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

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

Disclosure

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

Fondaparinux: Mechanism of Action

Intrinsic pathway Extrinsic pathway Antithrombin AT AT Xa AT Xa Fondaparinux Recycled

Turpie AGG et al. N Engl J Med. 2001;344:619.

II Fibrinogen IIa THROMBIN Fibrin clot

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

Randomization

UFH indicated

Randomization

Fondaparinux 2.5 mg Placebo Fondaparinux 2.5 mg UFH

Primary Efficacy Outcome Death/MI at 30 Days

UFH/Placebo Fondaparinux HR 0.86 95% CI 0.77-0.96

P=0.008

0 3 6 9 12 15 Days 18 21 24 27 30

Primary Efficacy Outcome Death/MI at 30 Days

No. of Patients Death or Re-MI

No. of Events (%) Control Fonda HR

6056 11.2

6036 9.7

0.86

95% CI

0.77-0.96

P

0.008

Death Reinfarction 8.9

3.0

7.8

0.87

0.77-0.98

0.026

2.5

0.81

0.65-1.01

0.057

Death at Study End (3 or 6 months)

UFH/Placebo Fondaparinux HR 0.88 95% CI 0.79-0.99

P=0.029

0 18 36 54 72 90 Days 108 126 144 162 180

Efficacy of Fondaparinux by Strata on Death/MI at Study End No. of Events (%) Control Fonda HR 95% CI

15.9

0.87

0.76-0.99

Stratum I (n = 5658) (Fonda vs. Placebo) 17.3

Stratum II (n = 6434) (Fonda vs. UFH) 12.7

11.2

0.88

0.76-1.02

Pre-Specified Subgroup Analyses Death or MI at 30 days N

12092

UFH/Placebo

11.2%

Fonda

9.7%

Interaction P value Overall Initial Reperfusion Rx

None Thrombolytic Primary PCI 2867 5436 3789

GRACE Risk Score

< 112 >=112 5958 6134 15.1

13.6

4.9

4.3

18.0

12.2

10.9

6.0

4.6

14.5

0.04

0.03

0.5

0.7 0.8

1.0 1.2 1.4 1.6

2.0

Fonda better UFH/Plac better

Hazard Ratio

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

Severe Hemorrhage at 9 Days No. of Events

Severe Hemorrhage Fatal ICH

Control Fonda

79 (1.3%) 49 61 (1.0%) 35 10 11 Retroperitoneal 2 0 Cardiac Tamponade Hg drop ≥ 5 g/dL 48 17 28 19

HR

0.77

0.72

1.10

0.59

1.12

95% CI

0.55-1.08

P

0.13

0.47-1.10

0.47-2.60

0.58-2.15

0.13

0.82

0.37-0.93

0.02

0.74

Severe Hemorrhage by type of reperfusion therapy at 180 Days No. of Events

None Thrombolytics Primary PCI

Control Fonda HR 95% CI

1.8% 2.3% 1.0% 1.6% 1.6% 0.84

0.47-1.50

0.66

0.44-0.98

1.2% 1.18

0.63-2.22

P

0.55

0.04

0.60

No Reperfusion

Death and Net Clinical Benefit at Study End

Death HR (95% CI)

0.84

(0.69-1.01)

P

0.06

Death/MI/Stroke/ Severe Hemorrhage HR (95% CI)

0.81

(0.69-0.96)

P

0.016

Thrombolytic 1 o PCI Overall 0.85

(0.73-0.99) 1.09

(0.83-1.44) 0.88

(0.79-0.99) 0.04

0.52

0.029

0.83

(0.73-0.95) 1.12

(0.90-1.39) 0.88

(0.80-0.97) 0.007

0.29

0.009

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

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

≥ 75 Yr ≥ 75 Yr ≥ 75 Yr ≥ 75 Yr

Death and MI at 30 days

≥ 75 Yr ≥ 75 Yr ≥ 75 Yr ≥ 75 Yr

Death and MI at 30 days

Severe hemorrhage at 30 days

Net clinical benefit

Death/MI/s ev.hemorr

hage Control Fonda difference <75 >= 75 10.0% 25.6% 8.6% 22.5% HR 1.4% 0.85

(0.74-0.97) 3.2% 0.87

(0.72-1.05)

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