a reaction to bosentan, especially those with trisomy 21. Patients were seen approximately three months after starting therapy to assess echocardiography, six minute walk test, clinical response and tolerability. All patients underwent monthly liver tests initially, but this was reduced to three-monthly in Q4 2015.
  
  
  RESULTS
  Fifteen patients with CHD-PH (eight male, seven female) were started on macitentan, median (range) age 38 (23-61) years, and eight patients with Down's syndrome. Eight patients had complex CHD with one having unoperated double inlet left ventricle with ventriculo-arterial discordance, one had double outlet right ventricle and six with complete atrio-ventricular septal defect. Six patients were ERA naïve and nine patients changed from bosentan to macitentan in order to achieve improved drug-drug interaction. Median length of time of treatment with macitentan is 289 (0-694) days to date. One discontinued due to rash and feeling unwell; one was unable to comply with medication due to learning difficulties and one died soon after commencing rescue therapy. This last patient was functional class IV with oxygen saturation of 67% at rest, with right heart failure and was unable to perform a walk test before commencing therapy. All patients who remained on therapy had significant increase in six minute walk test from median 286 (120-426) to 360m (150-450)(p <0.05), most notably in those treatment naïve. Functional class median remained at 3 but the range was reduced (1-3). Resting oxygen saturations improved from median 83 range (77-95%) at rest to 91 (77-96%) and at end walk from 78 (48-90%) to 79 (62-96%). Tricuspid regurgitant peak Doppler derived pressure drop did not change (as expected) at 4.6 (4.3-5.5)m/s. There were no episodes of liver dysfunction.
  
  
  CONCLUSIONS
  The introduction of this new therapy has been simple and mostly well tolerated in our sick group of patients. With the usual reservations concerning the open-label nature of our observations, macitentan has good signals regarding oxygen saturations and encouraging signals relating to efficacy.
authors.affiliation: Department of Congenital Heart Disease, Bristol Heart Institute, Bristol, UK.
authors.forename: S
authors.initials: S
authors.lastname: Herbert
authors.affiliation: Pulmonary Hypertension, Hammersmith Hospital, London, UK.
authors.forename: W
authors.initials: W
authors.lastname: Gin-Sing
authors.affiliation: Pulmonary Hypertension, Hammersmith Hospital, London, UK.
authors.forename: L
authors.initials: L
authors.lastname: Howard
authors.affiliation: Department of Congenital Heart Disease, Bristol Heart Institute, Bristol, UK. Electronic address: Robert.Tulloh@Bristol.ac.uk.
authors.forename: R M R
authors.initials: RMR
authors.lastname: Tulloh
mesh_terms: D000328:Adult; D004305:Dose-Response Relationship, Drug; D065130:Endothelin A Receptor Antagonists / Q000008:administration & dosage; D065627:Familial Primary Pulmonary Hypertension / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D005260:Female; D005500:Follow-Up Studies; D006330:Heart Defects, Congenital / Q000150:complications*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011669:Pulmonary Wedge Pressure / Q000187:drug effects*; D011743:Pyrimidines / Q000008:administration & dosage*; D013449:Sulfonamides / Q000008:administration & dosage*; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D065130:Endothelin A Receptor Antagonists; D011743:Pyrimidines; D013449:Sulfonamides; C533860:macitentan
keywords: Eisenmenger Syndrome; Endothelin receptor antagonists; Macitentan; Pulmonary hypertension; Trisomy 21