Standardized Bleeding Definitions for Cardiovascular Clinical Trials

HomeCirculationVol. 123, No. 23Standardized Bleeding Definitions for Cardiovascular Clinical Trials Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplementary MaterialsFree AccessResearch ArticlePDF/EPUBStandardized Bleeding Definitions for Cardiovascular Clinical TrialsA Consensus Report From the Bleeding Academic Research Consortium Roxana Mehran, MD, Sunil V. Rao, MD, Deepak L. Bhatt, MD, MPH, C. Michael Gibson, MS, MD, Adriano Caixeta, MD, PhD, John Eikelboom, MD, MBBS, Sanjay Kaul, MD, Stephen D. Wiviott, MD, Venu Menon, MD, Eugenia Nikolsky, MD, PhD, Victor Serebruany, MD, PhD, Marco Valgimigli, MD, PhD, Pascal Vranckx, MD, David Taggart, MD, PhD, Joseph F. Sabik, MD, Donald E. Cutlip, MD, Mitchell W. Krucoff, MD, E. Magnus Ohman, MD, Philippe Gabriel Steg, MD and Harvey White, MB, ChB, DSc Roxana MehranRoxana Mehran The BARC represents a collaboration of independent academic research organizations (Cardialysis, Rotterdam, the Netherlands; Cardiovascular Research Foundation, New York City, NY; Duke Clinical Research Institute, Durham, NC; TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA; Harvard Clinical Research Institute, Boston, MA; Green Lane Coordinating Centre, Auckland, New Zealand; Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, OH; and PERFUSE, Boston, MA), professional societies (European Society of Cardiology, and Society of Cardiac Angiography and Intervention), federal agencies (the US FDA, National Institutes of Health), and independent expert scientists and consultants (Appendix). Search for more papers by this author , Sunil V. RaoSunil V. Rao The BARC represents a collaboration of independent academic research organizations (Cardialysis, Rotterdam, the Netherlands; Cardiovascular Research Foundation, New York City, NY; Duke Clinical Research Institute, Durham, NC; TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA; Harvard Clinical Research Institute, Boston, MA; Green Lane Coordinating Centre, Auckland, New Zealand; Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, OH; and PERFUSE, Boston, MA), professional societies (European Society of Cardiology, and Society of Cardiac Angiography and Intervention), federal agencies (the US FDA, National Institutes of Health), and independent expert scientists and consultants (Appendix). Search for more papers by this author , Deepak L. BhattDeepak L. Bhatt The BARC represents a collaboration of independent academic research organizations (Cardialysis, Rotterdam, the Netherlands; Cardiovascular Research Foundation, New York City, NY; Duke Clinical Research Institute, Durham, NC; TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA; Harvard Clinical Research Institute, Boston, MA; Green Lane Coordinating Centre, Auckland, New Zealand; Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, OH; and PERFUSE, Boston, MA), professional societies (European Society of Cardiology, and Society of Cardiac Angiography and Intervention), federal agencies (the US FDA, National Institutes of Health), and independent expert scientists and consultants (Appendix). Search for more papers by this author , C. Michael GibsonC. Michael Gibson The BARC represents a collaboration of independent academic research organizations (Cardialysis, Rotterdam, the Netherlands; Cardiovascular Research Foundation, New York City, NY; Duke Clinical Research Institute, Durham, NC; TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA; Harvard Clinical Research Institute, Boston, MA; Green Lane Coordinating Centre, Auckland, New Zealand; Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, OH; and PERFUSE, Boston, MA), professional societies (European Society of Cardiology, and Society of Cardiac Angiography and Intervention), federal agencies (the US FDA, National Institutes of Health), and independent expert scientists and consultants (Appendix). Search for more papers by this author , Adriano CaixetaAdriano Caixeta The BARC represents a collaboration of independent academic research organizations (Cardialysis, Rotterdam, the Netherlands; Cardiovascular Research Foundation, New York City, NY; Duke Clinical Research Institute, Durham, NC; TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA; Harvard Clinical Research Institute, Boston, MA; Green Lane Coordinating Centre, Auckland, New Zealand; Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, OH; and PERFUSE, Boston, MA), professional societies (European Society of Cardiology, and Society of Cardiac Angiography and Intervention), federal agencies (the US FDA, National Institutes of Health), and independent expert scientists and consultants (Appendix). Search for more papers by this author , John EikelboomJohn Eikelboom The BARC represents a collaboration of independent academic research organizations (Cardialysis, Rotterdam, the Netherlands; Cardiovascular Research Foundation, New York City, NY; Duke Clinical Research Institute, Durham, NC; TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA; Harvard Clinical Research Institute, Boston, MA; Green Lane Coordinating Centre, Auckland, New Zealand; Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, OH; and PERFUSE, Boston, MA), professional societies (European Society of Cardiology, and Society of Cardiac Angiography and Intervention), federal agencies (the US FDA, National Institutes of Health), and independent expert scientists and consultants (Appendix). Search for more papers by this author , Sanjay KaulSanjay Kaul The BARC represents a collaboration of independent academic research organizations (Cardialysis, Rotterdam, the Netherlands; Cardiovascular Research Foundation, New York City, NY; Duke Clinical Research Institute, Durham, NC; TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA; Harvard Clinical Research Institute, Boston, MA; Green Lane Coordinating Centre, Auckland, New Zealand; Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, OH; and PERFUSE, Boston, MA), professional societies (European Society of Cardiology, and Society of Cardiac Angiography and Intervention), federal agencies (the US FDA, National Institutes of Health), and independent expert scientists and consultants (Appendix). Search for more papers by this author , Stephen D. WiviottStephen D. Wiviott The BARC represents a collaboration of independent academic research organizations (Cardialysis, Rotterdam, the Netherlands; Cardiovascular Research Foundation, New York City, NY; Duke Clinical Research Institute, Durham, NC; TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA; Harvard Clinical Research Institute, Boston, MA; Green Lane Coordinating Centre, Auckland, New Zealand; Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, OH; and PERFUSE, Boston, MA), professional societies (European Society of Cardiology, and Society of Cardiac Angiography and Intervention), federal agencies (the US FDA, National Institutes of Health), and independent expert scientists and consultants (Appendix). Search for more papers by this author , Venu MenonVenu Menon The BARC represents a collaboration of independent academic research organizations (Cardialysis, Rotterdam, the Netherlands; Cardiovascular Research Foundation, New York City, NY; Duke Clinical Research Institute, Durham, NC; TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA; Harvard Clinical Research Institute, Boston, MA; Green Lane Coordinating Centre, Auckland, New Zealand; Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, OH; and PERFUSE, Boston, MA), professional societies (European Society of Cardiology, and Society of Cardiac Angiography and Intervention), federal agencies (the US FDA, National Institutes of Health), and independent expert scientists and consultants (Appendix). Search for more papers by this author , Eugenia NikolskyEugenia Nikolsky The BARC represents a collaboration of independent academic research organizations (Cardialysis, Rotterdam, the Netherlands; Cardiovascular Research Foundation, New York City, NY; Duke Clinical Research Institute, Durham, NC; TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA; Harvard Clinical Research Institute, Boston, MA; Green Lane Coordinating Centre, Auckland, New Zealand; Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, OH; and PERFUSE, Boston, MA), professional societies (European Society of Cardiology, and Society of Cardiac Angiography and Intervention), federal agencies (the US FDA, National Institutes of Health), and independent expert scientists and consultants (Appendix). Search for more papers by this author , Victor SerebruanyVictor Serebruany The BARC represents a collaboration of independent academic research organizations (Cardialysis, Rotterdam, the Netherlands; Cardiovascular Research Foundation, New York City, NY; Duke Clinical Research Institute, Durham, NC; TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA; Harvard Clinical Research Institute, Boston, MA; Green Lane Coordinating Centre, Auckland, New Zealand; Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, OH; and PERFUSE, Boston, MA), professional societies (European Society of Cardiology, and Society of Cardiac Angiography and Intervention), federal agencies (the US FDA, National Institutes of Health), and independent expert scientists and consultants (Appendix). Search for more papers by this author , Marco ValgimigliMarco Valgimigli The BARC represents a collaboration of independent academic research organizations (Cardialysis, Rotterdam, the Netherlands; Cardiovascular Research Foundation, New York City, NY; Duke Clinical Research Institute, Durham, NC; TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA; Harvard Clinical Research Institute, Boston, MA; Green Lane Coordinating Centre, Auckland, New Zealand; Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, OH; and PERFUSE, Boston, MA), professional societies (European Society of Cardiology, and Society of Cardiac Angiography and Intervention), federal agencies (the US FDA, National Institutes of Health), and independent expert scientists and consultants (Appendix). Search for more papers by this author , Pascal VranckxPascal Vranckx The BARC represents a collaboration of independent academic research organizations (Cardialysis, Rotterdam, the Netherlands; Cardiovascular Research Foundation, New York City, NY; Duke Clinical Research Institute, Durham, NC; TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA; Harvard Clinical Research Institute, Boston, MA; Green Lane Coordinating Centre, Auckland, New Zealand; Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, OH; and PERFUSE, Boston, MA), professional societies (European Society of Cardiology, and Society of Cardiac Angiography and Intervention), federal agencies (the US FDA, National Institutes of Health), and independent expert scientists and consultants (Appendix). Search for more papers by this author , David TaggartDavid Taggart The BARC represents a collaboration of independent academic research organizations (Cardialysis, Rotterdam, the Netherlands; Cardiovascular Research Foundation, New York City, NY; Duke Clinical Research Institute, Durham, NC; TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA; Harvard Clinical Research Institute, Boston, MA; Green Lane Coordinating Centre, Auckland, New Zealand; Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, OH; and PERFUSE, Boston, MA), professional societies (European Society of Cardiology, and Society of Cardiac Angiography and Intervention), federal agencies (the US FDA, National Institutes of Health), and independent expert scientists and consultants (Appendix). Search for more papers by this author , Joseph F. SabikJoseph F. Sabik The BARC represents a collaboration of independent academic research organizations (Cardialysis, Rotterdam, the Netherlands; Cardiovascular Research Foundation, New York City, NY; Duke Clinical Research Institute, Durham, NC; TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA; Harvard Clinical Research Institute, Boston, MA; Green Lane Coordinating Centre, Auckland, New Zealand; Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, OH; and PERFUSE, Boston, MA), professional societies (European Society of Cardiology, and Society of Cardiac Angiography and Intervention), federal agencies (the US FDA, National Institutes of Health), and independent expert scientists and consultants (Appendix). Search for more papers by this author , Donald E. CutlipDonald E. Cutlip The BARC represents a collaboration of independent academic research organizations (Cardialysis, Rotterdam, the Netherlands; Cardiovascular Research Foundation, New York City, NY; Duke Clinical Research Institute, Durham, NC; TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA; Harvard Clinical Research Institute, Boston, MA; Green Lane Coordinating Centre, Auckland, New Zealand; Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, OH; and PERFUSE, Boston, MA), professional societies (European Society of Cardiology, and Society of Cardiac Angiography and Intervention), federal agencies (the US FDA, National Institutes of Health), and independent expert scientists and consultants (Appendix). Search for more papers by this author , Mitchell W. KrucoffMitchell W. Krucoff The BARC represents a collaboration of independent academic research organizations (Cardialysis, Rotterdam, the Netherlands; Cardiovascular Research Foundation, New York City, NY; Duke Clinical Research Institute, Durham, NC; TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA; Harvard Clinical Research Institute, Boston, MA; Green Lane Coordinating Centre, Auckland, New Zealand; Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, OH; and PERFUSE, Boston, MA), professional societies (European Society of Cardiology, and Society of Cardiac Angiography and Intervention), federal agencies (the US FDA, National Institutes of Health), and independent expert scientists and consultants (Appendix). Search for more papers by this author , E. Magnus OhmanE. Magnus Ohman The BARC represents a collaboration of independent academic research organizations (Cardialysis, Rotterdam, the Netherlands; Cardiovascular Research Foundation, New York City, NY; Duke Clinical Research Institute, Durham, NC; TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA; Harvard Clinical Research Institute, Boston, MA; Green Lane Coordinating Centre, Auckland, New Zealand; Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, OH; and PERFUSE, Boston, MA), professional societies (European Society of Cardiology, and Society of Cardiac Angiography and Intervention), federal agencies (the US FDA, National Institutes of Health), and independent expert scientists and consultants (Appendix). Search for more papers by this author , Philippe Gabriel StegPhilippe Gabriel Steg The BARC represents a collaboration of independent academic research organizations (Cardialysis, Rotterdam, the Netherlands; Cardiovascular Research Foundation, New York City, NY; Duke Clinical Research Institute, Durham, NC; TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA; Harvard Clinical Research Institute, Boston, MA; Green Lane Coordinating Centre, Auckland, New Zealand; Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, OH; and PERFUSE, Boston, MA), professional societies (European Society of Cardiology, and Society of Cardiac Angiography and Intervention), federal agencies (the US FDA, National Institutes of Health), and independent expert scientists and consultants (Appendix). Search for more papers by this author and Harvey WhiteHarvey White The BARC represents a collaboration of independent academic research organizations (Cardialysis, Rotterdam, the Netherlands; Cardiovascular Research Foundation, New York City, NY; Duke Clinical Research Institute, Durham, NC; TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA; Harvard Clinical Research Institute, Boston, MA; Green Lane Coordinating Centre, Auckland, New Zealand; Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, OH; and PERFUSE, Boston, MA), professional societies (European Society of Cardiology, and Society of Cardiac Angiography and Intervention), federal agencies (the US FDA, National Institutes of Health), and independent expert scientists and consultants (Appendix). Search for more papers by this author Originally published14 Jun 2011https://doi.org/10.1161/CIRCULATIONAHA.110.009449Circulation. 2011;123:2736–2747Advances in antithrombotic therapy, along with an early invasive strategy, have reduced the incidence of recurrent ischemic events and death in patients with acute coronary syndromes (ACS; unstable angina, non–ST-segment–elevation myocardial infarction [MI], and ST-segment–elevation MI).1–4 However, the combination of multiple pharmacotherapies, including aspirin, platelet P2Y12 inhibitors, heparin plus glycoprotein IIb/IIIa inhibitors, direct thrombin inhibitors, and the increasing use of invasive procedures, has also been associated with an increased risk of bleeding.Editorial see p 2664Bleeding complications have been associated with an increased risk of subsequent adverse outcomes, including MI, stroke, stent thrombosis, and death, in patients with ACS and in those undergoing percutaneous coronary intervention (PCI),5–10 as well as in the long-term antithrombotic setting.11,12 Thus, balancing the anti-ischemic benefits against the bleeding risk of antithrombotic agents and interventions is of paramount importance in assessing new therapies and in managing patients. Prior randomized trials comparing antithrombotic agents suggest that a reduction in bleeding events is associated with improved survival.13,14Because prevention of major bleeding may represent an important step in improving outcomes by balancing safety and efficacy in the contemporary treatment of ACS, bleeding events have been systematically identified as a crucial end point for the assessment of the safety of drugs during the course of randomized clinical trials, and are an important aspect of the evaluation of new devices and interventional therapies.15 Unlike ischemic clinical events (eg, cardiac death, MI, stent thrombosis), for which there is now general consensus on end-point definitions,16,17 there is substantial heterogeneity among the many bleeding definitions currently in use. Lack of standardization makes it difficult to optimally organize key clinical trial processes such as adjudication, and even more difficult to interpret relative safety comparisons of different antithrombotic agents across studies, or even within a given trial, because results may vary according to the definition(s) used for bleeding. Finally, as reflected by the various terms used to describe bleeding (serious, severe, catastrophic, major, life-threatening, etc), the heterogeneity of definitions may undermine the ability of clinical trials to meaningfully define the balance of safety and efficacy in vascular interventions.In response to the need to develop, disseminate, and ultimately adopt standardized bleeding end-point definitions for patients receiving antithrombotic therapy, the Bleeding Academic Research Consortium (BARC) convened in February 2010 at the US Food and Drug Administration (FDA) headquarters in White Oak, MD. Modeled after the 2006 Academic Research Consortium, which standardized key ischemic end-point definitions in studies aimed at evaluating coronary stents,17 the BARC effort brought together representatives from academic research organizations, the FDA, the National Institutes of Health, and pharmaceutical and cardiovascular device manufacturers and independent physician thought leaders in the field of cardiovascular disease to develop consensus bleeding definitions that would be useful for cardiovascular clinical trials. Application of these definitions is recommended for both clinical trials and registries.Importance of Bleeding as an End PointHemorrhagic complications occur with a frequency of 1% to 10% during treatment for ACS and after PCI.18–20 This wide variability in the measured incidence is due to several factors, including differences in patient characteristics, concomitant therapies, timing of event reporting, and definitions across data sets. Regardless of the definition used, several studies have demonstrated that bleeding is associated with an increased risk for short- and long-term adverse outcomes, including death,18,20 nonfatal MI,6 stroke,5 and stent thrombosis.9 The exact mechanisms underlying this relationship are not known, but may include the cessation of evidence-based therapies, including antiplatelet agents, β-blockers, and/or statin therapies, in patients who suffer bleeding complications,21,22 the direct effects of blood transfusion used to treat bleeding,20,23 or greater prevalence of comorbidities in patients who bleed,21 as well as a deleterious role of anemia.24The relationship between bleeding and morbidity and mortality is underscored by studies demonstrating that bleeding reduction strategies are associated with improved survival in patients with ACS and those undergoing PCI. The data summarized inTable 1 emphasize the importance of bleeding as a common, clinically relevant safety event. To optimize both the end point and its role in clinical trial designs, a consistent approach to collecting bleeding data and adjudicating events is critical.30 Toward this end, a thoughtful, broadly based consensus definition of what constitutes a bleeding event, similar to what has been done with MI and stent thrombosis, is the objective of BARC efforts.17Table 1. Impact of Major Bleeding on Mortality in Registries and Randomized Trials of Patients With Acute Coronary Syndromes or Undergoing Percutaneous Coronary InterventionsStudySetting, DesignPrimary Definition*PatientsPatients With Bleeding, n (%)Outcomes in Patients With Major or Severe Bleeding vs No BleedingEarly Deaths (In Hospital or at 30 d)Deaths up to 1 yDeath Rates, %Adjusted Risk Ratio for Death (95% CI)Death Rates, %Adjusted Risk Ratio for Death (95% CI)Kinnaird et al,7 2003PCI, registryTIMI10 974588 (5.4)7.5 vs 0.63.5 (1.9–6.7)17.2 vs 5.5Not significant†GRACE,10 2003ACS, registryGRACE24 045933 (3.9)18.6 vs 5.11.6 (1.2–2.3)……GRACE,21 2007ACS, registryGRACE40 0871140 (2.8)20.9 vs 5.61.9 (1.6–2.2)7.9 vs 5.20.8 (0.6–1.0)REPLACE-2,25 2007PCI, RCTREPLACE-2/ISAR-REACT 36001195 (3.2)5.1 vs 0.2…8.7 vs 1.92.7 (1.4–4.9)Rao et al,6 2005NSTE-ACS, meta-analysis of RCTsGUSTO26 452107 (0.4)25.7 vs 2.910.6 (8.3–13.6)35.1 vs 4.27.5 (6.1–9.3)Eikelboom et al,5 2006NSTE-ACS, meta-analysis of RCTs/registryCURE34 146783 (2.3)12.8 vs 2.59.8 (7.5–12.7)4.6 vs 2.9‡1.9 (1.3–2.8)ACUITY,9 2007NSTE-ACS, RCTACUITY13 819644 (4.7)7.3 vs 1.27.6 (4.7–12.2)…3.5 (2.7–4.4)Ndrepepa et al,15 2008PCI, meta-analysis of RCTsTIMI5384215 (4.0; n=59 major/n=156 minor)……12.2 vs 3.34.1 (2.1–8.3)EVENT,26 2009PCI, registryTIMI5961(3.0 overall: 0.7 major, 2.3 minor)……15.6 vs 2.43.8 (2.5–5.9)OASIS-5,27 2009NSTE-ACS, RCTESSENCE20 078990 (4.9): major, 423 (2.1) minor8.4 vs 2.73.5 (2.6–4.6)14.3 vs 5.43.1 (2.6–3.8)Amlani et al,28 2010STEMI, registryProtocol defined1389152 (10.9)19.7 vs 8.22.8 (1.8–4.3)……ISAR-REACT 3,29 2010PCI, RCTREPLACE-2/ISAR-REACT 34570555 (12.1) 174 major/381 minor……5.2 vs 1.34.1 (2.6–6.5)CI indicates confidence interval; PCI, percutaneous coronary intervention; TIMI, Thrombolysis in Myocardial Infarction; ACS, acute coronary syndrome; GRACE, Global Registry of Acute Coronary Events; RCT, randomized controlled trial; REPLACE-2, Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events; ISAR-REACT 3, Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment; NSTE, non–ST-elevation; GUSTO, Global Use of Strategies to Open Occluded Arteries; CURE, Clopidogrel in Unstable Angina to Prevent Recurrent Events; ACUITY, Acute Catheterization and Urgent Intervention Triage Strategy; EVENT, Evaluation of Drug Eluting Stents and Ischemic Events; and OASIS-5, Organization for the Assessment of Strategies for Ischemic Syndromes.*For Definitions, please seeTable 2.†Data not provided.‡Events between 30 days and 6 months.Bleeding Academic Research Consortium Composition and GoalsAn informal collaboration among academic research organizations from the United States and Europe, joined by representatives from the FDA and device manufacturers, led to a consensus document to standardize clinical end points for coronary stent trials.17 This Academic Research Consortium developed a rapid, scholarly, and clinically relevant process resulting in a portfolio of clinical end-point definitions that were endorsed by the FDA and broadly incorporated into clinical trial end points.31,32 The Academic Research Consortium process was a demonstration of effective collaboration among the academic community, FDA, and industry to respond to safety concerns over drug-eluting stents and to improve the conduct of clinical research. This initiative has since been expanded to other clinical domains, including percutaneous valves and peripheral arterial disease, and the effort to establish standardized bleeding definitions presented in this consensus document. These standardized definitions are intended to allow the clinical community to determine the relative safety of different antithrombotic strategies, to provide the industry with a framework in which to evaluate the safety of emerging antithrombotic therapies, and potentially to enhance the regulatory review of new anticoagulant and antiplatelet drugs.Heterogeneity of Bleeding Definitions Across TrialsSeveral definitions of bleeding have been used in published clinical trials and registries.33–35Table 2 highlights the lack of uniformity in bleeding definitions among recent ACS and PCI clinical trials. Current bleeding definitions consist of both laboratory parameters, such as decreases in hemoglobin and hematocrit scores, and clinical events, including the need for transfusion or surgery, cardiac tamponade, hematomas, and various degrees of bleeding. Each definition incorporates a different combination of these data elements and then rank orders these combinations into severity categories, which vary widely between definitions.Table 2. Heterogeneity in Bleeding Definitions Used in Acute Coronary Syndrome TrialsTrialBleeding DefinitionTIMI6,37,38Non-CABG related bleeding Major Any intracranial bleeding (excluding microhemorrhages <10 mm evident only on gradient-echo MRI)Clinically overt signs of hemorrhage associated with a drop in hemoglobin of ≥5 g/dLFatal bleeding (bleeding that directly results in death within 7 d)Minor Clinically overt (including imaging), resulting in hemoglobin drop of 3 to <5 g/dLRequiring medical attention Any overt sign of hemorrhage that meets one of the following criteria and does not meet criteria for a major or minor bleeding event, as defined aboveRequiring intervention (medical practitioner-guided medical or surgical treatment to stop or treat bleeding, including temporarily or permanently discontinuing or changing the dose of a medication or study drug)Leading to or prolonging hospitalizationPrompting evaluation (leading to an unscheduled visit to a healthcare professional and diagnostic testing, either laboratory or imaging)Minimal Any overt bleeding event that does not meet the criteria aboveBleeding in the setting of CABG Fatal bleeding (bleeding that directly results in death)Perioperative intracranial bleedingReoperation after closure of the sternotomy incision for the purpose of controlling bleedingTransfusion of ≥5 U PRBCs or whole blood within a 48-h period; cell saver transfusion will not be counted in calculations of blood products.Chest tube output >2 L within a 24-h periodGUSTO24Severe or life-threatening Intracerebral hemorrhageResulting in substantial hemodynamic compromise requiring treatmentModerate Requiring blood transfusion but not resulting in hemodynamic compromiseMild Bleeding that does not meet above criteriaCURE5Major bleeding Life-threatening (fatal, intracranial, requiring surgical intervention, results in substantial hypotension requiring the use of intravenous inotropic agents) Hemoglobin decrease ≥5 g/dL or required ≥4 U of bloodOther major bleed