Perspective on COMMIT/CCS-2 Trial of Metoprolol in STEMI
Christopher Cannon, M.D.
Brigham and Women’s Hospital
Boston, MA
First impression
Wow !?
I had predicted dramatic benefit with multiple 0’s in the P value
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
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
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
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
……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
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
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 Nitrates no benefit
HOPE Vasc. ACE inhibitor +benefit GISSI-Prev. Dis Vit E no benefit
PROVE IT- ACS High-dose statin +benefit TIMI 22 Antibiotic no benefit
COMMIT/ AMI Clopidogrel +benefit CCS-2 Metoprotol +/-benefit
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
?-blocker use
Outcome Immediate Deferred 2P
(n=720) (n=714) values
Death at day 7 17 17 0.98
Death or reinfarction 34 50 0.07
Reinfarction 75 87 0.02
Recurrent chest pain 134 170 0.02
TIMI-IIB: Effects of early ?-blocker following lytic therapy in acute MI
Circulation 1991:83:422-37