Does early beta-blockade decrease mortality in STEMI?

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Does early beta-blockade decrease mortality in
STEMI?

• Aric Storck PGY5
• August 31, 2006

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B-Blockers AMIBackground

• First trial in 1965
• gt 50 RCT to date
• Good evidence for benefit
• Reducing mortality
• Reducing reinfarction
• Reducing tachydysrhythmias
• Post Ischemic CHF

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B-BlockersMechanisms of Benefit

• Decrease myocardial O2 Demand
• Decrease HR / BP / contractility
• Increase myocardial O2 Supply
• Increase diastolic filling time
• Decrease ventricular dysrhythmias
• Blockade of sympathetic nervous system
• Increase VF threshold

• Improved LV diastolic function
• Modify remodeling
• Recruitment of stunned myocardium
• Reduce infarct size
• Decrease myocardial rupture

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Beta-blockadeLong vs Short-Term Prevention

• Short Term Trials
• B-blockade given up to six weeks
• Both early and late administration
• Long Term Trials
• B-blockade given for 6-48 months

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Long Term Trials

• 31 trials
• 24,974 patients
• OR for mortality
• 0.77 (0.69 to 0.85)

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Short Term Trials
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Short Term Trials

• 59 trials
• 29,260 patients
• OR for Mortality
• 0.96 (0.85 to 1.08)
• NOT SIGNIFICANT
• What about early beta-blockers?

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AHA 2005 Guidelines
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American Heart Association2005 Guidelines

• ß-blockers should be administered in the ED for
  ACS of all types unless contraindications are
  present. They should be given irrespective of the
  need for revascularization therapies.
• In the presence of moderate or severe heart
  failure, oral ß-blockers are preferred. They may
  need to be given in low and titrated doses after
  the patient is stabilized.

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American Heart Association2005
GuidelinesContraindications to beta-blockers

• Moderate to severe LV failure and pulmonary edema
• Bradycardia (lt60 bpm)
• Hypotension (SBP lt100 mm Hg)
• Shock
• Advanced 1st degree HB (pr gt 0.24)
• 2nd or 3rd degree HB

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Where does the evidence for early iv
beta-blockers in AMI come from?
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The Goteborg Trial

• N 1395 Suspected MI
• 809 confirmed MI
• 162 probable MI
• RCT
• Metoprolol 5/5/5 then 100 bid x 3 months vs
  placebo
• Did not give if HR lt45, sBP lt95, rales gt10 cm
• Predetermined guidelines for withdrawal of study
  med
• Bradycardia (HRlt40), hypotension (sBP lt90), heart
  block, dyspnea

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The Goteborg TrialResults

• Three month mortality
• Metoprolol 62 (5.7)
• Placebo 40 (8.9)
• RRR 36
• ARR 3.2
• NNT - 31

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The MIAMI TrialAm J Cardiol 1985

• RCT N5,778
• Inclusion
• Suspected AMI
• Intervention
• Metoprolol 5/5/5 iv then 200/day in divided
  doses x 15 days
• Primary Outcomes
• Mortality at 15 days

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MIAMI TrialResults
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MIAMIResults

• 15 day mortality
• Metoprolol 4.3
• Placebo 4.9 (NS)
• Authors suggestion study may have been
  underpowered

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• ISIS 2
• Streptokinase or ASA or both vs placebo
• ISIS 3
• tPA vs Streptokinase
• ASA alone vs ASA plus heparin
• ISIS 4
• Captopril, Mg, Oral Nitrates

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• RCT N16,027
• Inclusion
• Suspected AMI
• Intervention
• Atenolol 5/5 iv then 100 od
• Primary Outcomes
• Vascular mortality at one week
• Vascular mortality at end of study period (mean
  20 months)

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ISIS-1Exclusion Criteria

• HR lt50
• sBP lt100
• 2nd or 3rd degree HB
• severe CHF

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ISIS-1 - Results

• Early mortality
• Decreased mortality day 0-1
• Long-term mortality
• No difference in mortality days 2-7 or beyond

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So Beta Blockers worked in STEMI in the 1980s

• What about thrombolysis?

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Short-term effects of early IV treatment with a
beta-blocker or a specific bradycardic agent in
patients with AMI receiving thrombolytic therapy

• RCT N292 followed for 14 days
• Atenolol (N100) 5-10 mg IV then 25-50 po bid
• Alinidine (N98) 20-40 mg IV then 20-40 po tid
• Placebo (N94)
• All received alteplase 100mg
• Results
• No differences in mortality, vessel patency, EF,
  infarct size, WMA, dysrhythmias
• More nonfatal pulmonary edema with atenolol
• 6 vs. 1 (alinidine) and 0 (placebo), p 0.021

J Am Coll Cardiol, 1993 22407-416
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• RCT of thrombolytic strategies
• Observational study of beta-blockers
• Patients without hypotension, bradycardia, or CHF
  supposed to be treated with
• Atenolol 5/5 iv, then 50-100 bid
• Outcome
• 30 day mortality

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GUSTO-IResults

• Patients given any atenolol less sick
• Mortality
• Any atenolol vs no atenolol
• OR 0.20 (0.190.22) plt0.0001
• IV PO atenolol vs PO only
• OR 1.2 (1.0 1.3) p0.03

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• RCT
• tPA with conservative vs invasive strategy
• Metoprolol
• Early IV (5/5/5 iv then 50-100 po bid) within 2h
• Deferred (50100 po bid) started on day 6
• N 1434
• 730 - early BB
• 712 deferred BB

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TIMI-II-BExclusion Criteria

• Implanted pacemaker
• HR lt 55 bpm
• sBP lt100 mm Hg
• Moist rales gt 1/3 lung field
• Pulmonary edema
• Advanced 1st degree or higher heart block
• Already on BB or CCB

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TIMI-IIB

• Therapy stopped if
• PR gt 0.26 seconds
• 2nd or 3rd degree AV block
• Rales or wheeze gt 1/3 lung field
• Temporarily held (10 min) if
• HR lt45 bpm
• sBP lt90mmHg
• Resumed at 2.5mg dosing if HR gt49, sBP gt95 at 10
  min

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TIMI-IIB - Results

• Primary Outcome
• Resting Ejection Fraction No difference
• Secondary Outcomes
• Mortality
• No difference at 6 days, 6 weeks, and 1 year
• Reinfarction
• Less in early group at 6 days and 6 weeks
• No difference at 1 year
• Recurrent chest pain
• Early group 18.8 vs 24.1 (plt0.02) at 6 days
• No difference at 6 weeks or one year

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So early beta-blockade doesnt seem to work with
thrombolysis.
What about PCI?
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Beta-Blockade in PCI

• No RCT of BB in PCI

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• RCT N45,853
• 93 STEMI or new BBB
• 7 STD
• Intervention
• Metoprolol 5/5/5 iv then 50 qid vs placebo
• Outcomes
• Death, reinfarction, cardiac arrest
• Death from any cause

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Exclusion Criteria

• Patients going for PCI
• Likely to receive both ASA and clopidogrel
• High risk of adverse effects
• sBP lt 100
• HR lt50
• Heart Block
• Cardiogenic Shock
• Withdrew treatment if HRlt50, sBPlt90
• Did not exclude patients with moderate (Killip 2
  or 3) heart failure

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Killip Classification of CHF

• Class 1
• no clinical signs of heart failure
• Class 2
• crackles, S3 gallop and elevated jugular venous
  pressure
• Class 3
• frank pulmonary edema
• Class 4
• cardiogenic shock - hypotension (systolic lt 90
  mmHg) and evidence of peripheral vasoconstriction
  (oliguria, cyanosis, sweating)
• NB Higher class correlated with higher mortality

Killip and Kimball American Journal of
Cardiology 1967 20 457-464
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Results 1
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Timing of adverse events
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Metoprolol and Cardiogenic Shock

• Who was harmed (excess cases of shock)
• gt70 yo 23/1000
• sBP lt120 23/1000
• HR gt110 35/1000
• Killip 3 57/1000
• Who benefitted
• No identifiable group had significant benefit

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Conclusions

• No effect on primary or composite outcome
• Composite of death, reinfarction, cardiac arrest,
  shock
• Early effects (day 0-1)
• More hypotension, bradycardia, cardiogenic shock
• More heart failure
• Significantly NEGATIVE
• Late effects (day 2-28)
• Less VF
• Less reinfarction
• Significantly POSITIVE

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COMMIT TrialComments

• Excluded patients going for PCI
• Is this our population?
• Exclusion criteria vague different that AHA
  recommendations
• Included patients with moderate (Killip 2 or 3)
  heart failure

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So what is the bottom line?
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Early IV MetoprololTake Home Points

• No evidence of mortality benefit in thrombolytic
  and angioplasty era
• Early routine iv metoprolol may cause cardiogenic
  shock
• Consider using oral beta-blockers once patient
  stabilized

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the end