1. Seeking the Optimal Upstream Therapy for Patients with ACS: Fondaparinux- Low Bleeding Rate and Low Cost
Sanjit S. Jolly MD,
Interventional Cardiologist,
Hamilton Health Sciences, McMaster University, Hamilton, Canada

2. Disclosures Received Grant Support from Medtronic
Received Speakers honoria from GlaxoSmithKline, Sanofi-Aventis, Astra-Zeneca, Boehringer Ingelheim

3. Major Bleeding is Associated with an Increased Risk of Hospital Death in ACS Patients
GRACE Registry in 24,045 ACS patients
*After adjustment for comorbidities, clinical presentation and hospital therapies
**p<0.001 for differences in unadjusted death rates
OR (95% CI) (1.18 to 2.28*)
Overall ACS UA
NSTEMI
STEMI 10 20 30 **
5.1
18.6
3.0
16.1
5.3
15.3
7.0
22.8
In-hospital death (%)
In hospital major bleeding
Yes No 40
Moscucci et al. Eur Heart J 2003;24: 3

4. Strong, Independent Association Between Bleeding and Death, MI and Stroke
OASIS Registry, OASIS-2, CURE
N = 34,126
Outcome
Major
Bleed
No Major
Hazard
(Adjusted) P-
Value
Death
60/470
(12.8%)
833/33676
(2.5%)
5.37
( )
<0.0001 MI
46/436
(10.6%)
1375/33710
(4.1%)
4.44
( )
Stroke
12/469
(2.6%)
187/33677
(0.6%)
6.46
( )
Eikelboom JW et al. Circulation 2006;114(8): 4

5. Fondaparinux has Highly Predictable Activity
Fondaparinux concentration (µg/mL)
Inhibition of thrombin generation (%) 10 20 30 40 50 60 70
1.5 3
4.5 6
7.5
Linear, dose-dependent inhibition of ex vivo
thrombin generation in human platelet-depleted plasma
Lormeau JC, Herault JP. Thromb Haemost 1995;74:1474–7

6. The OASIS 5 Study
OASIS 5
N Engl J Med 2006;354:

7. OASIS 5: A Randomized, Double-Blind, Double-Dummy Trial
20,078 Patients with NSTE ACS, Chest discomfort < 24 hours
2 of 3: Age>60, ST Segment Δ,  cardiac markers
Exclude
Age < 21
Any contra-ind to Enox
Hem stroke< 12 mo.
Creat> 3 mg/dL/265 umol/L
Aspirin, Clopidogrel, GPIIb/IIIa inhibitor, planned Cath/PCI as per local practice
Randomization
Fondaparinux
2.5 mg subcut daily up to 8 days or hospital discharge
Enoxaparin
1 mg/kg subcut bid for 2-8 days
1 mg/kg subcut daily if ClCr<30mL/min
Mean treatment : 5.4 days
Mean time to PCI: 2.4 days
Mean treatment : 5.2 days
Mean time to PCI: 2.6 days
Michelangelo OASIS 5 Steering Committee. Am Heart J 2005;150:1107.e1-.e10
OASIS 5 Investigators. N Engl J Med2006;354:

8. Majority of Patients Undergoing Catheterization Went Early
OASIS 5
N = 14,206 50
44.2% 45
38.4% 40 35 30 25
Patients (%)
17.4% 20 15 10 5
<24 hrs
24-48 hrs
>48 hrs
Mehta SR. JACC. 2007;in press

9. Fondaparinux was Non-Inferior to Enoxaparin at Day 9 (Primary Efficacy)
OASIS 5
Death/MI/RI
Days
Cumulative Hazard
0.0
0.01
0.02
0.03
0.04
0.05
0.06 1 2 3 4 5 6 7 8 9
Enoxaparin
Fondaparinux
HR: 1.01
95% CI:
P non-inferiority: 0.007
OASIS 5 Investigators. N Engl J Med 2006;354:

10. Fondaparinux Halved Major Bleeding versus Enoxaparin at Day 9
OASIS 5
Days
Cumulative Hazard
0.0
0.01
0.02
0.03
0.04 1 2 3 4 5 6 7 8 9
HR: 0.52
95% CI: p<0.0001
Enoxaparin
Fondaparinux
4.1 %
2.2 %
48% relative risk reduction
OASIS 5 Investigators. N Engl J Med 2006;354:

11. Fondaparinux Significantly Reduced Mortality vs. Enoxaparin at Day 30
OASIS 5
0.04
3.5 %
17 % RRR
Enoxaparin
0.03
2.9 %
Fondaparinux
Cumulative Hazard
0.02
HR: 0.83
95% CI:
p=0.02
0.01
0.0 3 6 9 12 15 18 21 24 27 30
Days
Fondaparinux: 295 deaths
Enoxaparin: 352 deaths
OASIS 5 Investigators. N Engl J Med 2006;354:

12. Lower Rate of Ischemic Events at 6 Months with Fondaparinux
OASIS 5
0.8 1
1.2
11.3%
12.5%
Death/MI/Stroke
12.3%
13.2%
Death/MI/RI
1.3%
1.7%
Stroke
6.3%
6.6% MI
5.8%
6.5%
Death
10.5%
11.4%
Death/MI
0.06
0.05 NS
0.04
0.007
P value
Fondaparinux better
Enoxaparin better
Enoxaparin
Fondaparinux
Hazard Ratio
OASIS 5 Investigators. N Engl J Med 2006;354:

13. OASIS 5 Investigators. N Engl J Med 2006;354:1464-76
The Reduction in Major Bleeding was Consistent in Almost All Categories
OASIS 5
Major bleeding at day 9
Enoxaparin
(No. patients)
Fondaparinux
(No. Patients)
p value
No. Randomized
10,021
10,057
Total Major Bleeds
412 (4.1%)
217 (2.2%)
<0.001
Intracranial 7 NS
Requiring surgery to stop bleeding 77 41
Retroperitoneal 37 9
Transfusion
287
164
Associated with death at study end 79 38
OASIS 5 Investigators. N Engl J Med 2006;354:

14. Days after Randomization
Major Bleeding in PCI Patients According to the Day after Randomization.
OASIS 5
Days after Randomization
Fondaparinux N=3105
Enoxaparin N=3072
Relative Risk
P value
Same day
0.2
0.5
0.35
0.037 1
0.7
1.7
0.40
<0.001 2
1.1
2.8 3
1.4
3.6 4
4.0
0.42 5
1.8
4.3 6
2.0
4.7 7
2.2
5.0
0.43 8
2.4
0.45
Mehta SR., et al .JACC. 2007;50:

15. Background: OASIS 5 Fondaparinux vs
Background: OASIS 5 Fondaparinux vs. Enoxaparin in ACS patients undergoing PCI (n=6177)
Outcome Day 9
Enox
N = 3072
Fonda
N = 3105 HR
P value
Death, MI or Stroke
6.2
6.3
1.03
0.79
Major Bleeding
5.1
2.4
0.46
<
Catheter Thrombosis
0.4
0.9
3.59
0.001
Data from OASIS 5, that unfractionated heparin may prevent catheter thrombosis but optimal dose uncertain
FUTURA trial was designed to determine the optimal regimen of heparin to prevent catheter thrombus and ischemic events in fondaparinux treated patients,without increasing bleeding.
Mehta SR., et al .JACC. 2007;50:
Mehta SR, et al. Circulation, 2008;118:

16. Does additional UFH eliminate catheter thrombus
Schlitt A, et al. Coron Artery Dis :

17. UFH added to Fonda eliminate thrombus formation within catheter
Schlitt A, et al. Coron Artery Dis :

18. How much heparin to use for PCI in patients treated with fondaparinux?
Low vs. Standard Dose Unfractionated Heparin for PCI: the FUTURA/OASIS 8
How much heparin to use for PCI in patients treated with fondaparinux?
First large scale RCT of heparin dose during PCI

19. Coronary Angiography/PCI to be performed within 72 hours
Study Design
Adjunctive therapy
during PCI
NSTEACS
Fonda mg sc
Angio No PCI
30 Day Follow-Up
Angio with PCI R
Std Dose UFH
(85 U/kg or 60 U/kg with GP IIb/IIIa)
ACT guided*
Low Dose UFH
(50 U/kg irrespective of GP IIb/IIIa) –
without ACT
Coronary Angiography/PCI to be performed within 72 hours
Double
Blind
With at least 2 of following:
Age>60
elevated biomarkers
ECG changes
Patients were not eligible if required urgent coronary angiography (<120 min) due to clinical instability
Registry
*ACT Targets consistent with current guidelines

20. Standard dose UFH during PCI as per guidelines is recommended
Standard Dose UFH (n=1002)
Low
Dose UFH (n=1024) OR
95% CI P
Peri-PCI Major, Minor bleed and vascular complications
5.8%
4.7%
0.80
0.27
Peri-PCI major bleeding, death, MI, TVR
3.9%
1.51
0.05
Death, MI, TVR
2.9%
4.5%
1.58
0.06
Catheter thrombosis
0.1%
0.5%*
4.91
0.15
* One event occurred during coronary angiography after randomization

21. Comparison to OASIS 5 Major Bleeding (<48 h of PCI)
Adjusted
Major bleeding rate (95% CI)
OASIS 5 PCI Fondaparinux
Major bleeding
OASIS 5 PCI
Enoxaparin
FUTURA
standard dose UFH
1.1% ( )
1.5%
3.6%
low dose UFH
1.2% ( )
Unfractionated heparin + fondaparinux does not increase peri-PCI major bleeding with rates apparently lower than when enoxaparin is used.

22. Conclusions
The benefits and safety of fondaparinux are preserved with adding UFH for PCI
UFH as per guidelines eliminates catheter thrombus
Fondaparinux can be used seamlessly in the cath lab now

23. Fondaparinux is simpler and cheaper
Enoxaparin
Fondaparinux
Cost (red book)
$35-40/day*
$14/day
Regimen
Twice daily
Once daily
Formulation
Animal Byproducts
Synthetic
Dose Adjustment
needed in elderly and renal dysfunction
Not necessary

24. Summary Fondaparinux is simple Fondaparinux is safer :
Single dose 2.5 mg sc daily
Fondaparinux is safer :
lower mortality and lower bleeding compared to enoxaparin
Fondaparinux is less expensive