1. Pitfalls of the Current Bleeding Definitions
Sunil V. Rao MD
Assistant Professor of Medicine
Duke University Medical Center
Durham VA Medical Center
Duke Clinical Research Institute

2. Sunil V. Rao, MD DISCLOSURES Consulting Fees Honoraria
The Medicines Company, Bristol-Myers Squibb, Astra Zeneca
Honoraria
sanofi-aventis U.S. LLC
Grants/Contracted Research
Cordis, a Johnson & Johnson company, Momenta Pharmaceuticals, Inc., Portola Pharmaceuticals, Inc.
I intend to reference unlabeled/ unapproved uses of drugs or devices in my presentation.
I intend to reference Bivalirudin and Fondaparinux for ACS; Enoxaparin for PCI; Clopidogrel for stenting.

3. Disclosures Consultant, Speakers’ Bureau, Honoraria
Sanofi-Aventis, Bristol Myers Squibb
The Medicines Company
Astra Zeneca
Research funding
Cordis Corporation
Momenta Pharmaceuticals
Portola Pharmaceuticals
Off-label uses of drugs/devices may be discussed
Fondaparinux in NSTE ACS
Enoxaparin in PCI
Bivalirudin in NSTE ACS

4. Bleeding definitions Pitfalls
Bleeding definitions and Data elements
Bleeding and outcomes
What are the definitions designed to do?
What should the definitions do?
Future directions

5. Major bleeding definitions – a sampling
TIMI1
GUSTO1
CURE2
ACUITY3
TRITON
GUSTO, CHARISMA
CURE
ACUITY, HORIZONS-AMI
Fatal / life threatening (related to instrumentation, spontaneous, trauma), ICH, Hb ↓ ≥5 g/dL, or absolute
HCT ↓ ≥15%
ICH,
or causes haemodynamic compromise and requires intervention
Fatal / Life threatening
Fatal, ICH, requires surgery, hypotension requiring inotropes,
Hb ↓ ≥5 g/dL,
or transfusion ≥4 U
Other major
Disabling, intraocular
with vision loss, or transfusion 2-3 U
Intracranial, Retroperitoneal, Intraocular, Access site hemorrhage requiring surgical intervention, 5cm diameter hematoma, Reduction in hemoglobin concentration of 4g/dL without an overt source of bleeding or 3g/dL with an overt source of bleeding, Re-operation for bleeding, Use of any blood product transfusion
1. Rao SV, et al. J Am Coll Cardiol. 2006;47:
2. Yusuf S, et al. N Engl J Med. 2001;345:
3. Stone GW, et. Ak. N Engl J Med 2006;355:

6. Comparing “major” bleeding across ACS trials: Is it the patients, the trial, or the definition?
9.1 1 2 3 4 5
Percent
3.7
2.4
1.7
1.5
Eptifibatide + UFH
(GUSTO severe)
ASA + clopidogrel
Enoxaparin
ASA + prasugrel
The PURSUIT Investigators. N Engl J Med ; Yusuf S, et al. N Engl J Med. 2001
SYNERGY Trial Investigators. JAMA. 2004; Wiviott SD, et al. N Eng J Med. 2007
Bhatt DL, et al. N Engl J Med. 2006;354:

7. Kaplan Meier Curves for 30-Day Death, Stratified by Bleed Severity
Bleeding & Outcomes N=26,452 pts from PURSUIT, GUSTO IIb, PARAGON A & B
Kaplan Meier Curves for 30-Day Death, Stratified by Bleed Severity
log rank p-value for all four categories <0.0001
log-rank p-value for no bleeding vs. mild bleeding = 0.02
log-rank p-value for mild vs. moderate bleeding <0.0001
log-rank p-value for moderate vs. severe <0.001
Rao SV, et al. Am J Cardiol. 2005

8. TIMI bleeding and mortality N=10,974 PCI patients
In-hospital death
TIMI Major bleeding
Transfusion ≥ 2U
1-year death
Transfusion ≥ 2U
Odds ratio for death
Kinnaird et al. Am J Cardiol 2003

9. CURE Bleeding and Outcomes
N=34,146 ACS Patients from OASIS Registry, OASIS-2, and CURE 25 20 15 10 5
Mortality, % 30 60 90
120
180
150
No bleeding
Minor bleeding
Major bleeding
Life threatening
Days
OASIS = Organization to Assess Strategies for Ischemic Syndromes.
Eikelboom JW, et al. Circulation. 2006;114:

10. ACUITY major bleeding and outcomes N=13,819
Manoukian SV, et. al. JACC 2007

11. Transfusion in ACS N=24,111 pts from PURSUIT, PARAGON B, GUSTO IIb
Rao SV, et. al., JAMA 2004

12. Effect of Bleeding Definition on the Association of Bleeding and Death/MI
N=15,858 ACS patients from PURSUIT & PARAGON B
30-day death/MI
GUSTO Mild
GUSTO Moderate
TIMI Minimal
TIMI Minor
TIMI Major
1.00
Increased Risk
Decreased Risk
1.00 (0.85, 1.20)
1.08 (0.85, 1.36)
1.13 (0.97, 1.33)
3.48 (2.56, 4.73)
1.92 (1.58, 2.34)
1.19 (1.01, 1.41)
GUSTO Severe
Rao et al. JACC 2006.

13. Major bleeding data elements and outcomes: N=22,000 pts from REPLACE-2, ACUITY, HORIZONS-AMI
Event
Hazard ratio (95% CI)
Deaths within 1 y, n p
TIMI major bleed
4.85 (3.56–6.60) 53
<0.001
Non-TIMI major bleed with transfusion
2.98 (2.10–4.24) 40
Non-TIMI major bleed without transfusion
1.79 (1.09–2.93) 17
0.021
Large (≥5 cm) hematoma only
1.30 (0.58–2.92) 6
0.53
Mehran R. European Society of Cardiology 2009 Congress; September 2, 2009; Barcelona, Spain.

14. Hematomas and outcomes: N=3342 pts from STEEPLE
White HD, et. al. AHJ 2009

15. “Nuisance” Bleeding and Drug Discontinuation
N=2360 unselected pts. receiving DES
Prospective data collection
Major events adjudicated
Serebruany bleeding classification*
% discontinued
Even “nuisance’ bleeding can impact adherence. In this study, 11% of patients with nuisance bleeding discontinued their clopidogrel despite having a DES
*Alarming bleeding = ICH, life-threatening, + transfusion
Internal bleeding = hematoma, epistaxis, mouth or vaginal,
Melena, IO, hematuria or hematemesis
Nuisance bleeding = bruising, petechiae, ecchymosis
Overall rate of bleeding=32.4%
Roy P, et. al. AJC 2008

16. Bleeding and Evidence-based Therapies N=2498 ACS patients from the PREMIER Registry
Discharge ASA and thienopyridine
Pts. with bleeding vs. pts. without bleeding
Aspirin
OR (95% CI)
Thienopyridine
OR (95% CI)
0.45 (0.31, 0.64)
0.62 (0.42, 0.91)
Discharge
1 Month
6 Months
1 Year
0.68 (0.50, 0.92)
0.83 (0.59, 1.17)
0.63 (0.46, 0.87)
1.06 (0.78, 1.45)
Regardless of the bleeding definition that is used, the occurrence of a hemorrhagic complication is associated with a significant decrease in long-term medication adherence as seen in this study from the PREMIER registry
0.94 (0.66, 1.34)
1.12 (0.81, 1.55)
Wang TY, et. al. Circulation 2008

17. Deconstructing Definitions: Importance of data elements
Bleeding definition
Data Elements
Clinical
Laboratory
Consequences
ICH
Hematoma
Hemodynamic
compromise
Transfusion
Fatal
Hgb decrease
Severity Classification

18. What are bleeding definitions designed to do?
Assess the bleeding risk of a therapeutic strategy
BUT…the “risk” can be dialed up or down depending on the definition
So…what should bleeding definitions do?
They should allow clinicians to weight the risks and benefits of one therapy against another

19. What data elements should bleeding definitions use?
Rao SV, et. al. AHJ 2009

20. ABC Recommendations
Rao SV, et. al. AHJ 2009

21. Pitfalls of the current bleeding definitions
Little overlap in data elements
Some “major” definitions are considered “minor” by other scales and vice versa
Risk of “gaming” safety data
Although many appear to be associated with mortality, very few studies have directly compared two definitions in terms of prognosis

22. Arguments for and against a universal bleeding definition
Minimizes “gaming”
Allows for comparison across therapies
Would include clinically important data elements
There is precedent (MI, stent thrombosis)
Many definitions are associated with mortality
Doesn’t allow tailoring of trial designs
Medical Rx vs. PCI
Allows for post-hoc (or prespecified) reconstruction of traditional bleeding definitions

23. Pitfalls of the current bleeding definitions Conclusions
Many definitions are associated with adverse outcomes
Data elements are important
Some overlap across definitions; Many do not
“Minor” bleeding appears important in terms of medication adherence
Some studies call this “Major” bleeding

24. Pitfalls of the current bleeding definitions Conclusions
There are arguments for and against a universal bleeding definition
But, the time has probably come for a consensus definition
BARC meeting – 2/25/10

25. Duke Univ. Medical Center Duke Clinical Research Institute