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  • Effect of metoprolol CR/XL in chronic heart failure (MERIT-HF). Lancet. 1999;353:2001-2007.

Background

  • Historical treatment of heart failure (HF) included hydralazine, digoxin, and isosorbide, as beta blockers had limited evidence for efficacy and were known mechanistically to be negative chronotropes.2, 3

  • By 1993, ACE inhibitors had proved superior to standard therapy, and the MDC trial showed that 100–150mg daily of metoprolol tartrate improved HF symptoms and prevented disease progression but did not improve mortality.4, 5

  • While the MDC results were promising, a trial designed to prove mortality benefit was still needed in order to solidify the need for beta-blockade in HF.

Objective

  • This trial was designed to determine if metoprolol succinate can lower mortality in patients with heart failure with a decreased ejection fraction (HFrEF).

Study Design

  • Randomized, double-blinded, placebo-controlled, multinational clinical trial.

  • Following a 2-week placebo run-in period, patients from 313 clinical sites in 13 countries were stratified by site, age, sex, ethnicity, cause of HF, history of MI, EF, and NYHA class, then randomized into:

    1. Metoprolol CR/XL starting at 12.5mg/day and titrated over 6 weeks to target 200mg/day

    2. Control—Placebo

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Inclusion Criteria Exclusion Criteria
  • 40–80 years old

  • NYHA Class II–IV for >3 months

  • EF <40%

  • Resting HR >68

  • On optimal medication treatment × 2+ weeks

  • ACE inhibitor + diuretics

  • ARB/nitrate/hydralazine if no ACEi

  • Stable at randomization

  • MI within 28 days prior to randomization

  • Indication or contraindication for beta blockade

  • Taking drugs with beta blocking properties/amiodarone/diltiazem/verapamil

  • Taking a beta blocker within 6 weeks prior to enrollment

  • Scheduled cardiac surgery

  • Supine systolic BP <100mm Hg

Outcomes

  • Primary: All-cause mortality and all-cause mortality plus all-cause hospitalization

  • Secondary: Cardiovascular mortality; sudden death; death from worsening heart failure

Statistics

  • 1600 patients over 2.4 years of follow-up were needed for 80% power to detect a 30% risk reduction, assuming a 9.4% mortality rate in the control group with an alpha significance level of 0.04 for all-cause mortality, and 0.01 for all-cause mortality plus hospitalization

  • Predefined stopping criteria were to be assessed after 25%, 50%, and 75% of expected total deaths, and alpha values would be adjusted

  • Log-rank tests were used for comparisons and Cox proportional hazards model was used for relative risk and 95% CI calculations

  • Analyses were made on an intent to treat basis

Results

  • Study was ended early based on the second interim analysis, resulting in a mean follow-up time of 1 year (3980 patient-years)

  • Groups were similar at baseline for characteristics and therapies, but no statistics given

    • Mean age 64.4 years, 72% male, NYHA Class II:39%, Class III: 56%, Class IV: 5%

    • Mean LVEF: 27%, ACEi/ARB Tx: 96%

  • Metoprolol showed significant benefit across all ...

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