1. Does early beta-blockade decrease mortality in STEMI?
Aric Storck – PGY5
August 31, 2006

2. B-Blockers & AMI Background
First trial in 1965
> 50 RCT to date
Good evidence for benefit
Reducing mortality
Reducing reinfarction
Reducing tachydysrhythmias
Post Ischemic CHF
CAPRICORN – gave carvedilol >3 days post MI

3. B-Blockers Mechanisms 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
Reduce infarct size and myocardial rupture when not given with lytics

4. Cooperative Cardiovascular Project
Cooperative Cardiovascular Project. Analysis of 201,752 patients from acute care database. Similar reductions for STEMI and NSTEMI. STEMI 14.2 vs 23.6 percent. Did not address early versus late administration. Based on BB prescribed at discharge only

5. Beta-blockade Long 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

6. Long Term Trials 31 trials 24,974 patients OR for mortality
0.77 (0.69 to 0.85)

7. Short Term Trials Only 3 trials with >1000 patients
Only two trials with >1000 patients

8. 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?

9. AHA Guidelines

10. American Heart Association 2005 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.”

11. American Heart Association 2005 Guidelines Contraindications to beta-blockers
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

12. Where does the evidence for early iv beta-blockers in AMI come from?

13. The Goteborg Trial N = 1395 – Suspected MI RCT
809 confirmed MI
162 probable MI
RCT
Metoprolol 5/5/5 then 100 bid x 3 months vs placebo
Did not give if HR <45, sBP <95, rales >10 cm
Predetermined guidelines for withdrawal of study med
Bradycardia (HR<40), hypotension (sBP <90), heart block, dyspnea
If less than the full intravenous dose was given, one quarter of a tablet was given every 6 h during the first 48 h followed by one tablet every 12 h. Used LDH, AST, ALT as cardiac markers,32 patients unable to tolerate full dose
12 in metoprolol group, 20 in placebo group
Gave reduced po dose to patients unable to tolerate iv load

14. Drug stopped or switched to open label based on indications for or complications of beta blockade

15. The Goteborg Trial Results
Three month mortality
Metoprolol – 62 (5.7%)
Placebo – 40 (8.9%)
RRR – 36%
ARR – 3.2%
NNT - 31
Metoprolol significantly reduced 3-month mortality in the metoprolol group as a whole by 36%, in those aged years by 37%, in those aged years by 45% and by 34% in patients in whom definite MI developed.

16. The MIAMI Trial Am J Cardiol 1985
RCT – N=5,778
Inclusion
Suspected AMI
Intervention
Metoprolol 5/5/5 iv; then 200/day in divided doses x 15 days
Primary Outcomes
Mortality at 15 days
50 qid x 2 days, then 100 bid x 13 days

17. Before the second and third injections were given, the heart rate should have been >49 beats/min, the systolic blood pressure >99 mm Hg and the P-Q time <0.26 second. Further, it was required that there was no worsening of dyspnea or cold sweating before the second or third intravenous dose was
given.

18. MIAMI Trial Results
Powered for find 35% reduction in mortality with 7% mortality in placebo
Only had 13% reduction in mortality with 5% mortality in placebo
Estimated trial of 15,000 – 20,000 required to show difference of 13% with placebo mortality of 5%

19. MIAMI Results 15 day mortality
Metoprolol 4.3%
Placebo 4.9 % (NS)
Authors suggestion study may have been underpowered
High Risk Patients did better – contrast this with COMMIT where high risk patients did worse
NB – did not correct for multiple comparisons
Subgroup Analysis
Low-Moderate risk patients – NS
High Risk Patients (3 or more RF’s)
RRR 39% (CI 4-61)

20. ISIS 2 ISIS 3 ISIS 4 Streptokinase or ASA or both vs placebo
tPA vs Streptokinase
ASA alone vs ASA plus heparin
ISIS 4
Captopril, Mg, Oral Nitrates
Infarct Survival in Myocardial Infarction
ISIS-2 (1988) – ASA better than placebo
ISIS 3 – (1992) tPA vs strepto – more strokes but less repeat MI in tPA - no difference in mortality, asa + heparin had lower mortality
ISIS – 4 –(1995) captopril, oral nitrate, mg – only

21. RCT – N=16,027 Inclusion Intervention Primary Outcomes Suspected AMI
Atenolol 5/5 iv then 100 od
Primary Outcomes
Vascular mortality at one week
Vascular mortality at end of study period (mean 20 months)
>2000 Swedish patients

22. ISIS-1 Exclusion Criteria
HR <50
sBP <100
2nd or 3rd degree HB
“severe” CHF
Exclusion criteria designed to be “informal” to make it more applicable to practice

23. Antiplatelets not routinely given in 1986 – does not reflect reality in More patients in atenolol group discharged on B-blockers – likely makes this a trial of secondary prevention

24. ISIS-1 - Results Early mortality Long-term mortality
Decreased mortality day 0-1
Long-term mortality
No difference in mortality days 2-7 or beyond
NB – significantly more patients discharged on BB in atenolol group
During the treatment period (days 0-7) there were 313 (3.89%) vascular deaths in the atenolol group compared with 365 (4.57%) in the control group. This 15% lower vascular mortality in the atenolol group is conventionally
significant (2p<0-04), but the 95% confidence interval is wide, ranging from 1% to 27%. All of this apparent benefit was observed in days 0-1 (121 atenolol compared with 171 control deaths), with no further difference in days 2-3 (88
versus 91 extra deaths) or days 4-7 (104 versus 103 extra deaths). The very high formal statistical significance level for the difference in days 0-1 (2p<0 003) may be misleading since it takes no account of the fact that the hypothesis being
tested was entirely data-derived, there being no compelling prior reason to expect all, or even most, of any early mortality difference in the first couple of days.

25. So Beta Blockers worked in STEMI in the 1980’s
What about thrombolysis?

26. RCT – N=292 – followed for 14 days
Short-term effects of early IV treatment with a beta-blocker or a specific bradycardic agent in patients with AMI receiving thrombolytic therapy
RCT – N=292 – followed for 14 days
Atenolol (N=100) 5-10 mg IV then po bid
Alinidine (N=98) mg IV then po tid
Placebo (N=94)
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
Alinidine = bradycardic agent lacking negative inotropism, related to clonidine
J Am Coll Cardiol, 1993; 22:

27. 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 bid
Outcome
30 day mortality
GUSTO – RCT of four thrombolytic strategies, NON-RANDOMIZED for BB

28. GUSTO-I Results Patients given any atenolol less sick Mortality
Any 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

29. RCT N = 1434 tPA with conservative vs invasive strategy Metoprolol
Early IV (5/5/5 iv then po bid) within 2h
Deferred (50–100 po bid) started on day 6
N = 1434
730 - early BB
712 – deferred BB
Treated po for duration of study. No difference between invasive and conservative angiography

30. TIMI-II-B Exclusion 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

31. TIMI-IIB Therapy stopped if Temporarily held (10 min) 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

32. TIMI-IIB - Results Primary Outcome Secondary Outcomes
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% (p<0.02) at 6 days
No difference at 6 weeks or one year

33. So early beta-blockade doesn’t seem to work with thrombolysis.
What about PCI?

34. No RCT of BB in PCI Beta-Blockade in PCI
PAMI – recommended all pts without contraindications get iv BB. Compared pts receiving BB vs not after PCI. NOT RANDOMIZED and prone to bias.
CADILLAC – compared patients receiving pre PCI BB vs not. NOT RANDOMIZED. Also looked at GP2B3A and stents

35. RCT N=45,853 Intervention Outcomes 93% STEMI or new BBB 7% STD
Metoprolol 5/5/5 iv then 50 qid vs placebo
Outcomes
Death, reinfarction, cardiac arrest
Death from any cause
Study period until discharge or 4 weeks in hospital, received metoprolol 100 bid after first few days

36. Exclusion Criteria Patients going for PCI
Likely to receive both ASA and clopidogrel
“High risk of adverse effects”
sBP < 100
HR <50
Heart Block
Cardiogenic Shock
Withdrew treatment if HR<50, sBP<90
Did not exclude patients with moderate (Killip 2 or 3) heart failure
Exclusion criteria were guidelines only
Gave subsequent doses if sBP>90, HR>50

37. Killip Classification of CHF
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 < 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:

38. Results 1
Neither primary outcome significant

39. Timing of adverse events

40. Metoprolol and Cardiogenic Shock
Who was harmed (excess cases of shock)
>70 yo 23/1000
sBP < /1000
HR > /1000
Killip 3 57/1000
Who benefitted
No identifiable group had significant benefit
All harm statistics statistically significant

41. 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

42. COMMIT Trial Comments 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
Would have included patients with bradycardia and CHF
Kilip 3 = pulmonary edema

43. So what is the bottom line?

44. Early IV Metoprolol Take 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

45. the end