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

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

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

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. 1998 ; 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;354:1706-1717.

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

“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;47:809-816. 2. Yusuf S, et al. N Engl J Med. 2001;345:494-502. 3. Cannon CP, et al. J Am Coll Cardiol. 2007;50:1844-1851. 6 6

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;47:809-816.

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

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

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

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

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

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

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”