1. BARC: The New Bleeding Definition How they differ from the US view on bleeding
Sunil V. Rao MD
The Duke Clinical Research Institute
Duke University Medical Center

2. Sunil V. Rao, MD Honoraria: Ikaria
My presentation will include off-label discussions:
Bivalirudin for ACS, Fondaparinux for ACS and Clopidogrel post-stent

3. Disclosures Research funding Consultant Speakers’ Bureau
Cordis Corporation, Ikaria, sanofi-aventis
Consultant
Zoll, Terumo Medical, Daiichi Sankyo-Lilly
Speakers’ Bureau
The Medicines Co, Abbott Vascular, Boehringer Ingelheim
Off-label uses of drugs or devices may be discussed during this lecture

4. Comparing “major” bleeding across ACS trials:
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:

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

6. “Major” Bleeding Data Elements
Definition
TIMI1
GUSTO1
CURE2
Trial
TRITON
CHARISMA
CURE
Major –
fatal / life threatening or severe bleeding
Fatal / life threatening (related to instrumentation, spontaneous, trauma), ICH, Hb ↓ ≥5 g/dL, or absolute
HCT ↓ ≥15%
Fatal, 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
PLATO3
PLATO
Fatal / Life threatening
Fatal, ICH, intrapericardial with tamponade, hypovolaemic shock / hypotension requiring pressors or surgery,
Hb ↓ >5 g/dL,
or transfusion ≥4 U
Other major
Disabling (intraocular with permanent vision loss),
Hb ↓ 3-5 g/dL, or transfusion 2-3 U
ICH = intracranial haemorrhage; PLATO = Platelet Inhibition and Patient Outcomes.
1. Rao SV, et al. J Am Coll Cardiol. 2006;47:
2. Yusuf S, et al. N Engl J Med. 2001;345:
3. Cannon CP, et al. J Am Coll Cardiol. 2007;50: 6 6

7. Effect of Bleeding Definition on 30-Day Death / MI
N=15,858 NSTE ACS Patients from PURSUIT and PARAGON B
1.19 (1.01, 1.41)
GUSTO Mild
GUSTO Moderate
1.92 (1.58, 2.34)
3.48 (2.56, 4.73)
GUSTO Severe
TIMI Minimal
1.13 (0.97, 1.33)
1.08 (0.85, 1.36)
TIMI Minor
TIMI Major
1.00 (0.85, 1.20)
Decreased Risk
1.00
Increased Risk
Hazard ratio (95% confidence interval).
Rao SV, et al. J Am Coll Cardiol. 2006;47:

8. 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, et. al. JACC 2010

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

10. What data elements should bleeding definitions use?
Bleeding Academic Research
Consortium (BARC)
Eliminate subjective terms like “Major,” “Minor, “ etc.
Include CABG-related bleeding
Rely on adjudication to determine bleeding-related deaths
Rao SV, et. al. AHJ 2009

11. BARC Bleeding Type 0: No bleeding
Type 1: Bleeding that is not actionable, patient does not seek unscheduled performance of studies, hospitalization, or treatment
Type 2: Overt actionable type of bleeding
Does not meet criteria for Types 3, 4, or 5
Does require evaluation by a medical professional, require non-surgical intervention by a medical professional, lead to hospitalization or increased level of care
Type 3
3a – Overt bleeding with hgb drop 3 to < 5 g/dl, or any transfusion
3b – Overt bleeding with hgb drop ≥ 5 g/dl, tamponade, requiring surgical intervention, requiring pressors
3c – ICH or intra-ocular
Type 4 – CABG-related bleeding
Type 5: Fatal bleeding
5a – Probable fatal bleeding
5b – Definite fatal bleeding
Mehran R, et. al. Circulation 2011

12. ESC guidelines: Bleeding complications
Assessment of bleeding risk is an important part of the decision-making process and should be taken into account when deciding on a treatment strategy (I-B)
Minor bleeding should be managed without interruption of active Rx (I-C)
Major bleeding requires interruption/neutralization of antithrombotic Rx unless it can be adequately controlled (I-C)
The decision to transfuse should be made individually but withheld in stable patients with Hct > 25% or Hgb > 8g/dl (I-C)
Bassand JP. European Heart Journal 2007

13. The US view on bleeding: Informal polls www.crtonline.org

14. Summary The US view on bleeding has evolved
Guidelines slowly starting to recognize the prognostic importance of this complication
Clinical community ahead of the guidelines
European Society has been a leader
BARC is a new approach
Not perfect, but a start
Common lexicon to facilitate clinical care (choosing across therapeutic options)
Will need to be “validated”