In patients with HFrEF and NYHA class II-IV symptoms, does metoprolol succinate reduce morbidity and mortality?
In patients with symptomatic HFrEF with EF ≤40%, long-acting metoprolol led to a 34% reduction in all-cause mortality.
The original CIBIS trial (1994) 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 (1999) and COPERNICUS (2002), which demonstrated mortality benefit in a similar population with bisoprolol and carvedilol, respectively.
AHA/ACCF Heart Failure Guidelines (2013, adapted)
- Use of bisoprolol, carvedilol, or metoprolol sustained release for all patients with current or prior symptomatic HFrEF unless contraindicated (class I, level A)
- Multicenter, double-blinded, parallel-group, randomized, placebo-controlled trial
- 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
- 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
- Stable condition during 2-week placebo run-in phase prior to randomization
- ACS ≤28 days prior to randomization
- Indication or contraindication for beta-1-blocker
- Severe decompensated HF
- Supine systolic BP <100 mmHg
- 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
- 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
Comparisons are metoprolol XL vs. placebo. RR, risk reduction (not relative risk).
- 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)
- 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 provided by grants from AstraZeneca, the makers of Toprol XL.
- 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.
- CIBIS Authors. "The cardiac Insufficiency Bisoprolol Study II (CIBIS-II): A randomised trial." The Lancet. (1999):353;9146:9-13.
- Yancy CW, et al. "2013 ACCF/AHA guideline for the management of heart failure." Circulation. 2013;128:e240-e327.