Transcript 2006_08_31-Storck-Beta-Blockers_in_STEMI

Does early beta-blockade
decrease mortality in
STEMI?
Aric Storck – PGY5
August 31, 2006
B-Blockers & AMI
Background
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First trial in 1965
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> 50 RCT to date
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Good evidence for benefit
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Reducing mortality
Reducing reinfarction
Reducing tachydysrhythmias
Post Ischemic CHF
B-Blockers
Mechanisms of Benefit
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Decrease myocardial O2
Demand
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Modify remodeling
Recruitment of stunned
myocardium
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Reduce infarct size
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Decrease myocardial rupture
Increase diastolic filling time
Decrease ventricular
dysrhythmias
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Improved LV diastolic function
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Decrease HR / BP /
contractility
Increase myocardial O2 Supply
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Blockade of sympathetic
nervous system
Increase VF threshold
Beta-blockade
Long vs Short-Term Prevention
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Short Term Trials
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B-blockade given up to six weeks
Both early and late administration
Long Term Trials
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B-blockade given for 6-48 months
Long Term Trials
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31 trials
24,974 patients
OR for mortality
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0.77 (0.69 to 0.85)
Short Term
Trials
Only 3 trials with
>1000 patients
Short Term Trials
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59 trials
29,260 patients
OR for Mortality
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0.96 (0.85 to 1.08)
NOT SIGNIFICANT
What about early
beta-blockers?
AHA
2005 Guidelines
American Heart Association
2005 Guidelines

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“…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.”
American Heart Association
2005 Guidelines
Contraindications to beta-blockers
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Moderate to severe LV failure and
pulmonary edema
Bradycardia (<60 bpm)
Hypotension (SBP <100 mm Hg)
Shock
Advanced 1st degree HB (pr > 0.24)
2nd or 3rd degree HB
Where does the evidence for
early iv beta-blockers in AMI
come from?
The Goteborg Trial
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N = 1395 – Suspected MI
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809 confirmed MI
162 probable MI
RCT
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Metoprolol 5/5/5 then 100 bid x 3 months vs placebo
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Did not give if HR <45, sBP <95, rales >10 cm
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Predetermined guidelines for withdrawal of study med
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Bradycardia (HR<40), hypotension (sBP <90), heart block,
dyspnea
The Goteborg Trial
Results
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Three month mortality
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Metoprolol – 62 (5.7%)
Placebo – 40 (8.9%)
RRR – 36%
ARR – 3.2%
NNT - 31
The MIAMI Trial
Am J Cardiol 1985
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RCT – N=5,778
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Inclusion
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Intervention
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Suspected AMI
Metoprolol 5/5/5 iv; then 200/day in divided doses x 15 days
Primary Outcomes
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Mortality at 15 days
MIAMI Trial
Results
MIAMI
Results
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15 day mortality
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Metoprolol 4.3%
Placebo 4.9 % (NS)
Authors suggestion study may have been
underpowered
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ISIS 2
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ISIS 3
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Streptokinase or ASA or
both vs placebo
tPA vs Streptokinase
ASA alone vs ASA plus
heparin
ISIS 4
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Captopril, Mg, Oral Nitrates
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RCT – N=16,027
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Inclusion
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Intervention
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Suspected AMI
Atenolol 5/5 iv then 100 od
Primary Outcomes
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Vascular mortality at one week
Vascular mortality at end of study period (mean 20 months)
ISIS-1
Exclusion Criteria
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HR <50
sBP <100
2nd or 3rd degree HB
“severe” CHF
ISIS-1 - Results
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Early mortality
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Decreased mortality
day 0-1
Long-term mortality
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No difference in
mortality days 2-7 or
beyond
So Beta Blockers worked in
STEMI in the 1980’s
What about
thrombolysis?
Short-term effects of early IV treatment with a
beta-blocker or a specific bradycardic agent in
patients with AMI receiving thrombolytic therapy
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RCT – N=292 – followed for 14 days
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Atenolol (N=100) 5-10 mg IV then 25-50 po bid
Alinidine (N=98) 20-40 mg IV then 20-40 po tid
Placebo (N=94)
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All received alteplase 100mg
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Results
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No differences in mortality, vessel patency, EF, infarct
size, WMA, dysrhythmias
More nonfatal pulmonary edema with atenolol
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6% vs. 1% (alinidine) and 0% (placebo), p = 0.021
J Am Coll Cardiol, 1993; 22:407-416
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RCT of thrombolytic strategies
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Observational study of beta-blockers
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Patients without hypotension, bradycardia, or
CHF supposed to be treated with
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Atenolol 5/5 iv, then 50-100 bid
Outcome
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30 day mortality
GUSTO-I
Results
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Patients given any atenolol less sick
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Mortality
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Any atenolol vs no atenolol
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OR 0.20 (0.19–0.22) p<0.0001
IV & PO atenolol vs PO only
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OR 1.2 (1.0 –1.3) p=0.03
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RCT
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tPA with conservative vs invasive strategy
Metoprolol
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Early IV (5/5/5 iv then 50-100 po bid) within 2h
Deferred (50–100 po bid) started on day 6
N = 1434
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730 - early BB
712 – deferred BB
TIMI-II-B
Exclusion Criteria
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Implanted pacemaker
HR < 55 bpm
sBP <100 mm Hg
Moist rales > 1/3 lung field
Pulmonary edema
Advanced 1st degree or higher heart block
Already on BB or CCB
TIMI-IIB
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Therapy stopped if
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Temporarily held (10 min) if
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PR > 0.26 seconds
2nd or 3rd degree AV block
Rales or wheeze > 1/3 lung field
HR <45 bpm
sBP <90mmHg
Resumed at 2.5mg dosing if HR >49, sBP >95 at
10 min
TIMI-IIB - Results
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Primary Outcome
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Resting Ejection Fraction – No difference
Secondary Outcomes
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Mortality
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Reinfarction
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No difference at 6 days, 6 weeks, and 1 year
Less in early group at 6 days and 6 weeks
No difference at 1 year
Recurrent chest pain
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Early group 18.8% vs 24.1% (p<0.02) at 6 days
No difference at 6 weeks or one year
So early beta-blockade doesn’t
seem to work with thrombolysis.
What about PCI?
Beta-Blockade in PCI
No RCT of BB in PCI
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RCT N=45,853
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Intervention
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93% STEMI or new BBB
7% STD
Metoprolol 5/5/5 iv then 50 qid vs placebo
Outcomes
1.
2.
Death, reinfarction, cardiac arrest
Death from any cause
Exclusion Criteria
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Patients going for PCI
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Likely to receive both ASA and clopidogrel
“High risk of adverse effects”
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sBP < 100
HR <50
Heart Block
Cardiogenic Shock
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Withdrew treatment if HR<50, sBP<90
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Did not exclude patients with moderate (Killip 2 or 3)
heart failure
Killip Classification of CHF
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Class 1
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Class 2
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frank pulmonary edema
Class 4
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crackles, S3 gallop and elevated jugular venous pressure
Class 3
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no clinical signs of heart failure
cardiogenic shock - hypotension (systolic < 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
Results 1
Timing of adverse events
Metoprolol and Cardiogenic Shock
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Who was harmed (excess cases of shock)
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>70 yo
sBP <120
HR >110
Killip 3
23/1000
23/1000
35/1000
57/1000
Who benefitted
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No identifiable group had significant benefit
Conclusions
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No effect on primary or composite outcome
Composite of death, reinfarction, cardiac arrest,
shock
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Early effects (day 0-1)
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More hypotension, bradycardia, cardiogenic shock
More heart failure
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Significantly NEGATIVE
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Late effects (day 2-28)
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Less VF
Less reinfarction
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Significantly POSITIVE
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COMMIT Trial
Comments
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Excluded patients going for PCI
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Is this our population?
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Exclusion criteria vague & different that
AHA recommendations
Included patients with moderate (Killip 2
or 3) heart failure
So what is the
bottom line?
Early IV Metoprolol
Take Home Points
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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
the end