MERIT-HF

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Fagerberg B, et al. "Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure". The Lancet. 1999. 353(9169):2001-7.
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Clinical Question

In patients with HFrEF and NYHA class II-IV symptoms, does metoprolol succinate reduce morbidity and mortality?

Bottom Line

In patients with symptomatic HFrEF with EF ≤40%, long-acting metoprolol led to a 34% reduction in all-cause mortality.

Major Points

The original CIBIS trial (1994)[1] demonstrated a functional benefit for patients with systolic dysfunction with treatment with the beta blocker bisoprolol. The role of beta blockers in mortality reduction was unclear.

The 1999 Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF) randomized 3,991 patients with symptomatic HF with EF ≤40% to metoprolol XL or placebo. The study was stopped early after an interim analysis demonstrated a 34% reduction in all-cause mortality with metoprolol XL%. Additional secondary outcomes demonstrated a reduction in all-cause hospitalization and CV events. MERIT-HF established the survival benefit of extended-release metoprolol among patients with HFrEF. It was joined by CIBIS-II[2] (1999) and COPERNICUS (2002), which demonstrated mortality benefit in a similar population with bisoprolol and carvedilol, respectively.

Guidelines

AHA/ACCF Heart Failure (2013, adapted)[3]

  • Use of bisoprolol, carvedilol, or metoprolol sustained release for all patients with current or prior symptomatic HFrEF unless contraindicated (class I, level A)

Design

  • Multicenter, double-blinded, parallel-group, randomized, placebo-controlled trial
  • N=3,991
    • Metoprolol XL (n=1,990)
    • Placebo (n=2,001)
  • Setting: 313 centers in US and Europe
  • Enrollment: February 1997 to April 1998
  • Mean follow-up: 1 year
  • Analysis: Intention-to-treat

Population

Inclusion Criteria

  • Age 40-80 years
  • NYHA class II-IV for ≥3 months
  • EF ≤40%
    • If EF 36-40%, 6-min walk test must be ≤500 yards
  • Resting HR ≥68 bpm
  • Optimal medical therapy for ≥2 weeks
    • ACE inhibitor or hydralazine/nitrate/ARB if not tolerated
    • Diuretics
  • Stable condition during 2-week placebo run-in phase prior to randomization

Exclusion Criteria

  • ACS ≤28 days prior to randomization
  • Indication or contraindication for beta-1-blocker
  • Severe decompensated HF
  • Supine systolic BP <100 mmHg

Baseline Characteristics

  • Mean age: 64.4 years
  • Male: 72%
  • NYHA class:
    • II: 39%
    • III: 56%
    • IV: 5%
  • Mean LVEF: 27%
  • Prior MI: 51%
  • ACE/ARB treatment: 96%
  • Furosemide dose at entry: 66 vs. 65 mg/day
  • ACE inhibitor dose at study entry:
    • Enalapril: 14 mg/day in each
    • Captopril: 68 vs. 60 mg/day
    • Lisinopril: 17 vs. 16 mg/day

Interventions

  • Randomized to metoprolol XL or placebo daily
  • Metoprolol XL starting dose was 25mg for most patients, or 12.5mg for NYHA class III-IV patients
  • Dose doubled at 2-week intervals to target 200mg/day
  • Temporary reduction in dosage or increase in diuretic dosage if patient did not tolerate uptitration
  • Follow-up visits every 3 months, calculating NYHA functional class, Minnesota Living with Heart Failure questionnaire, McMaster Overall Treatment Evaluation questionnaire, and recounting hospitalization history
  • Hospitalizations defined as acute-case hospital care lasting for ≥24h
  • Hospitalization was due to HF if medical charts documented worsening HF as a reason for admission
  • Stopped early because interim analysis demonstrated significant reduction in the metoprolol XL group

Outcomes

Comparisons are metoprolol XL vs. placebo. RR, risk reduction (not relative risk).

Primary Outcomes

All-cause mortality
0.072 vs. 0.11 per patient-year (RR 0.34; 95% CI 0.19-0.47; P=0.00009)
All-cause mortality plus all-cause hospitalization
0.32 vs. 0.38 (RR 0.19; 95% CI 0.10-0.27; P<0.001)

Secondary Outcomes

All-cause mortality or HF hospitalization
0.16 vs. 0.22 (RR 0.31; 95% CI 0.20-0.40; P<0.001)
Death or heart transplant
0.075 vs. 0.10 (RR 0.32; 95% CI 0.16-0.45; P<0.001)
Cardiac death or nonfatal MI
0.069 vs. 0.11 (RR 0.39; 95% CI 0.25-0.51; P<0.001)
All-cause mortality or all-cause hospitalization or ED visit for HF
0.16 vs. 0.23 (RR 0.32; 95% CI 0.21-0.41; P<0.001)

Funding

Funding provided by grants from AstraZeneca, the makers of Toprol XL.

Further Reading

  1. Lechat P, et al. "A randomized trial of beta-blockade in heart failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS)." Circulation. (1994);90(4):1765-1773.
  2. CIBIS Authors. "The cardiac Insufficiency Bisoprolol Study II (CIBIS-II): A randomised trial." The Lancet. (1999):353;9146:9-13.
  3. Yancy CW, et al. "2013 ACCF/AHA guideline for the management of heart failure." Circulation. 2013;128:e240-e327.