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

doi:10.1016/S2213-8587(14)70241-4

The Lancet Diabetes & Endocrinology

Volume 3, Issue 2, February 2015, Pages 123-131

https://doi.org/10.1016/S2213-8587(14)70241-4 Get rights and content

Summary

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/m², 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.

Funding

Capital Region of Denmark, Rigshospitalet Research Fund, Danish Heart Association, Heart Centre Research Foundation, P A Messerschmidt and Wife Foundation, Westerberg Foundation, Beckett Foundation, Soren Segel and Wife Johanne Segel Research Foundation, and A P Møller and Chastine Mc-Kinney Møller Foundation.

Introduction

Hypertrophic cardiomyopathy is the most common hereditary cardiac disease, affecting one in 500 individuals.¹ The predominant cause is mutation of genes that encode protein components of the cardiac sarcomere.2, 3, 4, 5 The mechanisms that lead from a sarcomere gene mutation to phenotypic expression of hypertrophic cardiomyopathy are poorly understood, which impedes the search for a treatment that can disrupt the pathophysiological process.⁶ No medical treatment has been reliably shown to halt or reverse disease progression.⁷ Accordingly, treatment recommendations are focused on the alleviation of symptoms, prevention of thromboembolic events, and implantation of prophylactic implantable cardioverter defibrillators (ICDs) in patients at high risk of sudden cardiac death.⁸

The clinical diagnosis of hypertrophic cardiomyopathy is based on hypertrophy of the left ventricle that cannot be explained by extrinsic factors such as increased afterload.⁸ The course of the disease is highly variable, ranging from an asymptomatic, benign course with a normal life expectancy to a progressive disease characterised by angina, heart failure, atrial fibrillation, stroke, malignant arrhythmia, syncope, or sudden cardiac death. Disease progression can relate to increasing left ventricular hypertrophy and fibrosis leading to worsening of diastolic (and occasionally systolic) function, increased left ventricular end-diastolic pressure, and left atrial enlargement.9, 10, 11, 12

The angiotensin II receptor blocker (ARB) losartan reduces left ventricular hypertrophy caused by hypertension.¹³ Results from several animal studies and small clinical studies in patients with hypertrophic cardiomyopathy suggest that ARBs or angiotensin-converting-enzyme (ACE) inhibitors could affect hypertrophy, diastolic function, and collagen synthesis in hypertrophic cardiomyopathy, despite the fact that the disease is caused by intrinsic mechanisms and not by increased afterload.14, 15, 16, 17, 18, 19, 20, 21 Therefore, we aimed to assess the effect of losartan on left ventricular hypertrophy and fibrosis in patients with hypertrophic cardiomyopathy.

Section snippets

Study design and patients

The INHERIT trial (INHibition of the renin angiotensin system in hypertrophic cardiomyopathy and the Effect on hypertrophy—a Randomised Intervention Trial with losartan) was a single-centre, randomised, double-blind, placebo-controlled study done at the Unit for Inherited Cardiac Diseases, The Heart Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. We consecutively screened all adult patients (aged 18 years and older) with hypertrophic cardiomyopathy for possible inclusion.

Results

Of 318 patients screened between Dec 1, 2011, and May 1, 2013, 133 patients (mean age 52 years [SD 13], 35% women) from 118 families were enrolled in the study and randomly assigned, 69 to placebo and 64 to losartan (figure 1). CMR was done in 81 (61%) of 133 patients (40 in the placebo group and 41 in the losartan group) and CT in the remaining 52 (39%) patients (29 in the placebo and 23 in the losartan group) at baseline. Baseline demographic and clinical characteristics were well balanced

Discussion

Our results show that losartan does not have an effect on left ventricular mass compared with placebo in patients with hypertrophic cardiomyopathy. We also noted no effect on left ventricular maximum wall thickness, fibrotic mass, or left atrial volume. Treatment with losartan was well tolerated in patients with obstructive as well as non-obstructive hypertrophic cardiomyopathy (panel).

During the past decade several pilot studies have assessed the effect of ARBs on hypertrophy, fibrosis, and

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Cited by (91)

Mavacamten for Obstructive Hypertrophic Cardiomyopathy With or Without Hypertension: Post-Hoc Analysis of the EXPLORER-HCM Trial
2024, JACC: Heart Failure
Hypertension (HTN) is common in patients with hypertrophic cardiomyopathy (HCM), but its effect on the treatment of left ventricular outflow tract (LVOT) obstruction is undefined. Although elevated systolic blood pressure (SBP) may impact dynamic LVOT gradients, its response to cardiac myosin inhibition is unknown.
In a post hoc exploratory analysis of the EXPLORER-HCM trial (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy), the authors examined the characteristics of patients with obstructive HCM and HTN and the associations between HTN, SBP, and the response to mavacamten treatment of LVOT obstruction.
Patients were stratified by baseline history of HTN and mean SBP during 30-week treatment with mavacamten or placebo. The study estimated treatment differences and evaluated HTN and SBP groups by treatment interaction. Analysis of covariance was used to model changes in continuous endpoints, and a generalized linear model was used for binary endpoints.
HTN was present in 119 of 251 patients (47.4%), including 60 receiving mavacamten and 59 receiving placebo. Patients with HTN vs no HTN were older (63.4 vs 54.0 years; P < 0.001), had higher SBP (134 ± 15.1 mm Hg vs 123 ± 13.8 mm Hg; P < 0.001), more comorbidities, and lower peak oxygen consumption (19 ± 3 vs 20 ± 4 mL/kg/min; P = 0.021). Patients with HTN had similar NYHA functional class (NYHA functional class II, 72% vs 73%), Valsalva LVOT gradients (72 ± 34 mm Hg vs 74 ± 30 mm Hg), Kansas City Cardiomyopathy Questionnaire–Clinical Summary Scores (70.6 ± 18.8 vs 68.9 ± 23.1), and NT pro–B-type natriuretic peptide levels (geometric mean 632 ± 129 pg/mL vs 745 ± 130 pg/mL). Mavacamten-treated patients had improvement in all primary, secondary, and exploratory endpoints regardless of HTN status or mean SBP.
The clinical benefits of mavacamten in symptomatic, obstructive HCM were similar in patients with and without HTN, despite differences in baseline characteristics. (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy [EXPLORER-HCM]; NCT03470545)
Angiotensin receptor blockers in patients with hypertrophic cardiomyopathy: A comparison of VANISH and INHERIT randomized trials
2023, American Heart Journal
To identify the cause of discrepancy between the INHERIT trial and VANISH trial in regards to disease modification of angiotensin receptor II blockers in hypertrophic cardiomyopathy (HCM).
We replicated the data analysis used in VANISH, converting individual change in each component of the composite endpoint into a z-score and applying this z-score to the INHERIT results.
No significant improvement was identified in the composite z-score between the 2 groups at 12-month follow-up (P = .4). With the exception of tissue Doppler systolic (s’) velocity, we found no significant benefit or harm from losartan compared to placebo for any of the individual components of the composite score at 12-month follow-up. Results were similar in analyses without imputed data or when restricted to patients with sarcomeric HCM.
Despite applying the potentially more sensitive composite z-score endpoint as in the VANISH trial, no statistically significant benefits from the use of losartan compared to placebo could be detected at 12-month follow-up in patients with overt HCM participating in the INHERIT trial.
Cardiac Myosin Inhibitors for Managing Obstructive Hypertrophic Cardiomyopathy: JACC: Heart Failure State-of-the-Art Review
2023, JACC: Heart Failure
Hypertrophic cardiomyopathy (HCM) is frequently caused by pathogenic variants in genes encoding sarcomere proteins and is characterized by left ventricular (LV) hypertrophy, hypercontractility, and—in many cases—left ventricular outflow tract (LVOT) obstruction. Despite standard management, obstructive HCM (oHCM) can still cause substantial morbidity, highlighting the critical need for more effective disease-specific therapeutic approaches. Over the past decade, improved understanding of the molecular pathobiology of HCM has culminated in development of cardiac myosin inhibitors (CMIs), a novel drug class that in recent randomized clinical trials has been shown to decrease LVOT obstruction, improve exercise capacity, and ameliorate symptom burden in patients with oHCM. Although promising, areas of uncertainty remain, including the long-term safety and efficacy of CMIs and whether they have the potential to modify progression of disease. Herein, we review key milestones in the clinical development of CMIs, contextualize CMIs with established oHCM therapies, and discuss future challenges and opportunities for the use of CMIs across the HCM spectrum.
Clinical scenarios of hypertrophic cardiomyopathy-related mortality: Relevance of age and stage of disease at presentation
2023, International Journal of Cardiology
The evolving epidemiology of hypertrophic cardiomyopathy (HCM) has progressively changed our perception of HCM-related mortality. However, recent studies detailing individual causes of death based on age and clinical setting are lacking. Thus, the present study aimed to describe the modes of death in a consecutive cohort of HCM patients based on presenting clinical features and stage of disease.
By retrospective analysis of a large HCM cohort, we identified 161 patients with >1 year follow-up who died between 2000 and 2020 and thoroughly investigated their modes of death. HCM stage at presentation was defined as “classic”, “adverse remodeling” or “overt dysfunction”.
Of the 161 patients, 103 (64%) died of HCM-related causes, whereas 58 (36%) died of non-HCM-related causes. Patients who died of HCM-related causes were younger than those who died of non-HCM related causes. The most common cause of death was heart failure (HF). Sudden cardiac death (SCD) ranked third, after non cardiovascular death, and mostly occurred in young individuals. The proportion of HF related death and SCD per stage of disease was 14% and 27% in “classic”, 38% and 21% in “adverse remodeling” and 74% and 10% in “overt dysfunction”.
Most HCM patients die due to complications of their own disease, mainly in the context of HF. While SCD tends to be juvenile, HF related deaths often occur in age groups no longer amenable to cardiac transplant. Modes of death vary with the stage of disease, with SCD becoming less prevalent in more advanced phases, when competitive risk of HF becomes overwhelming.
Prognostic factors in hypertrophic cardiomyopathy in children: An MRI based study
2022, International Journal of Cardiology
Citation Excerpt :
Furthermore, comparing our LGE data with those reported in adult population by Todiere et al., we observed that LGE prevalence is lower (45% vs 81% respectively), such as the LGE extent (1,85% in sarcomeric-HCM vs 4% of LV mass). These data of prevalence and LGE extent, measured with the 6-standard deviation method (6 SD), are consistent with the well-established concept that fibrosis is a progressive phenomenon, both in adults and children [19–23]. In our cohort 21 patients had hard cardiac events (18%), mostly in sarcomeric HCM (69%).
Clinical and prognostic role of cardiac magnetic resonance (CMR) in adult population with hypertrophic cardiomyopathy (HCM) have been largely assessed.
We sought to investigate the role of CMR for predicting cardiovascular events in children with HCM.
CMR was performed in 116 patients with HCM (37 sarcomeric mutations, 31 other mutations, mean age 10.4 ± 4.3 yrs). CMR protocol included cine imaging for evaluation of morphology and function and late gadolinium enhancement (LGE). Hard cardiac events (sustained VT, resuscitated cardiac arrest, sudden cardiac death, end-stage heart failure, heart transplant and appropriate ICD intervention) were recorded through a median follow-up of 4 (1–7) years.
During follow-up 21 heart cardiac events occurred. At maximal-rank statistic the optimal cut-point for LGE extent for predicting events was ≥2%. Syncope, non-sustained ventricular tachycardia (NSVT) and LGE extent ≥2% were independent predictors of events. At Harrel's C statistic combination of LGE extent ≥2% and syncope was the strongest model for predicting events. HR of patients with LGE extent ≥2% and no history of syncope was 3.6 (1.1–12.2) that increased to 37.6 (5.4–161) in those with LGE extent ≥2% and syncope. The median time dependent AUC of LGE extent (0.88, 95% CI 0.86–0.89) was significantly higher than that of syncope (0.63, 95% CI 0.61–0.66, p < 0.0001) and NSVT (0.52, 95% CI 0.50–0.53, p < 0.0001).
In children with HCM, LGE and syncope were independent predictors of hard cardiac events at follow-up.
2020 AHA/ACC guideline for the diagnosis and treatment of patients with hypertrophic cardiomyopathy: A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines
2021, Journal of Thoracic and Cardiovascular Surgery

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

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and patients

Results

Discussion

Mayo Clin Proc

JACC Heart Fail

J Am Coll Cardiol

J Am Coll Cardiol

J Mol Diagn

Am J Cardiol

J Am Soc Echocardiogr

J Card Fail

Am J Cardiol

J Am Coll Cardiol

Am Heart J

JACC Cardiovasc Imaging

J Am Coll Cardiol

Prevalence of hypertrophic cardiomyopathy in a general population of young adults. Echocardiographic analysis of 4111 subjects in the CARDIA Study. Coronary Artery Risk Development in (Young) Adults

Circulation

Genetics of hypertrophic cardiomyopathy

Curr Opin Cardiol

Diagnostic yield, interpretation, and clinical utility of mutation screening of sarcomere encoding genes in Danish hypertrophic cardiomyopathy patients and relatives

Hum Mutat

Shared genetic causes of cardiac hypertrophy in children and adults

N Engl J Med

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