215 antibio
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ANTIBIO: ANTIBIO: ANTIBIOtic therapy ANTIBIOtic therapy
in patients after an acute in patients after an acute myocardial infarctionmyocardial infarction
an ALKK Studyan ALKK StudyR 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)
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 this agent in the pathogenesis of arteriosclerosis.
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.).
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).
ANTIBIO-Study
Principal InvestigatorR Zahn
Steering CommitteeJ Senges (chairman)U Tebbe M WeberKL Neuhaus§§ Dr. Neuhaus died before the end of the study
Advisory boardM GottwikU Höffler
Data and Safety Monitoring BoardR Schröder (chairman)W StilleH KatusR Dietz Statistical analysisS SchneiderKE Siegler Study coordinationH Dehn Financial support:Aventis Pharma gGmbH, Germany
Study designAcute myocardial infarction (AMI)
hospital admission <48 hours after symptom onset
- exclusion criteria fulfilled- declined to participate
randomisation within 5 days after admission
Roxithromycin300mg/OD for 6 weeks
Placebo1/OD for 6 weeks
12 months follow-up
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 leads.
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
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 calculated total sample size of 3922 patients.
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.
68 participating centers (ALKK)
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
randomised patientsn=872
roxithromycinn=433 (100%)
placebon=439 (100%)
completed < 4 of 6 weeks treatment n= 78 (18%)
completed < 4 of 6 weeks treatment n=48 (11 %)
12 month follow-upn=431 (99.5%)
12 month follow-upn=437 (99.5%)
lost for follow-up : n=2
lost for follow-up: n= 2
Results (2)
p=0.003
Patients characteristicsroxithromycin
n = 433placebon = 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
Concomitant diseasesroxithromycin
n = 433placebon = 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
Reperfusion therapy
roxithromycinn = 433
placebon = 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
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
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
Mortality: 12-months
6,5 6
0123456789
10
roxithromycin placebo
mor
talit
y (%
)
p=0.739
Kaplan-Meier survival curve
months after randomisation
Survival
no EPS response
0 1 2 3 4 5 6 7 8 9 10 11 120,7
0,75
0,8
0,85
0,9
0,95
1Placebo
Roxithromycinp=0.86
combined endpoint: hospital
18,7
14,1
02468
101214161820
roxithromycin placebo
com
bine
d en
dpoi
nt (%
)
p=0.068
death, MI, resuscitation, stroke, postinfarction angina
combined endpoint: 12-months
27,823,2
0
5
10
15
20
25
30
roxithromycin placebo
com
bine
d en
dpoi
nt (%
)
p=0.110
death, MI, resuscitation, stroke, angina leading to hosp.
endpoints: 12-months
1,6
4,9
16,9
6 5,5
2,13,4
13,3
6,54,9
02468
101214161820
death MI stroke resusc. UA
(%)
roxithromycin placebo
p=ns
CABG/PTCA: 12-months
56 53,3
0
10
20
30
40
50
60
roxithromycin placebo
CA
BG
/PT
CA
(%)
p=0.621
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 placeboall p=ns
intention-to-treat treatment-per-protocol
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 placeboall p=ns
intention-to-treat treatment-per-protocol
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.
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.