215 antibio

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


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


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

(%)


p=ns

CABG/PTCA: 12-months

56 53,3

0

10

20

30

40

50

60


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.

215 antibio

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