1. Is it possible to develop universal bleeding definition?
By Victor Serebruany, MD, PhD

2. Victor Serebruany, MD, PhD
DISCLOSURES
Victor Serebruany, MD, PhD
Receipt of Intellectual Property Rights/Patent Holder
British Technology Group, Novartis AG, Boehringer Ingelheim, Eli Lilly and Company, Pfizer, Inc., AtheroGenics, Inc., Eisai, Inx., AstraZeneca
Consulting Fees
Pfizer, Inc., Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership, McNeil, NPS Pharmaceuticals, Bayer AG, Eisai, Inc.
Speakers’ Bureau
Pfizer, Inc., Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership
Grants/Contracted Research
Pfizer, Inc., Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership, Novartis AG, Lundbeck A/S, Boehringer Ingelheim, Eli Lilly and Company, AtheroGenics, Inc., Guilford, Johnson & Johnson, Bayer AG, Merck & Co., Inc., FIBREX Medical, Cardax Pharmaceuticals, Inc., Eisai, Inc., Pronova BioPharma ASA
Ownership Interest (Stocks, Stock Options or Other Ownership Interest)
HeartDrug™ Research, LLC

3. Why Do We Need a Universal Bleeding Definition?
Bleeding is deadly
Vascular benefits are not impressive
Drug approval based on safety

4. Impact of Bleeding on Outcomes in 34,146 ACS Patients Pooled from OASIS, OASIS-2, and CURE
Variable
Major Bleed, n (%)
No Major Bleed, n (%)
HR (95% Cl) Unadjusted P
HR (95% Cl)
Death <30 d
12.8
2.5
9.77 (7.50—12.72)
<0.0001
5.37 (3.97—7.26)
Death 30 d – 6 m
4.6
2.9
1.86 (1.26—2.75)
0.002
1.54 ((1.01—2.36)
0.047
MI <30 d
10.6
4.1
6.98 (5.19—9.39)
4.44 (3.16—6.24)
MI 30 d – 6 m
1.6
1.8
1.15 (0.60—2.23)
0.67
1.14 (0.59—2.21)
0.69
Stroke < 30 d
2.6
0.56
8.63 (4.80—15.53)
6.46 (3.54—11.79)
Stroke 30 d– 6 m
0.8
0.6
1.70 (0.70—4.13)
0.24
1.30 (0.48—3.54)
0.60
Eikelboom Circ 2006;114:

5. Type of Bleeding and Mortality30 60 90
120
150
180
5.0
20.0
25.0
10.0
15.0
Life Threatening
Major
Mortality (%)
Minor
No Bleeding
Days
No. at Risk
Life Threaten
200
185
172
163
152
141
130
Major
132
129
125
121
117
112
107
Minor
379
375
370
368
349
326
308
No Bleeding
11851
11612
11514
11465
10790
10105
9368
EikelboomCirc 2006;114:

6. Bleeding and Outcomes in 10,974 PCI Patients from Washington Hospital Center (1991-2000)
Bleeding Complication
In-Hospital Clinical Events
Major
(n=588)
Minor
(n=1,394)
None
(n=8,992)
Death
7.5%*†
1.8%*
0.6%
Q-wave myocardial infarction
1.2%*
0.7%‡
0.2%
Non-Q-wave myocardial infarction
30.7%*†
16.8%*
11.8%
Repeat lesion angioplasty
1.9%*§
0.8%‡
0.3%
Major adverse cardiac event
6.6%*†
2.2%*
Kinnaird TD et al. AM J Cardiol 2003;92:930-5

7. Days after Randomization
Association of Blood Transfusion and Mortality
10% 4% 2% 6% 8%
Transfusion
No Transfusion
Log rank P<0.001
N=24,112 5 10 15 20 25 30
Days after Randomization
Rao et al. JAMA 2004;292:

8. Association of PCI-related Bleeding and Mortality
10% 4% 2% 6% 8%
p<.0001
With Major Hemorrhage
8.7%
Without Major Hemorrhage
1.9% 60
120
180
240
300
360
Days after Randomization
Feit et al. Am J Cardiol 2007;100:

9. “Optimal Anticoagulation” Myth
Bleeding
Thrombosis

10. Preception versus Cold ”Bloody” Facts
”Until recently, bleeding was thought to be inherent to the modern therapeutic approach to ACS, and was seen as the price to pay for an improvement in outcome.”
“Bleeding complications were more or less considered to be a non-event that could easily be fixed with appropriate measures, and blood transfusion if needed.”
Bassand JP: Heart 2008;94:661–666

11. Reporting Bleeding Events in Modern Antithrombotic Trials
Postulates
The medical community is lulled by the ever-appearing and obligatory refrain: “low incidence of bleeding events”, even in studies testing aggressive combination regimens
Bleeding is considered as an unfortunate but unavoidable shortcoming of antithrombotic therapy

12. Bleeding Classifications
TIMI ISTH
GUSTO CURE
ACUITY PLUTO
REPLACE BleedScore™
STEEPLE

13. What is Wrong with Current Classifications?
Descriptive, avoiding cause
Ignoring nuisance events
Hiding rather than fairly scaling events
Justifying the ”net clinical benefit” concept

14. Timing of Event Adjudications in TRITON

15. Myths and Realities of Bleeding After Conventional Clopidogrel
Event
Myth
Reality
Any Bleeding % %
Nucent Bleeding
Can be ignored
Observed in 50-60%
Non-compliance after 2-3 episodes
Relation to IPA
Direct
Only for moderate, but not major events
Serebruany EHJ 2010; 31:

16. Conclusions
Some critical data on bleeding (incidence, causes, and associated hazards) are lacking
Development of universal bleeding scale is extremely important for the success of future antithrombotics
A combined effort from academia, industry, regulatory, and clinical trialists is needed
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