INHibition of the renin angiotensin system in hypertrophic cardiomyopathy and the Effect on hypertrophy: a Randomized Intervention Trial with losartan - INHERIT

Description:

Animal models have demonstrated a favorable effect of angiotensin-receptor blockers (ARBs) on left ventricular (LV) mass and myocardial fibrosis in patients with hypertrophic cardiomyopathy (HCM). The current study sought to study the efficacy of losartan in improving LV morphology in patients with HCM.

Hypothesis:

Losartan would be superior to placebo in improving LV morphology in patients with HCM.

Study Design

  • Placebo Controlled
  • Randomized
  • Blinded
  • Parallel

Patient Populations:

  • HCM
  • ≥18 years
  • Sinus rhythm at inclusion

    Number screened: 318
    Number of enrollees: 133
    Duration of follow-up: 1 year
    Mean patient age: 51 years
    Percentage female: 35%

Exclusions:

  • Blood pressure >140/90 mm Hg
  • Angiotensin-converting enzyme inhibitor or ARB LV ejection fraction <50%
  • Significant valvular disease
  • Estimated glomerular filtration rate <30 ml/min/1.73 m2
  • Recent (≤6 months) septal reduction therapy

Primary Endpoints:

  • Change in LV mass as assessed by magnetic resonance imaging (MRI) or computed tomography

Secondary Endpoints:

  • LV fibrosis (late gadolinium enhancement on MRI
  • LV maximal wall thickness
  • Diastolic function
  • LV outflow tract gradient
  • Exercise tolerance
  • Symptoms

Drug/Procedures Used:

Patients with HCM were randomized in a 1:1 fashion to either losartan 100 mg daily or matching placebo.

Concomitant Medications:

Beta-blockers (57%), calcium channel blockers (14%)

Principal Findings:

A total of 133 patients were randomized, 64 to losartan and 69 to placebo. Baseline characteristics were fairly similar between the two arms. About 20% had undergone prior septal reduction therapy, 10% had treated hypertension, and 10% had suffered previous cardiac arrest/sustained ventricular tachycardia (VT)/appropriate implantable cardioverter-defibrillator (ICD) shock. Genetic testing was performed in >80% and a disease-specific gene was identified in 43% of patients. Baseline LV mass was 107 g/m2 with a mean maximal wall thickness of 23 mm. LV fibrosis was observed in 85% on cardiac magnetic resonance.

The primary endpoint, change in LV mass between baseline and 12 months, was similar between the losartan and placebo arms (difference 1 g/m2, 95% confidence interval -3 to 6 g/m2, p = 0.6). Change in maximal wall thickness (1 vs. 1 mm, p = 0.26), peak LV outflow gradient during Valsalva (7 vs. 2 mm Hg, p = 0.47), and % LV fibrosis (2 vs. 3%, p = 0.62) were similar between the two arms. Peak V02 max was also similar (p = 0.08). No differences were noted in clinical events such as sudden cardiac death (0 vs. 2), angioedema (1 vs. 0), and hyperkalemia (1 vs. 0); (p > 0.05 for all).

Interpretation:

The results of the INHERIT trial indicate that losartan is not superior in reducing LV mass and thickness compared with placebo in patients with HCM. There have been other smaller studies in this patient population, including with other angiotensin-receptor blockers (ARBs) such as candesartan, showing a possible improvement in LV geometry in HCM patients. Other studies are needed to assess the role of ARBs in this patient population. The magnitude of blood pressure lowering was not available in this trial, and will also need to be factored into future studies in these patients.

References:

Presented by Dr. Anna Axelsson at the American Heart Association Scientific Sessions, Chicago, IL, November 18, 2014.

Clinical Topics: Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Prevention, Vascular Medicine, Implantable Devices, SCD/Ventricular Arrhythmias, Novel Agents, Hypertension

Keywords: Losartan, Angiotensin Receptor Antagonists, Cardiomyopathy, Hypertrophic, Angioedema, Renin-Angiotensin System, Hyperkalemia, Genetic Testing, Tetrazoles, Tachycardia, Ventricular, Benzimidazoles, Hypertrophy, Heart Ventricles, Magnetic Resonance Spectroscopy, Hypertension, Death, Sudden, Cardiac, Defibrillators, Implantable, AHA Annual Scientific Sessions


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