Does early beta-blockade decrease mortality in STEMI?

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

2. B-Blockers & AMIBackground • First trial in 1965 • > 50 RCT to date • Good evidence for benefit • Reducing mortality • Reducing reinfarction • Reducing tachydysrhythmias • Post Ischemic CHF

3. 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 B-BlockersMechanisms of Benefit

5. 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

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

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

8. 59 trials 29,260 patients OR for Mortality 0.96 (0.85 to 1.08) NOT SIGNIFICANT What about early beta-blockers? Short Term Trials

9. AHA 2005 Guidelines

10. 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.”

11. American Heart Association2005 GuidelinesContraindications 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 • 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

15. The Goteborg TrialResults • Three month mortality • Metoprolol – 62 (5.7%) • Placebo – 40 (8.9%) • RRR – 36% • ARR – 3.2% • NNT - 31

16. The MIAMI TrialAm 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

18. MIAMI TrialResults

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

20. 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

21. RCT – N=16,027 • 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)

22. ISIS-1Exclusion Criteria • HR <50 • sBP <100 • 2nd or 3rd degree HB • “severe” CHF

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

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

26. 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 25-50 po bid • Alinidine (N=98) 20-40 mg IV then 20-40 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 J Am Coll Cardiol, 1993; 22:407-416

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 50-100 bid • Outcome • 30 day mortality

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

30. TIMI-II-BExclusion 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 • 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 • 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. Beta-Blockade in PCI No RCT of BB in PCI

35. RCT N=45,853 • 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

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

37. 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 < 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

38. Results 1

39. Timing of adverse events

40. Metoprolol and Cardiogenic Shock • Who was harmed (excess cases of shock) • >70 yo 23/1000 • sBP <120 23/1000 • HR >110 35/1000 • Killip 3 57/1000 • Who benefitted • No identifiable group had significant benefit

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 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

43. So what is the bottom line?

44. 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

45. the end