30 Day to 6 Month Death

According to Bleeding

Bleeding and 30 - Day Risk*

Event HR

Death 5.37

MI 4.44

Stroke 6.46

Eikelboom Circulation 2006;114: 774 - 782; published online August 14 2006

Dea

th

days

bleeding

no bleeding

*adjusted with bleeding as time -dependent covariate, baseline factors, propensity

Bleeding and Outcomes

OASIS Registry, OASIS - 2, CURE (n=34,146)

How Might Bleeding Increase Long -Term Mortality?

•Hemodynamic compromise

•Hyperadrenergic state

•Transfusion – induced microcirculatory disorder, NO depletion, immunologic effects

•Inflammatory response

•Discontinuation of antithrombotics

Through Q2 2004 (n=74,271)

CRUSADE Bleeding Risks – Transfusion by Age

4.5

10.3

14.1

9.7

17.9 18.5

0

5

10

15

20

<65 yrs 65-75 yrs > 75 yrs

% R

BC

Tra

nsf

usi

on

Non-CABG Overall

Yang, J Am Coll Cardiol 2005;46:1490-5

14.9% overall10.3% non -CABG

Algorithm for Management of NSTE ACS

Likely ACS Possible ACS

Risk Stratify

High Risk Indeterminate Risk

ASA 160-325mg stat then 81mg dailyClopidogrel 300mg stat, then 75mg dailyFondaparinux 2.5mg sc/day or Enoxaparin 1mg/kg BID or UFH Initiate referral to cardiac catheterisation labUnstable NSTE ACS

Eptifibatide or TirofibanConsider Intra-aortic balloon pumpEmergency referral to cath lab

Cardiac catheterization

in < 48 hours

ASA 160-325mg stat then 81mg dailyEnoxaparin 1mg/kg bid or Fondaparinux 2.5mg/sc/day for patients with prior cardiac history, non CVD or diabetes

Observe 8 - 12 hrsHigh Risk

FeaturesNo High Risk Features

Stress ECG/ Perfusion ScanHigh Risk Features

All Types of Bleeding were Reduced in the Fondaparinux Group at Day 9

Outcome Enoxaparin

(%)

Fondaparinux

(%)

P value

No. Randomized 10,021 10,057

Fatal bleeds 0.2 0.1 0.005

TIMI major bleeds 1.3 0.7 <0.001**

Total bleeds (OASIS 5 def’n) 7.3 3.3 <0.001*

Major bleeds 4.1 2.2 <0.001

Minor bleeds 3.2 1.1 <0.001

*HR (95% Cl): 0.44 (0.39-0.50); **HR (95* Cl): 0.55 (0.41-0.74)

The Reduction in Major Bleeding was Consistent in Almost All Categories

Major bleeding

at day 9

Enoxaparin

(No. patients)

Fondaparinux

(No. Patients)

P value

No. Randomized 10,021 10,057

Total Major Bleeds 421 (4.1%) 217 (2.2%) <0.001

Intracranial 7 7 NS

Requiring surgery to

stop bleeding

77 41 <0.001

Transfusion 287 164 <0.001

Retroperitoneal 37 9 <0.001

Associated with death

at study end

79 38 <0.001

OASIS 5 Investigators. N Engl J Med 2006; 354:1464-76

Maj

or B

leed

GFR mL/min/1.73m2

0.10

0.00

0.02

0.08

40 60 80

0.04

0.06

100 120 140

Enoxaparin

Fondaparinux

Fox KAA. Ann Int Med 2007; 147: 304-310

Major Bleeding Lower with Fondaparinux Irrespective of Renal Function

(dose adjusted for renal function)

The Benefit of Fondaparinux is Consistent Irrespective of the GRACE Risk Score, Supporting its Use in a Broad Range of Patients with NSTEMI

0

2

4

6

8

10

12

<100 100 - 126 >126Low risk Intermediate risk High risk

GRACE Score GRACE Score

<100 100 - 126 >126Low risk Intermediate risk High risk

4.55.2 5.3 5.2

7.5 7.2

HR 1.170.93-1.48

HR 0.960.79-1.18

HR 0.960.81-1.15

Death, MI and RI at 9 days (%) Major bleeding at 9 days (%)

HR 0.420.28-0.63

HR 1.680.53-0.88

HR 0.450.35-1.58

2.7

1.1

4.0

2.7

5.4

2.5

Enoxaparin Fondaparinus

Joyner C. et al. JACC 2006;47(4) Suppl A:abstract 1018-223

0

2

4

6

8

10

12

20.0

10.0

30.0

40.0

50.0

<2 hrs 2 – 12 hrs 12 – 24 hrs

Time from randomisation

1432723

Angiography

PCl

0.0

24 – 72 hrs Total < 72 hrs

2199

1039

3651

1658

8919

4254

1637

834

A High Proportion of Patients Underwent an Early Invasive Strategy

Mehta S. Presented at ESC 2007 Scientific Session Oral Presentation

Net Clinical Benefit Favours Fondaparinux in Patients Undergoing PCl and Early PCl

Mehta SR. JAAC 2007, in press

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 <0.00001

Death, MI, Stroke, Major Bleeding

10.4 8.2 0.78 0.004

Early PCl < 24 hours

Death, MI, Stroke 5.4 5.3 0.98 0.89

Major Bleeding 4.9 2.3 0.48 0.0005

Death, MI Stroke, Major Bleeing

9.5 7.3 0.76 0.005

No UFH Prior to PCl UFH Prior to PCl

Enox

(%)

Fonda (%)

HR

(95% Cl)

Enox

(%)

Fonda

(%)

HR

(95% Cl)

No. randomized 810 793 80 75

Death/MI/Stroke 60 (7.4) 57 (7.2) 0.97

(0.68-1.40)

5 (6.3) 3 (4.0) 0.62

(0.15-2.61)

Major Bleed 35 (4.3) 25 (3.3) 0.75

(0.45-1.25)

5 (6.2) 1 (1.3) 0.21

(0.02-1.79)

Catheter Thrombus 4 (0.5) 9 (1.1) 2.30

(0.71-7.4)

0 1 (1.3)* -

Final 1758 patients randomized*represents 1 patient with low dose of UFH 5 units/kg vs. mean dose of 47 units/kg

Mehta SR. JAAC 2007, in press

Catheter Thrombus in Both Groups Virtually Eliminated After Protocal Amendment

Adding UFH to Fondaparinux for PCl is Safe and Preserves the Lower Bleeding with Fondaparinux versus Enoxaparin

Enox Fonda HR Cl

No UFH post-randomization 1.2

(n=1277)

0.5

(n=1313)

0.45 0.18-1.11

UFH or equivalent placebo mandated by protocol during PCl

1.1

(n=1229)

0.4

(n=1279)

0.34 0.12-0.95

Open label UFH 2.7

(n=598)

1.3

(n=543)

0.48 0.20-1.17

Overall 1.5

(n=3104)

0.6

(n=3135)

0.42 0.24-071

Mean Dose of UFH for PCI Used in OASIS 5:47 units/kg

Yusuf S. et al. N Engl J Med 2006; 354:2829

Overall Enoxaparin Fondaparinux

(during blind study drug administration)

3.5%

1.6%

4.8%

2.4%2.3%

0.9%

Fondaparinux Reduces Major Bleeding in PCl Patients with Both Radial and Femoral Access

Hamon M, Mehta S. et al. AHA Scientific Sessions 2006 Abstract No. 9796

Femoral Radial

9 da

y ev

ents

(%

)