Controlled Release Metoprolol for Aortic Regurgitation - Metoprolol for AR

Jan 26, 2016
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Oslo University Hospital
Date Published:
12/09/2015
Original Posted Date:
01/26/2016
References

Description:

The goal of the trial was to assess the safety and efficacy of controlled-release, long-acting metoprolol (metoprolol CR/XL) on left ventricular (LV) size and function in patients with chronic asymptomatic moderate to severe aortic regurgitation (AR).

Contribution to the Literature: The trial showed that metoprolol CR/XL does not improve LV end-diastolic (LVEDV) or end-systolic volume (LVESV) in asymptomatic patients with moderate to severe AR compared with placebo.

Study Design

  • Randomized
  • Double-blind
  • Placebo-controlled

Patients with chronic asymptomatic severe AR were randomized to metoprolol CR/XL (n = 37) or matching placebo (n = 38). Metoprolol was started at a dose of 25 mg daily and doubled every 2 weeks to a target dose of 200 mg daily when feasible (median dose at 6 months was 184 mg).

Inclusion criteria:

  • Age 18-70 years
  • Asymptomatic hemodynamically significant AR
  • LV ejection fraction (LVEF) ≥50%
  • LV end-diastolic dimension (LVEDD) >5 cm

Exclusion criteria:

  • Symptoms of congestive heart failure (CHF)
  • History of myocardial infarction or symptomatic coronary artery disease
  • Significant aortic stenosis
  • Additional hemodynamically significant valvular or congenital heart disease
  • Indication for aortic valve surgery (severe AR in conjunction with either symptoms of heart failure, an LVEF <50%, or an LVED/LVES internal diameter >7.0/5.0 cm
  • Atrioventricular block
  • Intracardiac device
  • Renal or hepatic abnormalities
  • Total number of enrollees: 75
  • Duration of follow-up: 6 months
  • Mean patient age: 44 years
  • Percentage female: 11%

Other salient features/characteristics:

  • Diabetes: 1%
  • Bicuspid valve: 73%
  • Resting heart rate: 62 bpm
  • LVEDD/LVESD: 64 mm/42 mm
  • LVEF 55%
  • AR fraction: 42%

Principal Findings:

The primary endpoint, LVEDV on cardiac magnetic resonance (CMR) at 6 months for metoprolol vs. placebo, was 267 vs. 256 ml (p = 0.32).

Secondary outcomes:

  • LVESV on CMR at 6 months for metoprolol vs. placebo: 117 vs. 117 ml, p = 0.44
  • EF on CMR at 6 months: 57 vs. 55%, p = 0.04
  • Stroke volume on CMR at 6 months: 151 vs. 139 ml, p = 0.04
  • Peak VO2 at 6 months: 34.9 vs. 36.6 ml/kg/min, p = 0.08
  • Peak heart rate at exercise: 147 vs. 168 bpm, p < 0.001
  • NT-pro-B-type natriuretic peptide (NT-proBNP): 142 vs. 58 pg/ml, p < 0.001

Interpretation:

The results of this small trial indicate that metoprolol CR/XL does not improve LVEDV or LVESV in asymptomatic patients with moderate to severe AR compared with placebo. On the one hand, some measures were better with beta-blocker use such as EF and stroke volume. On the other hand, peak VO2 diminished and NT-proBNP levels went up, suggesting harm.

Beta-blockade in AR remains controversial. Although beta-blockers are generally useful in patients with CHF, they may, at least in theory, worsen LV overload by increasing diastole. The latter is particularly true for patients with acute and subacute AR. Further trials assessing the utility of beta-blockers in this patient population are necessary.

References:

Broch K, Urheim S, Lønnebakken MT, et al. Controlled release metoprolol for aortic regurgitation: a randomised clinical trial. Heart 2016;102:191-7.

Keywords: Adrenergic beta-Antagonists, Aortic Valve Insufficiency, Heart Failure, Heart Valve Diseases, Magnetic Resonance Spectroscopy, Metoprolol, Natriuretic Peptide, Brain, Peptide Fragments, Stroke Volume, Ventricular Function, Left


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