1. Perspective on COMMIT/CCS-2 Trial of Metoprolol in STEMI Christopher Cannon, M.D. Brigham and Women’s Hospital Boston, MA

2. First impression Wow !? I had predicted dramatic benefit with multiple 0’s in the P value

3. Older B-blocker trials (up to 1986) >27,000 patients from 28 trials Meta-analysis: –B-blocker (3.7%) –Control (4.3%) –16% relative risk reduction –95% CI: 1-30% –P=0.02 On re-looking: –Lower risk patients studied –Wide confidence intervals on mortality benefit

4. Evolution of use of B-Blockers in AMI Benefits seen in meta-analysis of RCTs: reduced mortality, re-MI, VF, rec. ischemia Initially contraindicated if CHF Then, trials in outpatients with LV dysfunction, (with slow up-titration of dose over 3-6 mos) B-blockers shown to reduce mortality The overlap: in AMI, CHF no longer seen as a contraindication to use of B blockers

5. Looking at the data in COMMIT/CCS-2 Benefit –Reduction in re-MI –Reduction in VF Risk –Increased development of cardiogenic shock Biologically plausible – a negative inotropic agent Increased risk of shock in first 24-48 hours Subgroup analysis: Shock developed in Patients with Killip III, tachycardia, or hypotension

6. Class I: Oral  -blocker therapy should be administered promptly to those patients without a contraindication, irrespective of concomitant fibrinolytic therapy or performance of primary PCI. (Level of evidence: A) Class IIa: It is reasonable to administer iv  - blocker promptly to STEMI patients without contraindications, especially if a tachyarrhythmia or hypertension is present. (Level of evidence: B) Current ACC/AHA guideline on the use of early  -blocker in acute MI (ACC/AHA Task Force Report. J Am Coll Cardiol 2004;44:671-719

7. ……the use of iv  -blockade in the acute phase of infarction in many countries is extremely low. There is a good case for the greater use of an iv  -blocker when there is tachycardia (in the absence of heart failure), relative hypertension, or pain unresponsive to opioids. It may be prudent to test the patient’s response to this form of therapy by first using a short-acting preparation. In most patients, however, oral  -blockade will suffice. Current ESC Guideline for the use of early  -blocker in acute MI (ESC Task Force Report. Euro Heart J 2003;24:28-66

8. Conclusions: B-Blockade in Acute MI One size does not fit all Avoid IV B-blocker for patients with evidence of compromised LV Function –Start oral B blocker after 1-2 days, when stable with lower doses, and titrate upward Low-medium risk patients benefit from early IV -> oral beta-blockade For all medications: Need to balance benefit and risk, for each patient

9. Lessons Learned from 2x2 Clinical Trials In 2x2 trial, if one is + and the other -, it provides a ‘negative control’ that reinforces the positive intervention ISIS-4/ AMI ACE inhibitor +benefit GISSI-3 Nitratesno benefit HOPEVasc. ACE inhibitor +benefit GISSI-Prev.Dis Vit Eno benefit PROVE IT-ACS High-dose statin +benefit TIMI 22 Antibioticno benefit COMMIT/AMI Clopidogrel +benefit CCS-2 Metoprotol+/-benefit

10. COMMIT/CCS-2: Major contribution 10 million AMI/year worldwide, ~3 million STEMI For metoprolol, –We learn appropriate use for ‘well-established’ class –New data will avoid excess risk, but allow benefit in appropriate patients For clopidogrel, –New addition for treatment for STEMI –Improved patency, mortality and morbidity –Could prevent 20,000 – 30,000 deaths, MI’s or strokes per year worldwide

12.  -blocker use Outcome ImmediateDeferred2P (n=720)(n=714) values Death at day 717170.98 Death or reinfarction34500.07 Reinfarction75870.02 Recurrent chest pain1341700.02 TIMI-IIB: Effects of early  -blocker following lytic therapy in acute MI Circulation 1991:83:422-37