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ESC 2007

Bleeding Definitions
Shamir R. Mehta MD, MSc, FRCPC, FACC
Director, Interventional Cardiology
Hamilton Health Sciences
Director, ACS Research Program
McMaster University
Hamilton, Canada

Is There an Ideal Bleeding Definition?


1. Sensitive enough to detect clinically important
differences when they exist
2. Specific enough to detect differences on top of
background bleeding risk (eg. on top of lytics)
3. Clinically relevant to the condition studied
4. Based on Objective Criteria that can be
systematically collected
5. Valid and prognositcally important

Bleeding Definitions in Current Use


TIMI Definitions
GUSTO Definition
OASIS Definition
ESSENCE and OASIS 5 Trial Definition
ACUITY Definition

Assessment of Bleeding in RCTs of


Antithrombotics
Systematic collection using a standardized
definition
Ideally investigator reported
Objective ascertainment of bleeding outcome
Blinding of trial medications or assessment by
adjudication committee blinded to treatment
allocation
Bleeding should be interpreted in context of
efficacy. Net benefit needs to be considered.

SYNERGY Trial: Similar Efficacy but More


Bleeding with Enoxaparin
Randomized, open-label, trial in 10,027 patients with UA/NSTEMI at high risk of ischemic
cardiac complications, managed with a planned early invasive treatment strategy
1.00

Freedom from death / MI

Bleeding
Enox
UFH
(n=4993) (n=4985)

0.95
Enoxaparin
1 mg/kg s.c. bid

0.90

0.85

UFH (aPTT 50-70 sec)


HR=0.96 (0.86-1.06)

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

Days from randomization


The SYNERGY Trial Investigators et al. JAMA 2004;292:45-54
Mahaffey et al. Am Heart J 2005;149:581-90

OASIS 5: Similar Efficacy but Reduced


Bleeding with Fondaparinux
0.06

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

Mortality Reduction at 30 days with Fondaparinux

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

There are 3 TIMI Major Bleeding Definitions in


Current Use
Phase I

Phase II

TIMI 7, 8 11B

Intracranial

Intracranial

Intracranial

Hb >5 g/dL

Hb >5 g/dL

Hb >3 g/dL

1 unit transfusion=1 1 unit transfusion=1 1 unit transfusion=1


g/dL Hb drop
g/dL Hb drop
g/dL Hb drop
Hemorrhagic Death Hemorrhagic Death
Cardiac Tamponade Cardiac Tamponade

Steinhubl et al. Am Heart J 2007;154:3-11

TIMI Minor Bleeding


Observed blood loss associated with Hgb
decrease = 3 g/dl or HCT decrease = 10%
No identifiable source but Hgb decrease = 4 g/dl
or HCT decrease = 12%

GUSTO Bleeding
Clinical Classification

Are there differences in Bleeding Definitions?


15,000 NSTE ACS patients: Adjusted 30 day Death
1.20

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

ESSENCE and OASIS-5 Trials


Clinically overt bleeding that is either
Fatal
A symptomatic intracranial hemorrhage
A retroperitoneal hemorrhage
An intraocular hemorrhage leading to significant vision
loss
a decrease in hemoglobin of at least 3.0 g/dL (with each
blood transfusion unit counting for 1.0 g/dL of Hb)
OR
Bleeds requiring transfusion of two or more units of red
blood cells or equivalent of whole blood.

ACUITY Bleeding Definition


Non CABG related bleeding
Intracranial bleeding or intraocular bleeding
Retroperitoneal bleeding
Access site bleed requiring intervention/surgery
Hematoma =5 cm
Hgb =3g/dL with an overt source or =4g/dL w/o
overt source
Blood product transfusion (any)
Reoperation for bleeding

Evaluating RCTs For Safety: What


Types of Bleeding are Reduced?
Some types of bleeding are more serious than
others:
Fatal Bleeding and ICH are the most serious types
of bleeding
Other bleeds with clinical consequences such as
those resulting in hemodynamic compromise,
requiring surgical correction to stop bleeding and
massive blood transfusion are also clinically
important, regardless of situation
Beware of definitions mixing less serious bleeding
with more serious bleeds

Conclusions Regarding Antithrombotic Safety


Can Vary Depending on Definition Used
Trial

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

Other Considerations in Standardizing


Bleeding Definitions
1. Baseline bleeding risk
In STEMI, too liberal a definition can dilute bleeding signal between
agents and in stable angina, too conservative a definition will fail to
detect a difference due to relatively low background bleeding risk
2. Qualifying Condition
Elective PCI, stable angina vs ACS with invasive approach vs STEMI
with lytics
In elective PCI, a groin hematoma is clinically important as it may prolong
hospitalization, whereas in rescue PCI in STEMI, it may not be as
serious.
3. Acute vs Chronic Rx
Less severe bleeding becomes clinically more important with long term
therapies (eg. ASA, thienopyridines, warfarin) because minor bleeds may
lead to discontinuation of antithrombotic by patient, physician, etc.

Assessment of Bleeding in Randomized


Trials of Antithrombotic Agents
RCTs should be large enough to allow a proper
assessment of both safety and efficacy
A small RCT showing no difference in major bleeding
should be interpreted with caution
In smaller RCTs difference in minor bleeding may be a
better indicator of difference in major bleeding in a
larger trial
All RCTs should report components of serious bleeding
systematically (fatal bleeds, ICH, transfusion > 2 U,
hemodynamic compromise, requiring surgical
correction), irrespective of composite definition used

Fatal Bleeding in RCTs of


Antithrombotic Agents
Trial

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

0.3% (0.5 mg)

0%

--

0.10

(Enox v UFH)

0% (0.75 mg)

(Fonda vs Enox)
OASIS 6
(Fonda v usual
care)

--

Bleeding Scales<: Are they useful?


Severity

Criteria

Points

Superficial

Easy bruising, bleeding from


small cuts, petechia, ecchymosis

Internal

Hematoma, epistaxis, blood loss


from mouth, vagina, melena, eye
bleed, hematuria, hematemesis

Alarming

Transfusion needed, intracranial,


life threatening

Serebruany. Am J Cardiol 2007;99:288 290

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.