COMMIT

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Chen ZM, et al. "Early intravenous then oral metoprolol in 45 852 patients with acute myocardial infarction: randomised placebo-controlled trial". The Lancet. 2005. 366(9497):1622-1632.
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Clinical Question

Among patients with acute MI who are not undergoing PCI, does metoprolol reduce rates of death, reinfarction, or cardiac arrest?

Bottom Line

Among patients with acute MI not undergoing PCI, a regimen of IV metoprolol followed by high-dose oral metoprolol succinate does not reduce the composite rate of death, reinfarction, or cardiac arrest, but does increase rates of cardiogenic shock.

Major Points

Published in 2005, the Clopidogrel and Metoprolol in Myocardial Infarction Trial/Second Chinese Cardiac Study (COMMIT/CCS-2) randomized 45,952 patients in China with acute MI to metoprolol or placebo at initial presentation. The majority of patients had STEMI or LBBB (93%) and about half underwent fibrinolysis; patients scheduled for PCI were excluded. Patients were given IV metoprolol followed by moderate/high-dose oral metoprolol. At 28 days, there were no differences in the co-primary outcomes of death (7.7% vs. 7.8%) or the composite outcome of death, reinfarction, or cardiac arrest (9.4% vs. 9.9%), but metoprolol increased rates of cardiogenic shock (5.0% vs. 3.9%) and shock-related mortality (2.2% vs. 1.7%). A post hoc subgroup analysis identified Killip class ≥2 as a predictor of the development of cardiogenic shock, and suggested that those with less severe disease may receive a marginal benefit from beta-blockade.

COMMIT was carried out on the heels of earlier trials that suggested early beta-blockade modestly reduced infarct size and possibly improved survival when administered early to patients not undergoing fibrinolysis or PCI. COMMIT differed from these trials in that about half of patients underwent fibrinolysis and because COMMIT did not exclude patients with evidence of heart failure (25% of patients in COMMIT had Killip class II-III). In addition, COMMIT deliberately excluded those undergoing PCI, as PCI patients were likely to receive a thienopyridine antiplatelet drug that would have interfered with the clopidogrel vs. placebo arm of COMMIT.

The trial was criticized for the particular regimen of beta-blockade it employed.[1] Specifically, patients were given up to three doses of IV metoprolol titrated to HR 50 bpm and systolic BP 90 mmHg, followed by high-dose metoprolol tartrate and then metoprolol succinate. Although the earlier MIAMI trial[2] used a similar regimen, such an aggressive use of beta-blockers may have been responsible for higher rates of cardiogenic shock, particularly among those with higher Killip class.

Guidelines

ACCF/AHA STEMI (2013, adapted)[3]

  • Start oral beta blocker therapy in the first 24 hours of STEMI therapy if none of the following are present (class I, level B):
    • Signs of HF
    • Evidence of low-output state
    • Increased risk for cardiogenic shock
    • General beta blocker contraindications including PR interval >0.24 seconds, second degree heart block, third degree heart block, active asthma, or reactive airway disease
  • Continue beta blockers during and following STEMI hospitalization if no contraindications (class I, level B)
  • If patients with STEMI initially have contraindications to beta blockers in the first 24 hours, they should be reevaluated for eligibility subsequently (class 1, level C)
  • IV beta blockers are reasonable to use at the time of STEMI presentation if no contraindications and ongoing ischemia or hypertension are present (class IIa, level B)

ACCF/AHA NSTE-ACS (2014, adapted)[4]

  • Start oral beta blocker therapy in the first 24 hours of NSTE-ACS therapy if none of the following are present (class I, level A):
    • HF signs
    • Clinical evidence of a low-output state
    • Elevated risk of cardiogenic shock
    • General beta blocker contraindications including PR interval >0.24 seconds, second degree heart block, third degree heart block, active asthma, or reactive airway disease
  • If NSTE-ACS and stabilized HFrEF, continue beta blocker therapy with metoprolol succinate, carvedilol, or bisoprolol (class I, level C)
  • It is reasonable to continue beta blocker therapy if NSTE-ACS and no LV dysfunction (class IIa, level C)
  • IV beta blocker administration to patients with NSTE-ACS at risk for shock is potentially harmful (class III, level B)

Design

  • Multicenter, randomized, placebo-controlled trial
  • N=45,852 patients with MI not undergoing PCI
    • Metoprolol (n=22,929)
    • Placebo (n=22,923)
  • Setting: 1,250 centers in China
  • Enrollment: 1999-2005
  • Follow-up: 28 days
  • Analysis: Intention-to-treat
  • Co-primary outcomes: composite of death, reinfarction, cardiac arrest; and all-cause mortality

Population

Inclusion Criteria

  • STEMI, LBBB, or ST depression within 24h of chest pain onset suggestive of MI
  • No clear indication for or contraindication to either study drug

Exclusion Criteria

  • Planned PCI (which would have been an indication for clopidogrel)
  • High risk of adverse events with study treatment (eg, shock, bradycardia, heart block)
  • Other life-threatening disease

Baseline Characteristics

From the metoprolol group.

  • Demographics: Age 61.4 years, female 28.0%,
  • PMH: MI 8.4%, HTN 43.4%,
  • Medications prior to admission: ASA 18.4%, beta-blocker 6.5%, fibrinolytics 49.7%
  • Hospital medications: Non-study beta-blocker 6.1% (vs. 15.7% in placebo group), fibrinolytics 54.3%, anticoagulants 74.4%, antiarrythmic 22.0%, ACE-inhibitor 67.2%, nitrate 94.1%, diuretic 24.2%, CCB 10.9%
  • ACS: Symptom duration 6.7 hours
  • Enrollment health data: SBP 128.2, HR 82.0, ST-elevation 86.7%, BBB 6.2%, ST-depression 7.1%
  • Killip class:
    • I: 75.3%
    • II: 19.9%
    • III: 4.7%

Interventions

  • Randomized to metoprolol or placebo:
    • Metoprolol 5mg IV up to three times titrated to HR of 50 bpm or SBP 90mmHg followed by metoprolol tartrate 50mg PO q6h for 48 hours then metoprolol succinate 200mg daily for 4 weeks
    • Matching IV and PO placebo
  • Patients further randomized to clopidogrel or placebo, but these results are not presented here.

Outcomes

Comparisons are metoprolol vs. placebo.

Primary Outcomes

All-cause mortality
7.7% vs. 7.8% (OR 0.99; 95% CO 0.92-1.05; P=0.69)
All-cause mortality, reinfarction, VF, or other cardiac arrest
9.4% vs. 9.9% (OR 0.96; 95% CI 0.90-1.01; P=0.10)

Secondary Outcomes

Arrhythmia mortality
1.7% vs. 2.2% (OR 0.78; 95% CI 0.68-0.89; P=0.0002; NNT=200)
Shock mortality

Excluded participants with shock and arrhythmia as cause.

2.2% vs. 1.7% (OR 1.29; 95% CI 1.13-1.47; P=0.0002; NNH=200)
Reinfarction
2.0% vs. 2.5% (OR 0.82; 95% CI 0.72-0.92; P=0.001; NNT=200)
VF
2.5% vs. 3.0% (OR 0.83; 95% CI 0.75-0.93; P=0.001; NNT=200)
Other cardiac arrest
3.0% vs. 2.8% (OR 1.08; 95% CI 0.97-1.21; P=0.14)
Cardiogenic shock
5.0% vs. 3.9% (OR 1.30; 95% CI 1.19-1.31; P<0.0001; NNH=91)

Subgroup Analysis

Several post hoc subgroup analyses were performed, but most interesting was the analysis based upon Killip class. There was no benefit in the composite efficacy and safety endpoint of death, reinfarction, ventricular fibrillation, other arrest, or cardiogenic shock among Killip class I patients (8.7% vs. 8.8%) or Killip class II patients (15.8% in each arm), and Killip class III patients received harm from metoprolol (25.1% vs. 20.7%).

Criticisms

  • The study's aggressive metoprolol dose and schedule of 15mg IV in divided doses titrated to relative hypotension and bradycardia, followed by high-dose metoprolol tartrate and then long-acting metoprolol succinate at near maximal doses of 200mg daily in patients, 93.5% of whom were beta-blocker-naive.
  • Included patients with signs of pulmonary congestion or frank heart failure (Killip class II-III) unlike earlier beta-blocker trials.

Funding

Sanofi-Aventis and Bristol-Myers Squibb (manufacturers of clopidogrel), AstraZeneca (manufacturers of metoprolol), and various UK foundations provided funding.

Further Reading

  1. Sabatine MS. "Something old, something new: beta blockers and clopidogrel in acute myocardial infarction." Lancet. 2005;366(9497):1587-9.
  2. MIAMI Trial Research Group. "Metoprolol in acute myocardial infarction (MIAMI). A randomised placebo-controlled international trial." European Heart Journal (1985):6;3:199-226.
  3. O'Gara PT, et al. "2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines." Circulation. 2013;127(4):e362-e425.
  4. Amsterdam EA, et al. "2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes." Journal of the American College of Cardiology. 2014;epublished 2014-09-23. Accessed 2014-09-24.