Bleeding Definitions

Shamir R. Mehta MD, MSc, FRCPC, FACC

Director, Interventional Cardiology

Hamilton Health Sciences

Director, ACS Research Program

McMaster University

Hamilton, Canada

ESC 2007

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 RCT’s 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

1.00

HR=0.96 (0.86-1.06)

0 5 10 15 20 25 300.80

0.85

0.90

0.95

Fre

ed

om

fro

m d

eath

/ M

I

Days from randomization

UFH (aPTT 50-70 sec)

Enoxaparin1 mg/kg s.c. bid

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

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

Enox UFH(n=4993) (n=4985) p value

TIMI major 9.1 7.6 0.008

CABG-related 6.8 5.9 0.08Non-CABG-related 2.4 1.8 0.03H/H* drop 15.2 12.5 <0.001

GUSTO severe 2.7 2.2 0.08

Bleeding

OASIS 5: Similar Efficacy but Reduced Bleeding with Fondaparinux

Days

Cu

mu

lati

ve

Ha

za

rd

0.0

0.01

0.02

0.03

0.04

0.05

0.06

0 1 2 3 4 5 6 7 8 9

Enoxaparin

Fondaparinux

HR: 1.01 95% CI: 0.90-1.13P for non-inferiority: 0.007

Cu

mu

lati

ve

Ha

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0.0

0.01

0.02

0.03

0.04

0 1 2 3 4 5 6 7 8 9

HR: 0.52 HR: 0.52 95% CI: 0.4495% CI: 0.44--0.61 p<0.00010.61 p<0.0001

Enoxaparin

Fondaparinux

4.1 %

2.2 %

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

Mortality Reduction at 30 days with Fondaparinux

Days

Cu

mu

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ve H

aza

rd0

.00

.01

0.0

20

.03

0 3 6 9 12 15 18 21 24 27 30

HR 0.83 95% CI 0.71-0.97

P=0.02

Enoxaparin

Fondaparinux

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 g/dL Hb drop

1 unit transfusion=1 g/dL Hb drop

1 unit transfusion=1 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/dlor HCT decrease = 12%

GUSTO Bleeding“Clinical” Classification

GUSTO Mild

GUSTO Mod

GUSTO Sev

TIMI Minimal

TIMI Minor

TIMI Major

1.20

3.28

5.57

1.84

1.64

1.45

1.00

Rao SV, et.al. JACC 2006;47: 809-16Rao SV, et.al. JACC 2006;47: 809-16

Are there differences in Bleeding Definitions?15,000 NSTE ACS patients: Adjusted 30 day Death

OASIS Bleeding“Combined Clinical and Laboratory”

Major (= lifethreatening + other major)

• Life-threatening

– fatal, intracranial, requiring surgical intervention or ³4 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 TrialsClinically 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 bleedingIntracranial bleeding or intraocular bleeding

–– Retroperitoneal bleedingRetroperitoneal bleeding

–– Access site bleed requiring intervention/surgeryAccess site bleed requiring intervention/surgery

–– Hematoma =5 cmHematoma =5 cm

–– Hgb Hgb ßß=3g/dL with an overt source or =3g/dL with an overt source or ßß=4g/dL w/o =4g/dL w/o overt sourceovert source

–– Blood product transfusion (any)Blood product transfusion (any)

• Reoperation for bleeding

Evaluating RCT’s 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

Replace II PCI Bivalirudin v UFH+IIb/IIIa TIMI major No difference

Replace II Reduced

STEEPLE PCI Enoxaparin v UFH TIMI Major No difference

GUSTO Major No difference

STEEPLE Reduced

OASIS 5 UA/NSTEMI Fondaparinux v Enoxaparin TIMI Major Reduced

OASIS 5/ESSENCE Reduced

SYNERGY UA/NSTEMI Enoxaparin v UFH TIMI Major Increased

GUSTO Increased

Other Considerations in Standardizing Bleeding Definitions1. 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

• RCT’s 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 RCT’s difference in minor bleeding may be a better indicator of difference in major bleeding in a larger trial

• All RCT’s 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 RCT’s of Antithrombotic AgentsTrial Agent Comparator Relative Risk P value

OASIS 5

(Fonda vs Enox)

0.07% 0.22% 0.32 P=0.005

OASIS 6

(Fonda v usual care)

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

(Enox v UFH)

0.3% (0.5 mg)

0% (0.75 mg)

0% -- 0.10

--

Bleeding Scales<: Are they useful?

Severity Criteria Points

Superficial Easy bruising, bleeding from small cuts, petechia, ecchymosis

1

Internal Hematoma, epistaxis, blood loss from mouth, vagina, melena, eye bleed, hematuria, hematemesis

3

Alarming Transfusion needed, intracranial, life threatening

6

Serebruany. Am J Cardiol 2007;99:288 –290

Bleeding ScalesAdvantages

• 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

Conclusions1. 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.