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Online Table 1. Key elements of the bleeding classifications used in this analysis BARC bleeding definition1 Type 0 No bleeding Type 1 Bleeding that is not actionable and does not cause the patient to seek unscheduled performance of studies, hospitalization, or treatment by a health care professional; may include episodes leading to selfdiscontinuation of medical therapy by the patient without consulting a health care professional Type 2 Any overt, actionable sign of hemorrhage (e.g., more bleeding than would be expected for a clinical circumstance, including bleeding found by imaging alone) that does not fit the criteria for type 3, 4, or 5 but does meet at least one of the following criteria: (1) Requiring nonsurgical, medical intervention by a health care professional (2) Leading to hospitalization or increased level of care (3) Prompting evaluation Type 3 Type 3a Overt bleeding plus hemoglobin drop of 3 to <5 g/dL* (provided hemoglobin drop is related to bleed) Any transfusion with overt bleeding Type 3b Overt bleeding plus hemoglobin drop ≥5 g/dL* (provided hemoglobin drop is related to bleed) Cardiac tamponade Bleeding requiring surgical intervention for control (excluding dental/nasal/skin/hemorrhoid) Bleeding requiring intravenous vasoactive agents Type 3c Intracranial hemorrhage (does not include microbleeds or hemorrhagic transformation, does include intraspinal) Subcategories confirmed by autopsy or imaging or lumbar puncture Intraocular bleed compromising vision Type 4 Perioperative intracranial bleeding within 48 hours Reoperation after closure of sternotomy for the purpose of controlling bleeding Transfusion of ≥5 U whole blood or packed red blood cells within a 48-hour period (only allogenic transfusions are considered transfusions for CABG-related bleeds) Chest tube output ≥2 L within a 24-hour period Notes: If a CABG-related bleed is not adjudicated as at least a type-3 severity event, it will be classified as not a bleeding event. If a bleeding event occurs with a clear temporal relationship to CABG (i.e., within a 48-hour time frame) but does not meet type-4 severity criteria, it will be classified as not a bleeding event. Type 5 Type 5a Probable fatal bleeding; no autopsy or imaging confirmation but clinically suspicious Type 5b Definite fatal bleeding; overt bleeding or autopsy or imaging confirmation TIMI bleeding definition2* Major Intracranial hemorrhage or a ≥5 g/dL decrease in the hemoglobin concentration or a ≥15% absolute decrease in the hematocrit Minor Observed blood loss: ≥3 g/dL but <5 g/dL decrease in the hemoglobin concentration or ≥10% but <15% decrease in the hematocrit No observed blood loss: ≥4 g/dL decrease in the hemoglobin concentration or ≥12% decrease in the hematocrit Requiring for a major or minor bleeding event, as defined above medical attention Any overt sign of hemorrhage that meets one of the following criteria and does not meet criteria Requiring 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 hospitalization Prompting evaluation (leading to an unscheduled visit to a health care professional and diagnostic testing, either laboratory or imaging) GUSTO bleeding definition Severe or lifethreatening Moderate Mild Intracranial hemorrhage A bleeding event that causes hemodynamic compromise and requires intervention A bleeding event that requires blood transfusion but does not result in hemodynamic compromise Bleeding that does not meet above criteria *All BARC and TIMI definitions take into account blood transfusions, so that hemoglobin and hematocrit values are adjusted by 1 g/dL or 3%, respectively, for each unit of blood transfused. Therefore, the true change in hemoglobin or hematocrit if there has been an intervening transfusion between 2 blood measurements is calculated as follows: Δ Hemoglobin (Hgb) = [baseline Hgb - post-transfusion Hgb] + [number of transfused units]; ΔHematocrit (Hct) = [baseline Hct - post-transfusion Hct] + [number of transfused units x 3]. BARC: Bleeding Academic Research Consortium, GUSTO: Global Strategies for Opening Occluded Coronary Arteries; TIMI: Thrombolysis In Myocardial Infarction. Online Table 2. Algorithm used to derive BARC categories from data adjudicated by the Clinical Events Committee 1-3 Original CEC classification Key data elements Corresponding BARC grade No bleeding occurred No evidence of bleeding Type 0 Bleeding not qualifying as any TIMI Bleeding that is not actionable and does not cause the patient to seek unscheduled performance of Type 1 bleeding but qualifying as GUSTO mild studies, hospitalization, or treatment by a health care professional bleeding TIMI bleeding requiring medical attention Any overt, actionable sign of hemorrhage* that does not fit the criteria for type 3, 4, or 5 but does meet and GUSTO mild bleeding at least one of the following criteria: TIMI minor or GUSTO moderate Requiring nonsurgical, medical intervention by a health care professional Leading to hospitalization or increased level of care Prompting evaluation Overt bleeding plus hemoglobin drop of 3 to <5 g/dL* (provided hemoglobin drop is related to bleeding bleed) Any transfusion with overt bleeding Type 2 Type 3a Original CEC classification Key data elements Corresponding BARC grade Non-CABG, non-fatal, non-ICH bleeding that satisfies of any of the following: TIMI major GUSTO severe Overt bleeding plus hemoglobin drop ≥5 g/dL* (provided hemoglobin drop is related to bleed) Cardiac tamponade Bleeding requiring surgical intervention for control (excluding dental/nasal/skin/hemorrhoid) Bleeding requiring intravenous vasoactive agents Intracranial hemorrhage (does not include microbleeds or hemorrhagic transformation, does Type 3b Reported pericardial bleeding and GUSTO severe (excluding CABG-related) bleeding Intracranial bleeding excluding ischemic stroke with hemorrhagic transformation TIMI major CABG related bleeding Fatal bleeding Type 3c include intraspinal) Subcategories confirmed by autopsy or imaging or lumbar puncture Intraocular bleed Perioperative intracranial bleeding within 48 hours Reoperation after closure of sternotomy for the purpose of controlling bleeding Transfusion of ≥5 U whole blood or packed red blood cells within a 48-hour period Chest tube output ≥2 L within a 24-hour period compromising vision Probable or definite fatal bleeding *E.g., more bleeding than would be expected for a clinical circumstance, including bleeding. Type 4 Type 5 BARC: Bleeding Academic Research Consortium, GUSTO: Global Strategies for Opening Occluded Coronary Arteries; TIMI: Thrombolysis In Myocardial Infarction; non-ICH; non-intracranial hemorrhage. Online Table 3. Mortality rates among subjects with BARC 3a, 3b, 3c, and 4 bleeding classes with or without transfusion BARC class Bleed Kaplan-Meier estimated death rate Death at 30 days post bleeding Death at 1 year post bleeding Death at 2 years post bleeding 3.5% (0.8%, 6.2%) 10.1% (5.3%, 14.9%) 12.4% (6.8%, 18%) 5.4% (1.9%, 8.9%) 18.5% (12.1%, 24.9%) 28.2% (19.3%, 37.1%) 12.8% (5.7%, 19.9%) 17.2% (8.8%, 25.6%) 20.2% (7.1%, 33.3%) 11.3% (6.4%, 16.2%) 23.5% (16.7%, 30.3%) 25.1% (17.8%, 32.4%) 33.9% (22.4%, 45.4%) 47.5% (33.8%, 61.2%) 47.5% (33.8%, 61.2%) 33.3% (-20%, 86.6%) — — 9.5% (-3.1%, 22.1%) 9.5% (-3.1%, 22.1%) 9.5% (-3.1%, 22.1%) Class 3a Without transfusion 168/344 (48.8%) With transfusion 176/344 (51.2%) Class 3b Without transfusion 86/250 (34.4%) With transfusion 164/250 (65.6%) Class 3c Without transfusion With transfusion 65/68 (95.6%) 3/68 (4.4%) Class 4 Without transfusion 21/155 (13.6%) With transfusion 134/155 (86.4%) 8.2% (3.5%, 12.9%) 15.2% (9.1%, 21.3%) 15.2% (9.1%, 21.3%) BARC: Bleeding Academic Research Consortium, GUSTO: Global Strategies for Opening Occluded Coronary Arteries; TIMI: Thrombolysis In Myocardial Infarction. Online Figure 1. Cumulative incidences of bleeding according to BARC criteria BARC: Bleeding Academic Research Consortium, GUSTO: Global Strategies for Opening Occluded Coronary Arteries; TIMI: Thrombolysis In Myocardial Infarction. Online Figure 2. Cumulative mortality following a BARC 2, 3, or 4 bleed during index stay and at different landmarks post discharge BARC: Bleeding Academic Research Consortium Online References 1. Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation. 2011;123(23):2736-47. 2. Anderson JL, Adams CD, Antman EM, et al. 2011 ACCF/AHA Focused Update Incorporated Into the ACC/AHA 2007 Guidelines for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial Infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011;123(18):e426-579. 3. Bassand JP, Hamm CW, Ardissino D, et al. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. Eur Heart J. 2007;28(13):1598660.