Post on 04-Dec-2015
description
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
za
rd
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
lati
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.