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215 antibio

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215 antibio

  1. 1. ANTIBIO:ANTIBIO: ANTIBIOtic therapyANTIBIOtic therapy in patients after an acutein patients after an acute myocardial infarctionmyocardial infarction an ALKK Studyan ALKK Study ANTIBIO:ANTIBIO: ANTIBIOtic therapyANTIBIOtic therapy in patients after an acutein patients after an acute myocardial infarctionmyocardial infarction an ALKK Studyan ALKK Study R Zahn, B Frilling, S Schneider, U Tebbe, M Weber, M Gottwik, E Altmann, F Seidel, J Rox, U Höffler, J Senges for the Arbeitsgemeinschaft Leitender Kardiologischer Krankenhausärzte (ALKK)
  2. 2. Background (1) •Inflammation plays a crucial role in the pathogenesis of arteriosclerosis. •Seroepidemiological studies have raised the question if bacterial infections, especially with Chlamydia pneumoniae, may contribute to this inflammatory process. •Histopathological studies could show a higher prevalence of Chlamydia pneumoniae in diseased coronary arteries. •Animal models also seem to support an active role of
  3. 3. Background (2) •Therefore therapy with a macrolide antibiotic may favourably influence the natural course in patients with coronary heart disease. •Some small clinical studies in patients with acute coronary syndromes indicated a potential beneficial effect of such a treatment (ROXIS study / study of Gupta et al.).
  4. 4. ANTIBIO • prospective • randomised • placebo controlled • double-blind Antibiotic therapy after an acute myocardial infarction to investigate the effect of treatment with roxithromycin in patients with an acute myocardial infarction (AMI).
  5. 5. ANTIBIO-Study Principal Investigator R Zahn Steering Committee J Senges (chairman) U Tebbe M Weber KL Neuhaus§ § Dr. Neuhaus died before the end of the study Advisory board M Gottwik U Höffler Data and Safety Monitoring Board R Schröder (chairman) W Stille H Katus R Dietz Statistical analysis S Schneider KE Siegler Study coordination H Dehn Financial support: Aventis Pharma gGmbH, Germany
  6. 6. Study design Acute myocardial infarction (AMI) hospital admission <48 hours after symptom onset - exclusion criteria fulfilled - declined to participate randomisation within 5 days after admission Roxithromycin 300mg/OD for 6 weeks Placebo 1/OD for 6 weeks 12 months follow-up
  7. 7. AMI diagnosis •Angina pectoris lasting for >20 minutes •Elevation of creatinine kinase more than three times the normal upper with significant CK-MB fraction or elevation of troponin T or troponin I •Changes in the electrocardiogram (ECG), either -ST elevation myocardial infarction (ST segment elevation of ≥ 1 mm in at least 2 standard leads or ≥ 2 mm in at least 2 contiguous precordial leads or the presence of a left bundle branch block) or -ST segment depression of > 1mm in two contiguous leads or inversion of the T waves of > 1mm in at least 3 contiguous
  8. 8. End points •Primary endpoint was total mortality at 12 months •Secondary endpoints were a -combined endpoint of death, reinfarction, resuscitation, stroke or postinfarction angina at hospital discharge -combined endpoint of death, reinfarction, resuscitation, stroke or unstable angina pectoris leading to hospital admission at 12 months -the rate of percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG) at 12 months
  9. 9. Statistics •A total mortality rate after 12 months of 10% in the placebo group and a 30% lower mortality rate in the active treatment group (7% mortality) were assumed. •For safety reasons total mortality at 8 weeks after randomisation was monitored in a sequential design (triangular test) according to the ´restricted procedure´ method reported by Whitehead. •The proposed decision to stop the study was based on 1% significance level for differences in total 8 week mortality. •The total test level was therefore adjusted according to Bonferroni´s method to a two sided α-level of 4%, with an 80% power to detect a significant difference. This resulted in a
  10. 10. Statistics •Primarily all analyses were performed on an intention-to-treat basis. •Afterwards, endpoints were analysed after adjusting for differences in base-line characteristics (logistic regression analysis). •Furthermore data were analysed on a “treatment-per-protocol” basis.
  11. 11. 68 participating centers (ALKK)
  12. 12. Results (1) •Inclusion of patients started on September 1999, end of inclusion was planned for 12/2000. •After continuous slow recruitment of patients, end of inclusion was extended to 4/2001. •4/2001 the steering committee decided to stop the study •872 patients were included, 433 treated with roxithromycin and 439 with placebo
  13. 13. randomised patients n=872 roxithromycin n=433 (100%) placebo n=439 (100%) completed < 4 of 6 weeks treatment n= 78 (18%) completed < 4 of 6 weeks treatment n=48 (11 %) 12 month follow-up n=431 (99.5%) 12 month follow-up n=437 (99.5%) lost for follow-up : n=2 lost for follow-up: n= 2 Results (2) p=0.003
  14. 14. Patients characteristics roxithromycin n = 433 placebo n = 439 p-value age (years) 60.4 61.0 0.689 male gender 79.0% 79.5% 0.851 STEMI 87.1% 88.8% 0.422 anterior wall MI* 48.1% 40.2% 0.027 cardiogenic shock 3.0% 3.9% 0.469 heart failure at ad 8.6% 8.5% 0.967 resuscitation 3.9% 3.6% 0.828 LBBB 1.2% 1.8% 0.418 atrial fibrillation 5.8% 4.3% 0.329 *in case of STEMI
  15. 15. Concomitant diseases roxithromycin n = 433 placebo n = 439 p-value renal failure 5.2% 3.9% 0.392 COPD 3.5% 6.9% 0.028 arterial hypert. 49.7% 53.5% 0.260 diabetes mellitus 15.9% 16.4% 0.816
  16. 16. Reperfusion therapy roxithromycin n = 433 placebo n = 439 p-value any reperfusion therapy 71.4% 69.5% 0.542 reperfusion therapy in STEMI 76.1% 73.9% 0.466 angioplasty in STEMI 45.1% 43.3% 0.624 thrombolysis in STEMI 41.9% 39.0% 0.408 88% ST elevation myocardial infarction
  17. 17. Medication <48h after ad. roxithromycin n = 433 placebo n = 439 p-value aspirin 98.9% 98.6% 0.779 IIb/IIIa antagonists 37.6% 35.4% 0.489 ß - blockers 89.6% 87.5% 0.322 ACE inhibitors 74.1% 71.5% 0.387 other antibiotics 3.5% 5.0% 0.260
  18. 18. Medication at discharge roxithromycin n = 425 placebo n = 431 p-value aspirin 92.9% 93.3% 0.849 clopidogrel/ticlopidine 50.2% 50.8% 0.866 statins 75.5% 72.6% 0.332 ß - blockers 92% 91% 0.583 ACE inhibitors 80.9% 79.8% 0.678
  19. 19. Mortality: 12-months 6,5 6 0 1 2 3 4 5 6 7 8 9 10 roxithromycin placebo mortality(%) p=0.739
  20. 20. Kaplan-Meier survival curve months after randomisation Survival no EPS response 0 1 2 3 4 5 6 7 8 9 10 11 12 0,7 0,75 0,8 0,85 0,9 0,95 1 Placebo Roxithromycin p=0.86
  21. 21. combined endpoint: hospital 18,7 14,1 0 2 4 6 8 10 12 14 16 18 20 roxithromycin placebo combinedendpoint(%) p=0.068 death, MI, resuscitation, stroke, postinfarction angina
  22. 22. combined endpoint: 12-months 27,8 23,2 0 5 10 15 20 25 30 roxithromycin placebo combinedendpoint(%) p=0.110 death, MI, resuscitation, stroke, angina leading to hosp.
  23. 23. endpoints: 12-months 1,6 4,9 16,9 6 5,5 2,1 3,4 13,3 6,5 4,9 0 2 4 6 8 10 12 14 16 18 20 death MI stroke resusc. UA (%) roxithromycin placebo p=ns
  24. 24. CABG/PTCA: 12-months 56 53,3 0 10 20 30 40 50 60 roxithromycin placebo CABG/PTCA(%) p=0.621
  25. 25. endpoints: 12-months 56 7,1 24,4 55,5 6 23,2 53,3 6,2 20,8 51 6,5 27,8 0 10 20 30 40 50 60 death CE revasc death CE revasc (%) roxithromycin placebo all p=ns intention-to-treat treatment-per-protocol
  26. 26. endpoints: disch - 12-months 25,1 5,1 11,6 23,2 4,1 11,2 23,1 4,4 21,2 4,6 11,6 11,5 0 5 10 15 20 25 30 death CE revasc death CE revasc (%) roxithromycin placebo all p=ns intention-to-treat treatment-per-protocol
  27. 27. Summary (1) •In patients with an AMI, 6 week treatment with roxithromycin (300mg/OD) did not result in a significant reduction in 12-month mortality or morbidity. •Results did not change if the analyses were performed on an „intention-to-treat“, „treatment-per-protocol“ basis or after adjustment for differences in patients characteristics.
  28. 28. Summary (2) •Despite the premature termination of our study after 872 patients instead of the intended 3922 patients, our results make it very unlikely, that we missed a clinically relevant benefit of treatment with roxithromycin. •Therefore routine treatment with roxithromycin in AMI patients can not be advised.

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