Anna Axelsson1, Kasper Iversen2, Niels Vejlstrup3, Carolyn Ho4, Jakob Norsk3, Lasse Langhoff3, Kiril Ahtarovski3, Pernille Corell5, Ole Havndrup5, Morten Jensen3, Henning Bundgaard3. 1. 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. 2. Department of Cardiology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark. 3. Unit for Inherited Cardiac Diseases, Department of Cardiology, The Heart Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. 4. Cardiovascular Division, Brigham and Women's Hospital, Boston, MA, USA. 5. Department of Cardiology, Roskilde Hospital, Roskilde, Denmark.
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. FINDINGS: 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. INTERPRETATION: 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.
RCT Entities:
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. FINDINGS: 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. INTERPRETATION: 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: Anna Axelsson Raja; Hoshang Farhad; Anne Marie Valente; John-Paul Couce; John Lynn Jefferies; Henning Bundgaard; Kenneth Zahka; Harry Lever; Anne M Murphy; Euan Ashley; Sharlene M Day; Mark V Sherrid; Ling Shi; David A Bluemke; Charles E Canter; Steven D Colan; Carolyn Y Ho Journal: Circulation Date: 2018-08-21 Impact factor: 29.690
Authors: Carolyn Y Ho; John J V McMurray; Allison L Cirino; Steven D Colan; Sharlene M Day; Akshay S Desai; Steven E Lipshultz; Calum A MacRae; Ling Shi; Scott D Solomon; E John Orav; Eugene Braunwald Journal: Am Heart J Date: 2017-02-16 Impact factor: 4.749
Authors: Styliani Vakrou; Ryuya Fukunaga; D Brian Foster; Lars Sorensen; Yamin Liu; Yufan Guan; Kirubel Woldemichael; Roberto Pineda-Reyes; Ting Liu; Jill C Tardiff; Leslie A Leinwand; Carlo G Tocchetti; Theodore P Abraham; Brian O'Rourke; Miguel A Aon; M Roselle Abraham Journal: JCI Insight Date: 2018-03-22