title: Efficacy and safety of the angiotensin II receptor blocker losartan for hypertrophic cardiomyopathy: the INHERIT randomised, double-blind, placebo-controlled trial.
abstract: BACKGROUND
  No medical treatment has been reliably shown to halt or reverse disease progression in hypertrophic cardiomyopathy, but the results of several pilot studies have suggested beneficial effects of angiotensin II receptor blockers on left ventricular hypertrophy and fibrosis, which are predictive of an adverse outcome. We aimed to assess the effect of the angiotensin II receptor blocker losartan on left ventricular hypertrophy and fibrosis in patients with hypertrophic cardiomyopathy.
  
  
  METHODS
  In this single-centre, randomised, double-blind, placebo-controlled trial, adult patients (aged 18 years and older) with obstructive or non-obstructive hypertrophic cardiomyopathy were randomly assigned via computer-based system to losartan (100 mg per day) or placebo for 12 months. Patients and investigators were masked to assigned treatment. The primary endpoint was change in left ventricular mass as assessed by cardiac magnetic resonance imaging (CMR) or CT. Efficacy analyses were done in the modified intention-to-treat population (all patients with data available at the 12-month follow-up). The trial is registered with ClinicalTrials.gov, number NCT01447654.
  
  
  RESULTS
  Between Dec 1, 2011, and May 1, 2013, 318 patients were screened. 133 patients (mean age 52 years [SD 13], 35% women) consented and were randomly assigned to placebo (n=69) or losartan (n=64). 124 (93%) patients completed the study and were included in the modified intention-to-treat analysis for the primary endpoint. After 12 months we noted no significant difference in the change in left ventricular mass between the placebo group and the losartan group (mean difference 1 g/m(2), 95% CI -3 to 6; p=0·60). A decrease in systolic blood pressure in the losartan group (from mean 127 mm Hg [SD 12] to 121 mm Hg [14]; p=0·0001) confirmed drug compliance; blood pressure did not decrease in the placebo group. Two (2%) patients, both in the placebo group, died from sudden cardiac death during follow-up. In the losartan group, one (1%) patient had angioedema, one (1%) had deterioration of renal function, and one (1%) had hyperkalaemia. Treatment was well tolerated by patients with left ventricular outflow obstruction at baseline.
  
  
  CONCLUSIONS
  Our findings challenge the generally held view that angiotensin II receptor blockers reduce cardiac hypertrophy. Treatment with losartan was safe, suggesting that it can be used for other indications in patients with hypertrophic cardiomyopathy, irrespective of obstructive physiology. Additional studies are needed to assess the effect of angiotensin II receptor blockers in preclinical hypertrophic cardiomyopathy-eg, in genotype-positive but phenotype-negative individuals.
authors.affiliation: Unit for Inherited Cardiac Diseases, Department of Cardiology, The Heart Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; Seidman Laboratory, Department of Genetics, Harvard Medical School, Boston, MA, USA. Electronic address: anna.axelsson@dadlnet.dk.
authors.forename: Anna
authors.initials: A
authors.lastname: Axelsson
authors.affiliation: Department of Cardiology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Kasper
authors.initials: K
authors.lastname: Iversen
authors.affiliation: Unit for Inherited Cardiac Diseases, Department of Cardiology, The Heart Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Vejlstrup
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Ho
authors.affiliation: Unit for Inherited Cardiac Diseases, Department of Cardiology, The Heart Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jakob
authors.initials: J
authors.lastname: Norsk
authors.affiliation: Unit for Inherited Cardiac Diseases, Department of Cardiology, The Heart Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Lasse
authors.initials: L
authors.lastname: Langhoff
authors.affiliation: Unit for Inherited Cardiac Diseases, Department of Cardiology, The Heart Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Kiril
authors.initials: K
authors.lastname: Ahtarovski
authors.affiliation: Department of Cardiology, Roskilde Hospital, Roskilde, Denmark.
authors.forename: Pernille
authors.initials: P
authors.lastname: Corell
authors.affiliation: Department of Cardiology, Roskilde Hospital, Roskilde, Denmark.
authors.forename: Ole
authors.initials: O
authors.lastname: Havndrup
authors.affiliation: Unit for Inherited Cardiac Diseases, Department of Cardiology, The Heart Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Jensen
authors.affiliation: Unit for Inherited Cardiac Diseases, Department of Cardiology, The Heart Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Henning
authors.initials: H
authors.lastname: Bundgaard
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000009:adverse effects / Q000627:therapeutic use*; D002312:Cardiomyopathy, Hypertrophic / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D005355:Fibrosis; D005500:Follow-Up Studies; D006352:Heart Ventricles / Q000473:pathology; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy*; D019808:Losartan / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D019808:Losartan