1. OASIS-5: Study Design Randomize N=20,078 Enoxaparin (N=10,021)
Patients with NSTE ACS, chest discomfort < 24 hours
2 of 3: age >60 y, ST-segment Δ,  cardiac markers
ASA, Clop, GP IIb/IIIa, planned Cath/PCI as per local practice
Randomize
N=20,078
Fondaparinux (N=10,057)
2.5 mg SC once daily
Enoxaparin (N=10,021)
1 mg/kg SC twice daily
PCI <6 h: No additional UFH
PCI >6 h: IV UFH
With IIb/IIIa, 65 U/kg
Without IIb/IIIa, 100 U/kg
PCI <6 h: IV Fonda 2.5 mg
without IIb/IIIa, 0 with IIb/IIIa
PCI >6 h: IV Fonda 2.5 mg with
and 5.0 mg without IIb/IIIa
Outcomes
The last set of anticoagulation data in UA/NSTEMI is from the Fifth Organization to Assess Strategies in Acute Coronary Syndromes (OASIS-5) trial that studied fondaparinux. This was a large trial with over 20,000 patients.
The study enrolled high risk, non-ST-segment elevation acute coronary syndrome patients all receiving the standard therapies with cath and PCI per local practice. A large percentage (more than 50%) had catheterization.
The dosing strategy in OASIS-5 used the standard enoxaparin strategy plus additional heparin for PCI if greater than six hours elapsed after the last dose. In the fondaparinux arm, there were also recommendations for giving additional fondaparinux if patients were undergoing PCI.
Primary Efficacy: Death, MI, refractory ischemia at 9 days
Safety: Major bleeding at 9 days
Risk benefit: Death, MI, refractory ischemia, major bleeds 9 days
Hypothesis: First test noninferiority, then test superiority
Yusuf S, et al. N Engl J Med. 2006;354:
Adapted with permission from .
Yusuf S, Mehta SR, Chrolavicius S, et al. Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med. 2006;354:

2. Major Bleeding Through Day 9
OASIS-5: Results
Death, MI, or Refractory Ischemia Through Day 9
Major Bleeding Through Day 9
0.06
Hazard ratio, 1.01 (95% CI, )
0.04
Hazard ratio, 0.52 (95% CI, )
P<.001
0.05
Fondaparinux
0.04
0.03
Enoxaparin
Cumulative Hazard
0.03
Cumulative Hazard
0.02
0.02
Enoxaparin
Fondaparinux
0.01
0.01
0.00
0.00 1
Days 9 1
Days 9
30 Day and 6 Month Results
Event
Fondaparinux
Enoxaparin P
Mortality Day 30
2.9%
3.5%
.02
Mortality 6 Months
5.8%
6.5%
.05
The outcomes had an efficacy end point of death, MI or refractory ischemia at nine days. The safety end point looked at major bleeding and an overall risk/benefit ratio. This slide shows the overall results. The primary endpoint, on the left, shows identical efficacy outcomes for the two different anticoagulant strategies. However, on the right, one sees the risk of bleeding was cut in half over this early time period with the use of fondaparinux as compared with enoxaparin.
Intriguingly, mortality ended up being lower with the fondaparinux strategy, both at 30 days and out through six months. This may be attributable to the avoidance of bleeding early on.
Low rates of catheter clotting were seen in the fondaparinux arm of OASIS-5. The investigators pointed out that catheter clotting with fondaparinux could be eliminated with careful flushing of the catheter and by using a very small dose of unfractionated heparin. They suggested the bleeding risk is low enough with fondaparinux that a small dose of heparin could safely be added.
1.5% thrombus on catheter (in fonda group) if no UFH given
Adapted with permission from Yusuf S, et al. N Engl J Med. 2006:354:
Yusuf S, Mehta SR, Chrolavicius S, et al. Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med. 2006;354:

3. ACUITY First Randomization - Antithrombin
Moderate-high risk unstable angina or NSTEMI
undergoing an invasive strategy (N = 13,800)
UFH or
Enoxaparin
+ GP IIb/IIIa
Bivalirudin
Alone R
Angiography within 72 h
Ischemic Composite
Bleeding
Net Clinical Outcome
7.3 %
5.7 %
11.7 %
7.7 %
5.3 %
11.8 %
7.8 %
3.0 %
10.1 %
CABG
Medical
management
PCI
Moderate-
high risk
ACS
ASA in all
clopidogrel
dosing and timing
per local practice
Endpoints: Death, MI, and unplanned revascularization for ischemia (30 days and 1 year);
major bleeding (30-days); composite of the above (30-days)
Stone G. American College of Cardiology 2006 Scientific Sessions; March 12, 2006; Atlanta, GA.

4. ACUITY Second Randomization – GP IIb/IIIa Inhibitor Timing
Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819)
Ischemic Composite
Bleeding
Net Clinical Outcome
7.1 %
6.1 %
11.7
7.9 %
4.9 %
11.7 %
UFH or enoxaparin
Routine upstream GPI
in all pts
Routine upstream
GPI in all pts
(4,605)
Deferred GPI
for PCI only
(n = 4,602) VS R
GPI started in CCL
for PCI only
UFH, Enoxaparin,
or Bivalirudin
Moderate-
high risk
ACS
(n = 13,819)
Bivalirudin
Routine upstream
GPI in all pts
GPI started in CCL
for PCI only
Bivalirudin
Alone
(n = 4,612)
Aspirin in all
clopidogrel
dosing and timing
per local practice
Endpoints: Death, MI, and unplanned revascularization for ischemia (30 days and 1 year);
major bleeding (30-days); composite of the above (30-days)
Stone G. American College of Cardiology 2006 Scientific Sessions; March 12, 2006; Atlanta, GA.

5. ExTract PCI Cohort: Primary Endpoint Death or Nonfatal MI by 30 days15
UFH
13.8%
ENOX 10
10.7%
RR 0.77
p=0.001
Death or MI (%) 5
The findings for the primary end point are shown here.
Through 30 days Death or nonfatal MI was reduced from 12.0 % in the UFH group to 9.9% in the enoxaparin group.
This 2.1% absolute risk difference corresponded to a 17% RRR with P <
Only 3 of the nearly 21,000 patients were lost to followup ! 5 10 15 20 25 30
Days

6. PCI Cohort: Safety Event ENOX UFH RR P-Value
n=2, n=2,377
TIMI Major Bleed 1.4% 1.6% 0.87 ( ) 0.56
TIMI Minor Bleed 3.3% 2.4% 1.34 ( ) 0.09
TIMI Major or 4.6% 4.0% 1.15 ( ) 0.31 Minor Bleed
ICH 0.2% 0.4% 0.42 ( ) 0.18
Stroke 0.3% 0.9% 0.30 ( ) 0.006