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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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 68 participating centers (ALKK)

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. 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. 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. 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. 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. 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. 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. Mortality: 12-months
6,5
6
0
1
2
3
4
5
6
7
8
9
10
roxithromycin placebo
mortality(%)
p=0.739

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. 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. 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. 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. CABG/PTCA: 12-months
56 53,3
0
10
20
30
40
50
60
roxithromycin placebo
CABG/PTCA(%)
p=0.621

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. 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. 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. 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.