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Efficacy and safety of the angiotensin II receptor blocker losartan for hypertrophic cardiomyopathy: the INHERIT randomised, double-blind, placebo-controlled trial

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@article{23daf0545c434fea86da09a0abeee7ef,
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.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.",
keywords = "Angiotensin II Type 1 Receptor Blockers, Cardiomyopathy, Hypertrophic, Double-Blind Method, Female, Fibrosis, Follow-Up Studies, Heart Ventricles, Humans, Hypertrophy, Left Ventricular, Losartan, Male, Middle Aged, Treatment Outcome",
author = "Anna Axelsson and Kasper Iversen and Niels Vejlstrup and Carolyn Ho and Jakob Norsk and Lasse Langhoff and Kiril Ahtarovski and Pernille Corell and Ole Havndrup and Morten Jensen and Henning Bundgaard",
note = "Copyright {\textcopyright} 2015 Elsevier Ltd. All rights reserved.",
year = "2015",
month = feb,
doi = "10.1016/S2213-8587(14)70241-4",
language = "English",
volume = "3",
pages = "123--31",
journal = "The Lancet Diabetes and Endocrinology",
issn = "2213-8587",
publisher = "London The Lancet, Diabetes & Endocrinology, 2013",
number = "2",

}

RIS

TY - JOUR

T1 - Efficacy and safety of the angiotensin II receptor blocker losartan for hypertrophic cardiomyopathy

T2 - the INHERIT randomised, double-blind, placebo-controlled trial

AU - Axelsson, Anna

AU - Iversen, Kasper

AU - Vejlstrup, Niels

AU - Ho, Carolyn

AU - Norsk, Jakob

AU - Langhoff, Lasse

AU - Ahtarovski, Kiril

AU - Corell, Pernille

AU - Havndrup, Ole

AU - Jensen, Morten

AU - Bundgaard, Henning

N1 - Copyright © 2015 Elsevier Ltd. All rights reserved.

PY - 2015/2

Y1 - 2015/2

N2 - 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.

AB - 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.

KW - Angiotensin II Type 1 Receptor Blockers

KW - Cardiomyopathy, Hypertrophic

KW - Double-Blind Method

KW - Female

KW - Fibrosis

KW - Follow-Up Studies

KW - Heart Ventricles

KW - Humans

KW - Hypertrophy, Left Ventricular

KW - Losartan

KW - Male

KW - Middle Aged

KW - Treatment Outcome

U2 - 10.1016/S2213-8587(14)70241-4

DO - 10.1016/S2213-8587(14)70241-4

M3 - Journal article

C2 - 25533774

VL - 3

SP - 123

EP - 131

JO - The Lancet Diabetes and Endocrinology

JF - The Lancet Diabetes and Endocrinology

SN - 2213-8587

IS - 2

ER -

ID: 46172692