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Bleeding Definitions
Shamir R. Mehta MD, MSc, FRCPC, FACC
Director, Interventional Cardiology
Hamilton Health Sciences
Director, ACS Research Program
McMaster University
Hamilton, Canada
Bleeding
Enox
UFH
(n=4993) (n=4985)
0.95
Enoxaparin
1 mg/kg s.c. bid
0.90
0.85
0.80
0
10
15
20
25
TIMI major
CABG-related
Non-CABG-related
H/H* drop
GUSTO severe
p value
9.1
7.6
0.008
6.8
2.4
15.2
5.9
1.8
12.5
0.08
0.03
<0.001
2.7
2.2
0.08
30
HR: 0.52
95% CI: 0.440.440.61 p<0.0001
0.05
Cumulative Hazard
Cumulative Hazard
Enoxaparin
0.04
Fondaparinux
0.03
0.02
4.1 %
Enoxaparin
0.04
0.03
2.2 %
0.02
Fondaparinux
HR: 1.01
0.01
95% CI: 0.90-1.13
P for non-inferiority:
0.007
0.01
0.0
0.0
Days
OASIS 5 Investigators. N Engl J Med 2006;354:1464-76
0.02
Fondaparinux
0.01
HR 0.83
95% CI 0.71-0.97
P=0.02
0.0
Cumulative Hazard
0.03
Enoxaparin
12
15
Days
18
21
24
27
30
Phase II
TIMI 7, 8 11B
Intracranial
Intracranial
Intracranial
Hb >5 g/dL
Hb >5 g/dL
Hb >3 g/dL
GUSTO Bleeding
Clinical Classification
GUSTO Mild
3.28
GUSTO Mod
5.57
GUSTO Sev
1.84
TIMI Minimal
1.64
TIMI Minor
1.45
TIMI Major
1.00
Rao SV, et.al. JACC 2006;47: 809-16
OASIS Bleeding
Combined Clinical and Laboratory
Major (= lifethreatening + other major)
Life-threatening
fatal, intracranial, requiring surgical intervention or
4 units of blood or plasma expanders
Other major
bleeding episodes requiring transfusion of 2 or 3
units or judged to be disabling
Minor
Other bleeding episodes not classified as major
Setting
Antithrombotic
Definition
Result
CURE
UA/NSTEMI
Clopidogrel v Placebo
OASIS
Increased
TIMI Major
No difference
GUSTO
No difference
TIMI major
No difference
Replace II
Reduced
TIMI Major
No difference
GUSTO Major
No difference
STEEPLE
Reduced
TIMI Major
Reduced
OASIS 5/ESSENCE
Reduced
TIMI Major
Increased
GUSTO
Increased
Replace II
STEEPLE
OASIS 5
SYNERGY
PCI
PCI
UA/NSTEMI
UA/NSTEMI
Bivalirudin v UFH+IIb/IIIa
Enoxaparin v UFH
Fondaparinux v Enoxaparin
Enoxaparin v UFH
Agent
Comparator
Relative Risk
P value
OASIS 5
0.07%
0.22%
0.32
P=0.005
0.58%
0.81
0.72
0.13
EXTRACT (Enox
v UFH)
0.80%
0.44%
2.22
0.01
CURE (Clop v
placebo)
0.2%
0.1%
2.0
ns
STEEPLE
0%
--
0.10
(Enox v UFH)
0% (0.75 mg)
(Fonda vs Enox)
OASIS 6
(Fonda v usual
care)
--
Criteria
Points
Superficial
Internal
Alarming
Bleeding Scales
Advantages
Standardized reporting: Avoids issue of different definitions
across trials
Sensitive for major bleeding, since evaluation of bleeding will
use a continuous variable
Objective assessment
Weights severity of bleeds according to their prognostic
importance
Challenges
Identifying, defining and validating data elements
Assigning appropriate score based on each component
Multiple databases and collaboration across several groups
is necessary
Conclusions
1. Bleeding definitions vary across trials--depending on the
definition reported, this may affect conclusions regarding
safety
2. Relative importance of bleeding may differ depending on
underlying condition and timing of bleed (acute vs long term)
3. Regardless of definition used, clinicians should scrutinize
each trial for individual components of bleeding
4. Efficacy should always be considered alongside bleeding. In
cases were efficacy is similar between agents, bleeding
becomes even more important
5. Bleeding scales offer the possibility to standardize reporting of
bleeding, but there are major challenges with respect to
defining and validating variables and assigning scores to each
variable.