1. Importance and Impact of Bleeding on ACS Clinical Outcomes
Christopher Granger, MD
Director, Cardiac Care Unit

2. Consequences of Recurrent Ischemia GUSTO IIb
Mortality at 1 year (%)
Armstrong et al. Circulation. 1998;98:

3. Focus on the antithrombotic effects
direct TIs
lytics
clopidogrel
GP IIb/IIIa inhibitors
LMWH
Heparin
Aspirin

4. Beware of unintended targets

5. Net Clinical Benefit Benefit  thrombotic events Risk  bleeding
Key factors modifying rates (and balance)
Antithrombotics: ASA, UFH, LMWH, GP IIb/IIIa, clopidogrel, lytics, combinations
Patient factors (elderly, renal fx)
Procedures

6. Bleeding is Common

7. CRUSADE Site Distribution
Total sites = 463
(Active sites = 409) WA
(7)
VT (1) ME
(0) MT
(0) ND
(1) MI
NH (2) MN
(4) OR
(5) NY
(37)
MA (11) ID
(0) SD
(2) WI
(5) MI
(22)
RI (1) WY
(0) PA
(37)
CT (8) IA
(5)
NJ (10)
NE (4) OH
(30) IN
(7) NV
(1) IL
(14)
DE (3) UT
(1) WV
(3) VA
(16)
MD (13) CO
(8) KS
(3) MO
(12) KY
(8)
DC (1) CA
(35) NC
(15) TN
(11) OK
(9) SC
(6) AZ
(9) AR
(3) NM
(2) MS
(6) AL
(11) GA
(15) LA
(8) TX
(17) FL
(33) AK
(0)
HI (1)
150,00 patients included
as of September 2005

8. CRUSADE Bleeding Risks – Transfusion by Age
14.9% overall
10.3% non-CABG
Through Q (n=74,271)
-- Yang, J Am Coll Cardiol 2005;46:1490-5

9. Bleeding is Bad

10. 30 Day Death According to Bleeding OASIS Registry, OASIS-2, CURE (n=34,146)12 10
Bleeding
Cumulative Events, % 8
5-fold  risk 6 4 2
No Bleeding 5 10 15 20 25 30
Days
No. at Risk
No Bleeding
33676
33419
33157
32990
32879
32769
32710
Bleeding
470
459
440
430
420
410
408
Eikelboom Circulation 2006;114: ; published online August

11. 30 Day to 6 Month Death According to Bleeding
Bleeding and Outcomes OASIS Registry, OASIS-2, CURE (n=34,146)
Bleeding and 30-Day Risk*
Event HR
Death 5.37
MI 4.44
Stroke 6.46
Death
days
bleeding
no bleeding
30 Day to 6 Month Death According to Bleeding
*adjusted with bleeding as time-dependent covariate, baseline factors, propensity
Eikelboom Circulation 2006;114: ; published online August

12. Prognostic Implications of Bleeding Risk Ratio of Early Death
ACS1 PCI2 CABG3
Bleeding 2 to 8* 3.7* to 8
Transfusion 3.5 to 4.0* 2.4* to to 1.9*
14 selected studies:
1. Moscucci Eur Heart J 2003, Eikelboom Circulation 2006, Rao Am J Cardiol 2005, Rao JACC 2006, Rao JACC 2005, Yang JACC 2005, Rao JAMA 2005
2. Rao Am J Cardiol 2005, Stone J Invasive Cardiol 2004, Kinnaird Am J Cardiol 2003, Attubato Am J Cardiol 2004, Manoukian 2005
3. Kuduvalli Eur J Cardiothorac Surg 2005 , Engoren Ann Thorac Surg 2002
* adjusted

13. Transfusion (Blood Cell Allogeneic Transplantation) May Be Part of the Problem

14. blood saves lives 1948

15. Transfusion and Outcome (non-CABG population)
-- Yang, J Am Coll Cardiol 2005;46:1490-5

16. Transfusion Post PCI: REPLACE 2 One Year Mortality
One-year mortality was also increased in transfused patients, with an OR of 4.26 (95% CI= ; p<0.0001) after adjusting for differences in baseline demographic variables.
P<0.0001
-Manoukian SV et al. 2005

17. 30 Day Survival By Transfusion Group GUSTO IIb, PURSUIT, PARAGON B (n=24,000; 10% transfused)
0.9
0.92
0.94
0.96
0.98 1 5 10 15 20 25 30 35
Days
Survival Rates
No Transfusion
Transfusion
OR 3.9, time-dependent covariate analysis adjusted for baseline characteristics, bleeding propensity, transfusion propensity, & nadir HCT
-- Rao SV, et. al., JAMA 2004

18. Cochrane Collaboration Risk reduction with restrictive transfusion strategy N=10 randomized trials
Hill SR, et. al. Cochrane Database of Systematic Reviews 2004

19. Properties of packed RBCs
Low 2,3 DPG*
High O2 affinity*
Depleted of Nitric Oxide
NO plays a fundamental role in O2 exchange†
Effects of Transfusion
*Welch HG, et. al. Ann Int Med 1992
†Stamler JS, et. al. Science 1997
Packed red cells
Depleted of NO
Function as NO “sinks”
Lead to vasoconstriction, platelet aggregation, ineffective O2 delivery
Associated with increases in CRP and IL6*
*Fransen E, et. al. Chest 1999

20. Does Prevention of Bleeding Improve Long-term Outcome?

21. Cumulative Percentage of Events Time from randomization in days
1-Year Mortality
All patients
3.0
Heparin+GPIIb/IIIa
N=3008
Bivalirudin
2.5
N=2994
2.5%
2.0
1.9%
Cumulative Percentage of Events
1.5
1.0
p-value=0.16
0.5
0.0 60
120
180
240
300
360
Time from randomization in days

22. Bleeding vs. MI – Risk for mortality
Multivariable analysis of predictors of 1-year mortality
Independent Variable
Odds Ratio
(95% CI)
P Value
CrCl <30 mL/min
10.28
( )
<0.001
CHF
4.26
( )
<0.0001
Major hemorrhage
3.53
( )
MI at 30 days
2.59
( )
0.0005
Hx angina
2.11
( )
0.007
Diabetes
1.59
( )
0.018
Key Message: The REPLACE-2 regression analysis indicates that major bleeding was a significant predictor of mortality at 1 year, more so than MI or urgent revascularization.
Attubato MJ et al. Am J Cardiol. 2004;94(6 suppl 1):39E.

23. Major Bleeding: 9 Days HR 0.53 95% CI 0.45-0.62 P<<0.00001
Enoxaparin
0.04
HR 0.53
95% CI P<<
0.03
Cumulative Hazard
0.02
Fondaparinux
0.01
0.0 1 2 3 4 5 6 7 8 9
NEJM 2006;354: March 14
Days

24. Mortality: Day 30 HR 0.83 95% CI 0.71-0.97 P=0.022 Enoxaparin
0.03
Fondaparinux
0.02
Cumulative Hazard
HR 0.83
95% CI
P=0.022
0.01
0.0 3 6 9 12 15 18 21 24 27 30
NEJM 2006;354: March 14
Days

25. Relation Between Bleeding Reduction at 9 Days and Long Term Mortality
Deaths at 6 months
Patients with
Enox
Fonda
Difference
No Bleed
526
523 -3
Minor Bleed 33 13
-20
Major Bleed 79 38
-41
Total Deaths:
638
574
-64
- 61 (95.3%)
95.3% of difference in death at 6 months is explained
by bleeding within the first 9 days
NEJM 2006;354: March 14

26. Impact on Ischemic and Bleeding Endpoints and Long-term Mortality
Early Late
(re)-MI bleeding mortality
GUSTO V   =
REPLACE-2 =  
SYNERGY =  =
OASIS-5 =  
EXTRACT   ?
ACUITY =  ?
death/MI

27. How Might Bleeding Increase Long-Term Mortality?
Hemodynamic compromise
Hyperadrenergic state
Transfusion-induced microcirculatory disorder, NO depletion, immunologic effects
Inflammatory response
Discontinuation of antithrombotics

28. What else can be done to reduce bleeding?

29. Excessive Dosing of Anticoagulants by Age
42% of patients got excess
-- Alexander JAMA 2005;294:

30. Dosing Combinations and Transfusions: Heparin + GP IIb-IIIa Inhibitors*
* Among patients receiving both Heparin (UFH or LMWH) and GP IIb-IIIa Inhibitors
-- Alexander JAMA 2005;294:

31. ACS: Importance of Bleeding
Bleeding is at least as bad as recurrent MI with respect to long term impact
Each is associated with worse long term outcome and should be prevented
Strategies are needed to prevent thrombosis AND to prevent (or minimize) bleeding