Does early beta-Does early beta-blockade decrease blockade decrease mortality in STEMI?mortality in STEMI?

Aric Storck – PGY5Aric Storck – PGY5

August 31, 2006August 31, 2006

B-Blockers & AMIB-Blockers & AMIBackgroundBackground

First trial in 1965First trial in 1965

> 50 RCT to date> 50 RCT to date

Good evidence for benefitGood evidence for benefit Reducing mortalityReducing mortality Reducing reinfarctionReducing reinfarction Reducing tachydysrhythmiasReducing tachydysrhythmias Post Ischemic CHFPost Ischemic CHF

B-BlockersB-BlockersMechanisms of BenefitMechanisms of Benefit

Decrease myocardial O2 Decrease myocardial O2 DemandDemand Decrease HR / BP / Decrease HR / BP /

contractilitycontractility

Increase myocardial O2 Increase myocardial O2 SupplySupply Increase diastolic filling timeIncrease diastolic filling time

Decrease ventricular Decrease ventricular dysrhythmiasdysrhythmias Blockade of sympathetic Blockade of sympathetic

nervous systemnervous system Increase VF thresholdIncrease VF threshold

Improved LV diastolic Improved LV diastolic functionfunction Modify remodelingModify remodeling Recruitment of stunned Recruitment of stunned

myocardiummyocardium

Reduce infarct sizeReduce infarct size

Decrease myocardial Decrease myocardial rupturerupture

Beta-blockadeBeta-blockadeLong vs Short-Term PreventionLong vs Short-Term Prevention

Short Term TrialsShort Term Trials B-blockade given up to six weeksB-blockade given up to six weeks Both early and late administrationBoth early and late administration

Long Term TrialsLong Term Trials B-blockade given for 6-48 monthsB-blockade given for 6-48 months

Long Term Long Term TrialsTrials

31 trials31 trials 24,974 patients24,974 patients OR for mortalityOR for mortality

0.77 (0.69 to 0.85)

Short Term Short Term TrialsTrials

Only 3 trials with >1000 patients

Short Term Short Term TrialsTrials

59 trials59 trials 29,260 patients29,260 patients OR for MortalityOR for Mortality

0.96 (0.85 to 1.08)

NOT SIGNIFICANT

What about early beta-blockers?

AHAAHA 2005 2005

GuidelinesGuidelines

“…“…ß-blockers should be administered in ß-blockers should be administered in the ED for ACS of all types unless the ED for ACS of all types unless contraindications are present. They should contraindications are present. They should be given irrespective of the need for be given irrespective of the need for revascularization therapies.”revascularization therapies.”

““In the presence of moderate or severe In the presence of moderate or severe heart failure, oral ß-blockers are preferred. heart failure, oral ß-blockers are preferred. They may need to be given in low and They may need to be given in low and titrated doses after the patient is titrated doses after the patient is stabilized.”stabilized.”

American Heart AssociationAmerican Heart Association2005 Guidelines2005 Guidelines

Moderate to severe LV failure and Moderate to severe LV failure and pulmonary edemapulmonary edema

Bradycardia (<60 bpm)Bradycardia (<60 bpm) Hypotension (SBP <100 mm Hg)Hypotension (SBP <100 mm Hg) ShockShock Advanced 1Advanced 1stst degree HB (pr > 0.24) degree HB (pr > 0.24) 22ndnd or 3 or 3rdrd degree HB degree HB

American Heart AssociationAmerican Heart Association2005 Guidelines2005 Guidelines

Contraindications to beta-blockersContraindications to beta-blockers

Where does the evidence for Where does the evidence for early iv beta-blockers in AMI early iv beta-blockers in AMI

come from?come from?

The Goteborg TrialThe Goteborg Trial N = 1395 – Suspected MIN = 1395 – Suspected MI

809 confirmed MI809 confirmed MI 162 probable MI162 probable MI

RCTRCT Metoprolol 5/5/5 then 100 bid x 3 months vs placeboMetoprolol 5/5/5 then 100 bid x 3 months vs placebo

Did not give if HR <45, sBP <95, rales >10 cmDid not give if HR <45, sBP <95, rales >10 cm

Predetermined guidelines for withdrawal of study Predetermined guidelines for withdrawal of study medmed Bradycardia (HR<40), hypotension (sBP <90), heart block, Bradycardia (HR<40), hypotension (sBP <90), heart block,

dyspneadyspnea

The Goteborg TrialThe Goteborg TrialResultsResults

Three month Three month mortalitymortality Metoprolol – 62 Metoprolol – 62

(5.7%)(5.7%) Placebo – 40 (8.9%)Placebo – 40 (8.9%) RRR – 36%RRR – 36% ARR – 3.2%ARR – 3.2% NNT - 31NNT - 31

The MIAMI TrialThe MIAMI TrialAm J Cardiol 1985Am J Cardiol 1985

RCT – N=5,778RCT – N=5,778

InclusionInclusion Suspected AMISuspected AMI

InterventionIntervention Metoprolol 5/5/5 iv; then 200/day in divided doses x 15 Metoprolol 5/5/5 iv; then 200/day in divided doses x 15

daysdays

Primary OutcomesPrimary Outcomes Mortality at 15 daysMortality at 15 days

MIAMI TrialMIAMI TrialResultsResults

MIAMIMIAMIResultsResults

15 day mortality15 day mortality Metoprolol 4.3%Metoprolol 4.3% Placebo 4.9 % (NS)Placebo 4.9 % (NS)

Authors suggestion study may have Authors suggestion study may have been underpoweredbeen underpowered

ISIS 2ISIS 2 Streptokinase or ASA or Streptokinase or ASA or

bothboth vs placebo vs placebo

ISIS 3ISIS 3 tPA vs StreptokinasetPA vs Streptokinase ASA alone vs ASA alone vs ASA plus ASA plus

heparinheparin

ISIS 4ISIS 4 CaptoprilCaptopril, Mg, Oral , Mg, Oral

NitratesNitrates

RCT – N=16,027RCT – N=16,027

InclusionInclusion Suspected AMISuspected AMI

InterventionIntervention Atenolol 5/5 iv then 100 odAtenolol 5/5 iv then 100 od

Primary OutcomesPrimary Outcomes Vascular mortality at one weekVascular mortality at one week Vascular mortality at end of study period (mean 20 Vascular mortality at end of study period (mean 20

months)months)

ISIS-1ISIS-1Exclusion CriteriaExclusion Criteria

HR <50HR <50 sBP <100sBP <100 22ndnd or 3 or 3rdrd degree HB degree HB ““severe” CHFsevere” CHF

ISIS-1 - ResultsISIS-1 - Results

Early mortalityEarly mortality Decreased mortality Decreased mortality

day 0-1day 0-1

Long-term Long-term mortalitymortality No difference in No difference in

mortality days 2-7 mortality days 2-7 or beyondor beyond

So Beta Blockers worked in So Beta Blockers worked in STEMI in the 1980’sSTEMI in the 1980’s

What about What about thrombolysis?thrombolysis?

Short-term effects of early IV treatment with Short-term effects of early IV treatment with a beta-blocker or a specific bradycardic a beta-blocker or a specific bradycardic

agent in patients with AMI receiving agent in patients with AMI receiving thrombolytic therapythrombolytic therapy

RCT – N=292 – followed for 14 daysRCT – N=292 – followed for 14 days Atenolol (N=100) 5-10 mg IV then 25-50 po bidAtenolol (N=100) 5-10 mg IV then 25-50 po bid Alinidine (N=98) 20-40 mg IV then 20-40 po tidAlinidine (N=98) 20-40 mg IV then 20-40 po tid Placebo (N=94)Placebo (N=94)

All received alteplase 100mg All received alteplase 100mg

ResultsResults No differences in mortality, vessel patency, EF, No differences in mortality, vessel patency, EF,

infarct size, WMA, dysrhythmiasinfarct size, WMA, dysrhythmias More nonfatal pulmonary edema with atenololMore nonfatal pulmonary edema with atenolol

6% vs. 1% (alinidine) and 0% (placebo), p = 0.021 6% vs. 1% (alinidine) and 0% (placebo), p = 0.021

J Am Coll Cardiol, 1993; 22:407-416

RCT of thrombolytic strategiesRCT of thrombolytic strategies

ObservationalObservational study of beta-blockers study of beta-blockers

Patients without hypotension, bradycardia, Patients without hypotension, bradycardia, or CHF or CHF supposedsupposed to be treated with to be treated with Atenolol 5/5 iv, then 50-100 bidAtenolol 5/5 iv, then 50-100 bid

OutcomeOutcome 30 day mortality30 day mortality

GUSTO-IGUSTO-IResultsResults

Patients given any atenolol less sickPatients given any atenolol less sick

MortalityMortality Any atenolol vs no atenololAny atenolol vs no atenolol

OR 0.20 (0.19–0.22) p<0.0001 IV & PO atenolol vs PO only

OR 1.2 (1.0 –1.3) p=0.03

RCTRCT tPA with conservative vs invasive strategytPA with conservative vs invasive strategy MetoprololMetoprolol

Early IV (5/5/5 iv then 50-100 po bid) within 2hEarly IV (5/5/5 iv then 50-100 po bid) within 2h Deferred (50–100 po bid) started on day 6Deferred (50–100 po bid) started on day 6

N = 1434N = 1434 730 - early BB730 - early BB 712 – deferred BB712 – deferred BB

TIMI-II-BTIMI-II-BExclusion CriteriaExclusion Criteria

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-IIBTIMI-IIB Therapy stopped if

PR > 0.26 seconds 2nd or 3rd degree AV block Rales or wheeze > 1/3 lung field

Temporarily held (10 min) if HR <45 bpm sBP <90mmHg

Resumed at 2.5mg dosing if HR >49, sBP >95 at 10 min

TIMI-IIB - ResultsTIMI-IIB - Results Primary OutcomePrimary Outcome

Resting Ejection Fraction – No differenceResting Ejection Fraction – No difference

Secondary OutcomesSecondary Outcomes

MortalityMortality No difference at 6 days, 6 weeks, and 1 yearNo difference at 6 days, 6 weeks, and 1 year

ReinfarctionReinfarction Less in early group at 6 days and 6 weeksLess in early group at 6 days and 6 weeks No difference at 1 yearNo difference at 1 year

Recurrent chest painRecurrent chest pain Early group 18.8% vs 24.1% (p<0.02) at 6 daysEarly group 18.8% vs 24.1% (p<0.02) at 6 days No difference at 6 weeks or one yearNo difference at 6 weeks or one year

So early beta-blockade So early beta-blockade doesn’t seem to work with doesn’t seem to work with

thrombolysis.thrombolysis.

What about PCI?What about PCI?

Beta-Blockade in PCIBeta-Blockade in PCI

No RCT of BB in PCINo RCT of BB in PCI

RCT N=45,853RCT N=45,853 93% STEMI or new BBB93% STEMI or new BBB 7% STD7% STD

InterventionIntervention Metoprolol 5/5/5 iv then 50 qid vs Metoprolol 5/5/5 iv then 50 qid vs

placeboplacebo OutcomesOutcomes

1.1. Death, reinfarction, cardiac arrestDeath, reinfarction, cardiac arrest

2.2. Death from any causeDeath from any cause

Exclusion CriteriaExclusion Criteria Patients going for PCIPatients going for PCI

Likely to receive both ASA and clopidogrelLikely to receive both ASA and clopidogrel

““High risk of adverse effects”High risk of adverse effects” sBP < 100sBP < 100 HR <50HR <50 Heart BlockHeart Block Cardiogenic ShockCardiogenic Shock

Withdrew treatment if HR<50, sBP<90Withdrew treatment if HR<50, sBP<90

Did not exclude patients with moderate (Killip 2 Did not exclude patients with moderate (Killip 2 or 3) heart failureor 3) heart failure

Killip Classification of CHFKillip Classification of CHF Class 1Class 1

no clinical signs of heart failure no clinical signs of heart failure Class 2Class 2

crackles, S3 gallop and elevated jugular venous pressure crackles, S3 gallop and elevated jugular venous pressure Class 3Class 3

frank pulmonary edema frank pulmonary edema Class 4Class 4

cardiogenic shock - hypotension (systolic < 90 mmHg) cardiogenic shock - hypotension (systolic < 90 mmHg) and evidence of peripheral vasoconstriction (oliguria, and evidence of peripheral vasoconstriction (oliguria, cyanosis, sweating) cyanosis, sweating)

NB: Higher class correlated with higher mortalityNB: Higher class correlated with higher mortality

Killip and Kimball: American Journal of Cardiology 1967; 20: 457-464

Results 1Results 1

Timing of adverse eventsTiming of adverse events

Metoprolol and Cardiogenic Metoprolol and Cardiogenic ShockShock

Who was harmed (excess cases of Who was harmed (excess cases of shock)shock) >70 yo >70 yo 23/100023/1000 sBP <120 sBP <120 23/100023/1000 HR >110 HR >110 35/100035/1000 Killip 3Killip 3 57/100057/1000

Who benefittedWho benefitted No identifiable group had significant benefitNo identifiable group had significant benefit

ConclusionsConclusions No effect on primary or composite outcomeNo effect on primary or composite outcome

Composite of death, reinfarction, cardiac Composite of death, reinfarction, cardiac arrest, shockarrest, shock Early effects (day 0-1)Early effects (day 0-1)

More hypotension, bradycardia, cardiogenic shockMore hypotension, bradycardia, cardiogenic shock More heart failureMore heart failure Significantly NEGATIVESignificantly NEGATIVE

Late effects (day 2-28)Late effects (day 2-28) Less VFLess VF Less reinfarctionLess reinfarction Significantly POSITIVESignificantly POSITIVE

COMMIT TrialCOMMIT TrialCommentsComments

Excluded patients going for PCIExcluded patients going for PCI

Is this our population?Is this our population?

Exclusion criteria vague & different Exclusion criteria vague & different that AHA recommendationsthat AHA recommendations

Included patients with moderate Included patients with moderate (Killip 2 or 3) heart failure(Killip 2 or 3) heart failure

So what is the So what is the bottom line?bottom line?

Early IV MetoprololEarly IV MetoprololTake Home PointsTake Home Points

No evidence of mortality benefit in No evidence of mortality benefit in thrombolytic and angioplasty erathrombolytic and angioplasty era

Early routine iv metoprolol may Early routine iv metoprolol may cause cardiogenic shockcause cardiogenic shock

Consider using oral beta-blockers Consider using oral beta-blockers once patient stabilizedonce patient stabilized

the endthe end