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COMMIT/CCS-2 ( C l O pidogrel & M etoprolol in M yocardial I nfarction T rial)

COMMIT/CCS-2 ( C l O pidogrel & M etoprolol in M yocardial I nfarction T rial). Designed, conducted, analysed and interpreted independently by COMMIT/CCS-2 collaboration Sources of funding (US$ 3M): SanofiAventis/BMS AstraZeneca British Heart Foundation UK Medical Research Council.

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COMMIT/CCS-2 ( C l O pidogrel & M etoprolol in M yocardial I nfarction T rial)

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  1. COMMIT/CCS-2(ClOpidogrel & Metoprolol in MyocardialInfarction Trial) • Designed, conducted, analysed and interpreted independently by COMMIT/CCS-2 collaboration • Sources of funding (US$ 3M): • SanofiAventis/BMS • AstraZeneca • British Heart Foundation • UK Medical Research Council

  2. COMMIT: Study design • TREATMENT: Metoprolol 15 mg iv over 15 mins, then 200 mg oral daily vs matching placebo • INCLUSION: Suspected acute MI (ST change orLBBB) within 24 h of symptom onset • EXCLUSION: Shock, systolic BP <100 mmHg, heart rate <50/min or II/III AV block • 1 OUTCOMES: Death & death, re-MI or VF/arrest up to 4 weeks in hospital (or prior discharge) • Mean treatment and follow-up: 16 days

  3. COMMIT: Baseline characteristics • Characteristic Metoprolol Placebo (n=22,928) (n=22,923) • Aged 70+ 26.1% 26.0% • Time delay <6 h 34.0% 33.5% • SBP <120 mmHg 33.7% 33.5% • Anterior infarct 49.8% 49.6% • Killip class II 20.0% 19.8% • III 4.1% 4.2% • Fibrinolytic given 49.8% 49.7%

  4. COMMIT: Treatment compliance • Compliance Metoprolol Placebo • (n=22,927) (n=22,923) • First iv dose given 98.5% 98.6% • 3 iv doses completed 90.2% 96.0% • Oral treatment completed 86.2% 91.6%

  5. COMMIT: Effects of METOPROLOL on Reinfarction Outcome Metoprolol Placebo Odds ratio & 95% CI after Re-MI (22,927) (22,922) Metop. better Placebo better Died 206 (0.9%) 226 (1.0%) Survived 261 (1.1%) 342 (1.5%) 18% SE 6 ALL COMBINED 467 (2.0%) 568 (2.5%) (2P = 0.002) 0.4 0.7 1.0 1.3 1.6 1.9

  6. Effects of iv then oral -blockeron reinfarction in 3 major trials of acute MI Trial ß-blocker Control Odds ratio & 95% CI (33,841) (33,813) ß-blocker better Control better MIAMI 85 (3.0%) 111 (3.8%) ISIS-1 148 (1.8%) 161 (2.0%) COMMIT 467 (2.0%) 568 (2.5%) 17% SE 5 OVERALL 700 (2.1%) 840 (2.5%) (2P = 0.0003) 0.4 0.6 0.8 1.0 1.2 1.4 1.6

  7. COMMIT: Effects of METOPROLOL on Cardiac Arrest Events Metoprolol Placebo Odds ratio & 95% CI (22,927) (22,922) Metop. better Placebo better VF 582 (2.5%) 699 (3.0%) 17% SE 5 Other arrest 882 (3.8%) 899 (3.9%) 2% SE 5 5% SE 4 ANY OF ABOVE 1267 (5.5%) 1332 (5.8%) (2P > 0.1; NS) 0.4 0.7 1.0 1.3 1.6 1.9

  8. COMMIT: Effects of METOPROLOL on Death in hospital Placebo: 1798 deaths (7.8%) Metoprolol: 1776 deaths (7.7%) 1% (SE 3) relative risk reduction (2P=0.7) % dead Days since randomisation

  9. COMMIT: Effects of METOPROLOL on Death by attributed cause(s) Cause(s) Metoprolol Placebo Odds ratio & 95% CI (22,927) (22,922) Metop. better Placebo better Arrhythmia 388 (1.7%) 498 (2.2%) 22% SE 6 Shock 496 (2.2%) 384 (1.7%) -29% SE 8 Other causes 892 (3.9%) 916 (4.0%) 3% SE 5 1% SE 3 ANY DEATH 1776 (7.7%) 1798 (7.8%) (2P > 0.1; NS) 0.4 0.7 1.0 1.3 1.6 1.9

  10. COMMIT: Effects of METOPROLOL on CardiogenicShock by day of event Day of event Metoprolol Placebo Odds ratio & 95% CI (22,927) (22,922) Metop. better Placebo better 0 475 (2.1%) 317 (1.4%) 1 282 (1.2%) 210 (0.9%) 2+ 384 (1.7%) 361 (1.6%) -29% SE 5 ALL 1141 (5.0%) 888 (3.9%) (2P < 0.00001) 0.4 0.7 1.0 1.3 1.6 1.9

  11. COMMIT: Effects of METOPROLOL on CardiogenicShock by Killip class Baseline Metoprolol Placebo Odds ratio & 95% CI Killip class (22,927) (22,922) Metop. better Placebo better I 611 (3.5%) 487 (2.8%) II 362 (7.9%) 296 (6.5%) III 155 (16.2%) 100 (10.4%) -29% SE 5 ALL 1141 (5.0%) 888 (3.9%) (2P < 0.00001) 0.4 0.7 1.0 1.3 1.6 1.9

  12. COMMIT: Absolute effects of METOPROLOL on Re-MI, VF, Shock and Death by KILLIP class

  13. COMMIT: Effects of METOPROLOL on Death, Re-MIor Arrest by prognosis & fibrinolytic Baseline Metoprolol Placebo Odds ratio & 95% CI features (22,927) (22,922) Metop. better Placebo better Prognostic index Good 248 (3.3%) 284 (3.7%) Average 575 (7.5%) 642 (8.4%) Poor 1350 (17.6%) 1338 (17.5%) Lytic given Yes 1031 (9.0%) 1137 (10.0%) No 1142 (9.9%) 1127 (9.8%) 4% SE 3 ALL 2173 (9.5%) 2264 (9.9%) (2P > 0.1; NS) 0.4 0.6 0.8 1.0 1.2 1.4 1.6

  14. COMMIT: Effects of METOPROLOL on Deathby shock index Shock Metoprolol Placebo Odds ratio & 95% CI index (22,927) (22,922) Metop. better Placebo better Good 654 (4.1%) 719 (4.5%) Average 569 (12.1%) 598 (12.6%) Poor 553 (25.9%) 481 (23.4%) 1% SE 3 ALL 1776 (7.7%) 1798 (7.8%) (2P > 0.1; NS) 0.4 0.7 1.0 1.3 1.6

  15. COMMIT: Conclusions • Metoprolol (15 mg iv, then 200 mg oral daily) in acute MI did not significantly reduce mortality in hospital •  It reduced the absolute risks of reinfarction by 5 per 1000 (P=0.001) and of VF by 5 per 1000 (P<0.001) •  But, overall, it increased the risk of cardiogenic shock by 11 per 1000 (P<0.00001), chiefly on days 0-1 • In acute MI, it may be better to start beta-blocker when the patient is stable (and then continue long-term) • Slides available on: www.commit-ccs2.org

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