1. Efficacy and Safety of Fondaparinux in Elderly Patients With ST-Segment Elevation Myocardial Infarction: Data From the OASIS 6 Trial Ron J.G. Peters, MD Cardiologist Department of Cardiology University of Amsterdam Amsterdam, Netherlands

2. Efficacy and safety of fondaparinux in elderly patients with STEMI results of the OASIS 6 trial
RJ Peters, C Joyner, JP Bassand,
R Afzal, S Chrolavicius, JW Eikelboom, SR Mehta, Fox KAA, S Yusuf,
For the OASIS 6 investigators

3. Disclosure Funded by Organon, Sanofi-Aventis, GSK
All authors have received grants and honoraria
from these companies and from several others

4. Fondaparinux: Mechanism of Action
Intrinsic
pathway
Extrinsic pathway
Antithrombin AT AT AT Xa Xa
Fondaparinux II
IIa
THROMBIN
Recycled
Fibrinogen
Fibrin clot
Turpie AGG et al. N Engl J Med. 2001;344:619.

5. OASIS 6: Randomized, Double Blind, Double Dummy
12,000 Patients with STEMI < 12 h of symptom onset
Inclusion: ST   2 mm prec leads or  1 mm limb leads
Exclusion: Contra-ind. for anticoagulant, INR>1.8, pregnancy, ICH<12 mo.
Lytics (SK, TPA, TNK, RPA), Primary PCI or no reperfusion (eg. late)
Stratification
UFH not indicated
UFH indicated
In the ISAR-REACT study, patients (N=2,159, mean age 66 years) received 600 mg clopidogrel at least 2 hours before a PCI procedure with aspirin and a heparin bolus of 70 U/kg.
They were then randomized to either abciximab (bolus 0.25 mg/kg, infusion mg/kg/min for 12 hours) or a placebo infusion. Thereafter, all patients received clopidogrel 75 mg twice daily until discharge and then 75 mg clopidogrel daily for at least 4 weeks along with aspirin (100 mg/d).
All patients had symptomatic coronary artery disease, but patients with acute coronary syndromes and other patients considered to be at high risk were excluded.*
*High-risk exclusion criteria: acute coronary syndromes; acute myocardial infarction within 14 days, ST-segment depression, positive biomarkers, insulin-dependent diabetes, chronic total occlusions, ejection fraction  30%, thrombus and lesions in bypass grafts.
Schömig A, Mehilli J, Dotzer F, et al. ISAR-REACT: glycoprotein IIb/IIIa inhibition with abciximab in patients undergoing coronary stenting after pretreatment with a high loading dose of clopidogrel: a multicenter, randomized, double blind, placebo-controlled trial. Presented at: 52nd Annual Scientific Session of the American College of Cardiology; March 30-April 2, 2003; Chicago, Ill.
Randomization
Randomization
Fondaparinux
2.5 mg
Placebo
Fondaparinux
2.5 mg
UFH

6. Primary Efficacy Outcome Death/MI at 30 Days
0.12
UFH/Placebo
0.10
Fondaparinux
0.08
0.06
Cumulative Hazard
HR 0.86
95% CI
P=0.008
0.04
0.02
0.0 3 6 9 12 15 18 21 24 27 30
Days

7. Primary Efficacy Outcome Death/MI at 30 Days
No. of Events (%)
Control
Fonda HR
95% CI P
No. of Patients
6056
6036
Death or Re-MI
11.2
9.7
0.86
0.008
Death
8.9
7.8
0.87
0.026
Reinfarction
3.0
2.5
0.81
0.057

8. Death at Study End (3 or 6 months)
0.12
UFH/Placebo
0.10
Fondaparinux
0.08
0.06
Cumulative Hazard
HR 0.88
95% CI
P=0.029
0.04
0.02
0.0 18 36 54 72 90
108
126
144
162
180
Days

9. Efficacy of Fondaparinux by Strata on Death/MI at Study End
No. of Events (%)
Control
Fonda HR
95% CI
Stratum I (n = 5658)
(Fonda vs. Placebo)
17.3
15.9
0.87
Stratum II (n = 6434)
(Fonda vs. UFH)
12.7
11.2
0.88

10. Pre-Specified Subgroup Analyses
Death or MI at 30 days
Interaction P value N
UFH/Placebo
Fonda
Overall
12092
11.2%
9.7%
Initial Reperfusion Rx
0.04
None
2867
15.1
12.2
Thrombolytic
5436
13.6
10.9
Primary PCI
3789
4.9
6.0
GRACE Risk Score
0.03
< 112
5958
4.3
4.6
>=112
6134
18.0
14.5
0.5
0.7
0.8
1.0
1.2
1.4
1.6
2.0
Fonda better
UFH/Plac better
Hazard Ratio

11. Severe Hemorrhage definition
Fatal
Intracranial
Cardiac tamponade
Clinically significant hemorrhage with decrease Hb > 5 gm/dl with each unit of transfusion counting for 1 gm/dl Hb

12. Severe Hemorrhage at 9 Days
No. of Events
Control
Fonda HR
95% CI P
Severe Hemorrhage
79 (1.3%)
61 (1.0%)
0.77
0.13
Fatal 49 35
0.72
ICH 10 11
1.10
0.82
Retroperitoneal 2 -
Cardiac Tamponade 48 28
0.59
0.02
Hg drop ≥ 5 g/dL 17 19
1.12
0.74

13. Severe Hemorrhage by type of reperfusion therapy at 180 Days
No. of Events
Control
Fonda HR
95% CI P
None
1.8%
1.6%
0.84
0.55
Thrombolytics
2.3%
0.66
0.04
Primary PCI
1.0%
1.2%
1.18
0.60

14. Death and Net Clinical Benefit at Study End
Death/MI/Stroke/
Severe Hemorrhage HR
(95% CI) P
No Reperfusion
0.84
( )
0.06
0.81
( )
0.016
Thrombolytic
0.85
( )
0.04
0.83
( )
0.007
1o PCI
1.09
( )
0.52
1.12
( )
0.29
Overall
0.88
( )
0.029
( )
0.009

15. Elderly patients with STEMI
Higher risk of adverse outcome
Higher risk of bleeding with thrombolytics
Higher risk of bleeding with anticoagulants
Net clinical outcome not predictable

16. Elderly patients in OASIS 6 methods
Post hoc analysis
 ≥ 75 years versus < 75 years
Primary endpoints as in main study
Net clinical benefit: death, MI, severe hemorrhage at 30 days

18. Death and MI at 30 days
≥ 75 Yr
≥ 75 Yr
≥ 75 Yr
≥ 75 Yr

19. Death and MI at 30 days
≥ 75 Yr
≥ 75 Yr
≥ 75 Yr
≥ 75 Yr

20. Severe hemorrhage at 30 days

21. Death/MI/sev.hemorrhage
Net clinical benefit
Death/MI/sev.hemorrhage
Control
Fonda
difference HR
<75
10.0%
8.6%
1.4%
0.85
( )
>= 75
25.6%
22.5%
3.2%
0.87
( )

22. conclusions In patients with STEMI who are not treated with PPCI:
The efficacy and safety of fondaparinux as compared to control treatment are consistent across age groups
Consequently, the net clinical benefit of fondaparinux is consistent across age groups

23. Question
&
Answer