OASIS in ACS:

with Updates on 2011 ESC Guidelines

on Anticoagulation
Donato Maranon, MD, FPCP, FPCC, FACC

Dramatic Improvement of Outcome over

the Last 30 years
Antiplatelet agents
Anticoagulants
Revascularization / Reperfusion / Thrombolysis
Long term treatment / secondary prevention
Implementation of guidelines

Therapeutic Options in Acute Coronary

Syndromes

Anti-ischemic treatment

Antiplatelet agents

Anticoagulants

Revascularization/Reperfusion/Thrombolysis

Long term treatment/secondary prevention

Targets for antithrombotics

Tissue factor

Collagen
Aspirin

Plasma clotting
cascade

Direct Xa inhib

Thromboxane A2
Prothrombin

Fondaparinux
LMWH
Heparin

ADP

AT
AT
Bivalirudin
Hirudin
Dabigatran

Factor
Xa

Clopidogrel
Prasugrel
AZD 6140

Conformational
activation of GPIIb/IIIa
Thrombin

Fibrinogen

Platelet aggregation
Fibrin
Thrombus

GPIIb/IIIa
inhibitors

ROADMAP TO UA/NSTEMI
Early Conservative Strategy

Bedrest, O2 if indicated
Nitrates, Morphine, BB, ACEi
Aspirin, Clopidogrel
LMWH or UFH or Fondaparinux
Monitor with serial ECG and cardiac biomarkers
Eptifibatide or Tirofiban, if with continuing ischemia,
elevated TnT or TnI, and other high risk factors

ROADMAP TO UA/NSTEMI
Early Invasive Strategy

Bedrest, O2 if needed
Nitrates, Morphine, BB, ACEi
Aspirin, LMWH or UFH
GP IIb/IIIa, tirofiban, eptifibatide, or abciximab
is added to aspirin, clopidogrel and heparin if
PCI needed

Guidelines Recommendations for Anticoagulation

Anticoagulation is recommended for all patients in
addition to antiplatelet therapy (I-A)
Anticoagulation should be selected according to the
risk of both ischaemic and bleeding events (I-B)
Several anticoagulants are available, namely UFH,
LMWH, Fondaparinux, bivalirudin. The choice depends
on the initial strategy (urgent invasive, early invasive, or
conservative strategies (I-B)
In an urgent invasive strategy UFH (I-C), or enoxaparin
(IIa-B) or bivalirudin (I-B) should be immediately started
2007 ESC Guidelines

Guidelines Recommendations for Anticoagulation

In a non-urgent situation, as long as decision between
early invasive or conservative strategy is pending:
Fondaparinux is recommended on the basis of the
most favourable efficacy/safety profile (I-A)
Enoxaparin with a less favourable efficacy/safety
profile than fondaparinux should be used only if the
bleeding risk is low (IIa-B)
As efficacy/safety profile of LMWH (other than
enoxaparin) or UFh relative to fondaparinux is
unknown; these anticoagulants cannot be recommended
over fondaparinux (IIa-B)
2007 ESC Guidelines

OASIS 5: An International, Multicenter, Randomized,

Double-Blind, Double-Dummy Trial in 41 Countries
20,078 patients with UA/NSTEMI
Aspirin, Clopidogrel, anti-GPIIb/IIIa, planned
Cath/PCI as per local practice

Randomization

Fondaparinux
2.5 mg s.c. od up to 8 days

Enoxaparin
1 mg/kg s.c. bid for 2-8 days
1 mg/kg s.c. od if ClCr<30mL/min

Vital status ascertained in 20,066 (99.9%)

Lost to follow-up at day 9: fondaparinux: n=7 and enoxaparin: n=5
1. Michelangelo OASIS 5 Steering Committee. Am Heart J 2005;150:1107.e1-.e10
2. OASIS 5 Investigators. N Engl J Med 1464-76

Study Objectives and Outcomes

Objectives
Primary efficacy objective: To demonstrate non-inferiority of fondaparinux
compared with enoxaparin
Primary safety objective:
To determine whether fondaparinux was
superior to enoxaparin in preventing major
bleeding

Outcomes (centrally adjudicated)

Primary efficacy:1st occurrence of the composite of death, MI, or refractory
ischemia (RI) up to day 9
Primary safety:

Major bleeding up to day 9

Risk benefit:

Death, MI, refractory ischemia, major bleeds up to day 9

Secondary:

Above & each component separately at days 30 and 180

1. Michelangelo OASIS 5 Steering Committee. Am Heart J 2005;150:1107.e1-.e10

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

Key Messages from OASIS 5

1.

Major bleeding risk reduction

2.

Significant risk reduction for death and death/

MI/ stroke 30 days and 6 months

3.

Consistent effect in every subset of patients

1.
2.
3.
4.

4.

PCI
Elderly
Renal failure
Irrespective of initial risk category

Excess of catheter thrombus formation during

PCI

0.01 0.02 0.03 0.04 0.05 0.06

HR 1.01
95% CI 0.90-1.13
Enoxaparin
Fondaparinux

0.0

Cumulative Hazard

Death/MI/RI: Day 9

5
Days

Major Bleeding: 9 Days

0.02

0.03

HR 0.53
95% CI 0.45-0.62
P<<0.00001

0.01

Fondaparinux

0.0

Cumulative Hazard

0.04

Enoxaparin

5
Days

Mortality: Day 30

0.02

Fondaparinux

0.01

HR 0.83
95% CI 0.71-0.97
P=0.022

0.0

Cumulative Hazard

0.03

Enoxaparin

12

15

Days

18

21

24

27

30

Mortality at 6 Months

0.04

Fondaparinux

0.02

HR 0.89
95% CI 0.79-0.99
P=0.037

0.0

Cumulative Hazard

0.06

Enoxaparin

20

40

60

80

100

Days

120

140

160

180

Increased Mortality at Days 30/180 in Patients

with Major Bleeds by Day 9 in OASIS 5

Cumulative Hazard

Maj Bleed 9 days

No Maj Bleed 9 days

Adjusted HR (95% CI) at day 30: 5.06 (4.59-5.62); at day 180: 3.16 (2.92-3.44)

30

60

90

Days
Budaj et al. JACC 2006;abstract 972-224

120

150

180

Bleeding Rates: Day 9

Outcome

Enox
(%)

Fonda
(%)

HR (95% CI)

P value

No. Randomized

10021

10057

Total Bleed

7.3

3.3

0.44 (0.39-0.50) <<0.0001

Major Bleed

4.1

2.2

0.52 (0.44-0.61) <<0.0001

TIMI Major Bleed

1.3

0.7

0.55 (0.41-0.74) <<0.0001

Minor Bleed

3.2

1.1

0.35 (0.28-0.43) <<0.0001

Categories of Major Bleeds

at 9 Days
Enox
(No. Pts)

Fonda
(No. Pts)

10021

10057

412 (4.1%)

217 (2.2%)

Intracranial

Surgery reqd to stop bleed

77

41

0.0001

Retroperitoneal

37

0.0001

Hb 3 g/dL

312

150

0.0001

Transfusion 2 units

287

164

0.0001

No. Rand.
Total Bleeding

<<0.0001

Does the Lower Bleeding Rate at 9 Days

Translate into Lower Long Term Mortality?
No. Deaths at 30 Days
Patients with

Enox

Fonda

Difference

No Bleeds

278

260

-18

Minor Bleeds

19

10

-9

Major bleeds

55

25

-30

Total:

352

295

-57

-39 (68.4%)

No. Deaths at 180 Days

No. Bleeds

528

518

-10

Minor Bleeds

31

13

-18

Major Bleeds

76

35

-41

Total:

635

566

-69

-59 (85.5%)

Relative Impact of MI, Refractory Ischemia

or Bleeding on Mortality
OASIS-5

Nonfatal MI

Crude Odds Ratio for Death

(95% CI)
30 Days
30 to 180
180 Days
Days
9.6 (7.7-12.0) 2.2 (1.5-3.3) 5.6 (4.6-6.7)

Refractory
Ischemia
Major Bleeds

4.0 (2.9-5.6)

1.4 (0.8-2.3)

2.6 (2.0-3.5)

6.5 (5.1-8.2)

2.1 (1.4-3.0)

4.1 (3.3-5.0)

Minor Bleeds

3.0 (2.1-4.3)

1.5 (0.9-2.4)

2.2 (1.6-2.9)

Impact of Major Bleeding, Re-MI and Transfusion

on risk of Death: ACUITY trial

Myocardial infarction

Hazard Ratio
(95% CI)

Deaths

P value

3.1 (2.4 to 3.9)

77

<0.001

Major bleeding

3.5 (2.7 to 4.4)

93

<0.001

Blood transfusion

4.5 (3.4 to 5.9)

70

<0.001

0.5

Hazard ratio (95%CI)

Mehran, R. et al. Eur Heart J 2009 30:1457-1466

OASIS-5
Less Bleeding = Less Deaths
Bleeding Reduced by 50%

Deaths Reduced by 17%

Yusuf S, Mehta S, et al. OASIS-5 Investigators NEJM 2006

A Shift in the Paradigm

Fondaparinux makes it possible to
reduce both ischemic risk (death,
death/MI, death/MI/stroke) and
bleeding risk
First ever observed with an anticoagulant
in ACS

Comparison of
Anticoagulant Activities
of Enoxaparin and
Fondaparinux in OASIS 5

Anderson J. J Thromb Haemostasis 2010; 8: 243-9

OASIS 5

0.01 0.02 0.03 0.04 0.05 0.06

Cumulative Hazard

Death/MI/RI: Day 9

Enoxaparin vs Fondaparinux
Enoxaparin (n=42)

Fondaparinux (n=48)

Mean

SD

Mean

SD
0.2

6hr anti-Xa
(IU/ml)

1.2

0.45

0.5

6hr Xa-clot
(seconds)

111.8

29.6

64.9

6hr ETP AUC

(mA)

206.4

90.6

386.7

<0.0001

HR
17.7 1.01 <0.001
95% CI 0.90-1.13
51.5 Enoxaparin
<0.001

Fondaparinux

0.0

P-value

2
3 thrombin
4 potential
5 area
6 under 7
ETP1AUC, endogenous
the curve8
Days

A New Concept is Born

1.
2.
3.

4.

Bleeding carries a high risk of death, MI and stroke

Rate of major bleeding is as high as the rate of death at the
acute phase of NSTE-ACS
Prevention of bleeding is equally as important as
prevention of ischemic events and results in a
significant risk reduction for death, MI and stroke
Risk stratification for bleeding should be part of the decision
making process

OASIS 5 Conclusions
Patients Undergoing PCI
1.

A lower incidence of vascular access site complications was observed

with fondaparinux

2.

Fewer bleeding complications with fondaparinux irrespective of the

timing of last study drug administration

3.

Fewer bleeding complications with fondaparinux irrespective of the use

of UFH prior to PCI

4.

A higher rate of guiding catheter thrombosis was observed with

fondaparinux when PCI was performed without UFH, but this was largely
avoided if UFH was used just before/during the procedure

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

Fondaparinux in PCI

Clinical Events after PCI:

Day 30
P=0.004

P=0.60
P=0.68

P<0.0001

Vascular Access Site Complications, Large

Hematomas and Pseudo-aneurysms
HR 0.41
P<<0.0001
HR 0.36
P<<0.0001
HR 0.63
P=0.033

Catheter-Related Thrombus with

Enoxaparin and Fondaparinux
Enoxaparin
8 cases total: 6 when PCI performed within 6 h of last enox
dose where no UFH was given
Rate is 6/1431=0.42%
In Enoxaparin patients receiving study UFH, there was 1 case.
1 case time of PCI not ascertained
Fondaparinux
29 cases (UFH was not routinely given to fonda group)
Rate is 29/3135=0.9%
When open label UFH was used prior to PCI (5000 U mean),
only 1 case of catheter thrombus was reported

Mean dose of UFH for PCI used in OASIS 5: 47 IU/kg

Adding UFH to Fondaparinux for PCI is Safe and

Preserves the Lower Bleeding with Fondaparinux

No UFH post-Randomization
UFH or equivalent placebo
mandated by protocol during
PCI
Open Label UFH
Overall

Enox

Fonda

HR

CI

1.2

0.5

0.45

0.181.11

(n=1,277)

(n=1,313)

1.1

0.4

0.34

0.120.95

(n=1,229)

(n=1,279)

2.7

1.3

0.48

0.201.17

(n=598)

(n=543)

1.5

0.6

0.42

0.240.71

(n=3,104)

(n=3,135)

Mean dose of UFH for PCI used in OASIS 5: 47 IU/kg

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

OASIS 5 PCI: Net Clinical Benefit Favours

Fondaparinux in Invasively Managed Patients
Death/MI/Stroke/Major Bleeding
RR 0.78
P=0.004

Mehta et al. JACC 2006;abstract 821-5

Mehta et. al. JACC 2007, in press

RR 0.76
P=0.035

Conclusions for PCI

1.

Patients who underwent an early invasive strategy in

OASIS 5 trial had superior net benefit with fondaparinux
compared to enoxaparin

2.

Fondaparinux is safe and effective as upstream therapy

in patients undergoing PCI and reduces bleeding by half
compared to enoxaparin

3.

Catheter thrombus occurs very rarely in comparison

with death or re-MI and appears to be avoided with
standard UFH for the PCI itself without increasing major
bleeding

4.

Adjunctive UFH (50 IU/kg) with or without GP IIb/IIIa

antagonist is recommended as PCI anticoagulation

Simple Transition of Patients Initiated on

Fondaparinux to the Catheterization Lab

Treat with ASA, clopidogrel and fondaparinux,

+/- IV glycoprotein IIb/IIIa inhibitor in the ER

Proceed to Cath Lab as usual*

If PCI needed, give UFH (dose 50 units/kg) +/glycoprotein IIb/IIIa inhibitor

Post procedure, follow usual practice for sheath

removal. Immediate removal if closure device or
radial and 6 hours after last fondaparinux subcut
dose if no closure device used

*May perform cath>6 hours after last subcut dose if this was
centers usual practice with using LMWH

Low vs. Standard Dose Unfractionated Heparin

for Percutaneous Coronary Intervention
in Acute Coronary Syndromes Patients
treated with Fondaparinux:
the FUTURA/OASIS 8 Randomised Trial

Sanjit S. Jolly on behalf of

FUTURA/OASIS 8 Trial Group

FUTURA Trial Study Objectives

Primary Objective: To determine whether Low fixed dose vs.
Standard ACT guided unfractionated heparin during PCI
reduces the composite of peri-PCI* major, minor bleeding and
vascular access site complications in ACS patients treated
with fondaparinux
Secondary Objective: To determine if major bleeding rates in
FUTURA (with unfractionated heparin added to fondaparinux)
are higher than OASIS 5 PCI (with Fondaparinux used alone)
*Peri-PCI defined within 48 hours following PCI

Study Design
Adjunctive therapy
during PCI
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

Study Outcome Definitions

Major Bleeding
(OASIS 5)

Fatal
Symptomatic ICH
Retroperitoneal hemorrhage
Intraocular bleeding leading to significant vision loss
Requiring surgical intervention
Hb drop of 3 g/dL
Blood transfusion of > two units RBCs

Minor Bleeding Any other significant bleeding leading to transfusion of one

unit of blood or discontinuation of antithrombotic therapy.
Major Vascular
Access Site
Complications

Large hematoma (5 cm or requiring intervention)

Pseudoaneurysm requiring treatment
Arterio-venous fistula
Other vascular surgery related to the access site

Baseline and Procedural Characteristics

Standard Dose UFH
N=1002

Low Dose UFH

N=1024

Age (years)

65.5

65.3

Male (%)

68.5

67.3

Diabetes (%)

27.9

26.1

ECG changes (%)

74.6

75.3

Elevated Troponin I or T (%)

78.8

81.3

Aspirin (%)

96.1

95.4

Clopidogrel (%)

96.3

94.6

Procedural GP IIb/IIIa (%)

26.4

25.8

Femoral Access (%)

62.4

64.2

Any Stents placed (%)

94.0

93.7

Primary Outcome at 48 h

Peri-PCI major, minor

bleeds and vascular
access complications

Standard
Dose UFH
(n=1002)

Low
Dose UFH
(n=1024)

OR

95% CI

5.8%

4.7%

0.80

0.54-1.19

0.27

Primary Outcome at 48 h

Peri-PCI major, minor

bleeds and vascular
access complications

Standard
Dose UFH
(n=1002)

Low
Dose UFH
(n=1024)

OR

95% CI

5.8%

4.7%

0.80

0.54-1.19

0.27

Components of primary outcome (Peri-PCI)

Major bleeds

1.2%

1.4%

1.14

0.53-2.49

0.73

Minor bleeds

1.7%

0.7%

0.40

0.16-0.97

0.04

Major vascular access

site complications

4.3%

3.2%

0.74

0.47-1.18

0.21

Secondary Outcomes at 30 days

Standard
Low
Dose UFH Dose UFH
(n=1002)
(n=1024)

OR

95% CI

Key Secondary outcome:

Peri-PCI major bleeding,

death, MI, TVR

3.9%

5.8%

1.51

1.00-2.28

0.05

Death, MI, TVR

2.9%

4.5%

1.58

0.98-2.53

0.06

Death

0.6%

0.8%

1.31

0.45-3.78

MI

2.5%

3.0%

1.22

0.72-2.08

TVR

0.3%

0.9%

2.95

0.80-10.9

Stent thrombosis

0.5%

1.2%

2.36

0.83-6.73

0.11

Catheter thrombosis

0.1%

0.5%*

4.91

0.57-42.1

0.15

* One event occurred during coronary angiography after randomization

Outcomes to 30 days
Major Bleed at 30 days

0.05

Death/MI/TVR at 30 days

0.05
0.04

0.04

Low dose 2.2% vs. Standard dose 1.8%,

HR 1.20 (95% CI 0.64-2.23, p=0.57)

0.03

0.03

Low dose 4.5% vs. Standard dose 2.9%

HR 1.56 (95% CI 0.98-2.48, p=0.06)

0.02

0.02
0.01

0.01

Standard Dose
Low Dose

Standard Dose
Low Dose

0.0

0.0
0

12

No. at Risk
Standard Dose 1002

986

981

Low Dose

1002

1001

1024

15
Days

18

21

24

27

30

12

No. at Risk

980

980

978

Standard Dose 1002

980

975

998

997

994

Low Dose

997

988

1024

15
Days

18

21

24

27

30

975

974

971

982

981

978

Subgroup analysis showed consistent results for primary outcome

and for death/MI/TVR for pre-specified subgroups of: Age, Sex,
GP IIb/IIIa, BMI, CrCl, Arterial access site

Comparison to OASIS 5 Major

Bleeding
Adjusted
Major
bleeding* rate
(95% CI)
FUTURA
standard
dose UFH

1.1% (0.6-2.1)

FUTURA
low dose
UFH

1.2 % (0.6-2.2)

OASIS 5 PCI
Fondaparinux
Major bleeding*

OASIS 5 PCI
Enoxaparin
Major bleeding*

1.5%

3.6%

Adding unfractionated heparin during PCI to

fondaparinux does not appear to increase peri-PCI
major bleeding
*Major bleeding rates within 48 hours following PCI

Conclusions
No significant difference in major/minor bleeding or
vascular complications between Low fixed dose and
Standard dose unfractionated heparin
While low dose heparin reduced minor bleeding there
was a trend towards reduced efficacy
The use of unfractionated heparin for PCI on a
background of fondaparinux did not increase major
bleeding when compared to fondaparinux alone and
lower than that previously observed with enoxaparin

Implications
ACS patients treated with fondaparinux can
undergo PCI safely with unfractionated heparin
No evidence to depart from guideline recommended
standard dose regimen of unfractionated heparin during
PCI
Adding unfractionated heparin during PCI to
fondaparinux preserves the benefits and safety of
fondaparinux (ie. reduced bleeding) while minimizing
catheter thrombus

Highlights of the Latest European Society

of Cardiology Guidelines on
Anticoagulants

ESC Guidelines 2011

European Heart Journal

ESC Guidelines
European Heart Journal
doi:10.1093/eurheart/ehr236

ESC 2011 Guidelines in ACS in patients without presenting persistent STsegment elevation

Fondaparinux
(2.5mg subcutaneously daily)
is recommended as having the
most favourable efficacy safety
profile with respect to
anticoagulation
GRADE 1 A

ESC Guidelines
European Heart Journal
doi:10.1093/eurheart/ehr236

ESC 2011 Guidelines in ACS in patients without presenting persistent STsegment elevation

Fondaparinux
Contraindicated in severe
renal failure
(CrCl<20mL/min).
Drug of choice in patients
with moderately reduced
renal function (CrCl 30 60
mL/min)

ESC Guidelines
European Heart Journal
doi:10.1093/eurheart/ehr236

Recommendation for Invasive evaluations and revascularization

ESC Guidelines
European Heart Journal
doi:10.1093/eurheart/ehr236

How Should Fondaparinux Be Used

in Patients with UA/NSTEMI?

Administer fondaparinux (2.5 mg sc od) for up to

8 days or until hospital discharge if earlier

If a patient needs to undergo an invasive procedure

during the treatment period, the following is
recommended:
PCI: UFH should be used during the procedure
CABG surgery: fondaparinux where possible
should not be given during the 24 h before
surgery and may be restarted 48 h post-operatively

THANK YOU