Clinical event adjudication: Bleeding

For the list of clinical event adjudication definitions, click here Editors-in-Chief: C. Michael Gibson, M.S., M.D. [mailto:mgibson@perfuse.org]

=Bleeding= This chapter presents bleeding definitions used in the Clinical Event Committee adjudication processes. These definitions are current as of 5/18/10.

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. Examples include but are not limited to bruising, hematoma, nosebleeds, and hemorrhoidal bleeding.

Type 2 (Minor)
Any overt sign of hemorrhage (e.g., more bleeding than would be expected for a clinical circumstance; including bleeding found by imaging alone) that does not meet criteria for Type 3 BARC bleeding, Type 4 BARC bleeding (CABG-related), or Type 5 BARC bleeding (fatal bleeding) that is actionable. The bleeding must require diagnostic studies, hospitalization or treatment by a health care professional. In particular, the bleeding must meet at least one of the following criteria: 1) Requiring intervention: defined as a health care professional-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. Examples include but are not limited to surgical repair, coiling, compression, drainage or cautery of a bleeding site, reversal of vitamin K antagonism, protamine administration, local lidocaine administration to reduce oozing or a reduction in the dose of or a temporary/permanent cessation of antiplatelet or antithrombin therapy; 2) Leading to hospitalization or an increased level of care: defined as leading to or prolonging hospitalization or transfer to a hospital unit capable of providing a higher level of care; and 3) Prompting evaluation: defined as leading to an unscheduled visit to a healthcare professional and diagnostic testing (laboratory or imaging). Examples include but are not limited to hematocrit testing, hemoccult testing, endoscopy, colonoscopy, computed tomography scanning or urinalysis.

Type 3 (Major)
Elements of the definition should include clinical, laboratory, and imaging data; physician response to bleeding; and site specific parameters. In order to curb the influence of physician judgment and decision-making, hemodynamic compromise and transfusion are included in the definition. It is subcategorized in:


 * a. BARC Type 3a Bleeding
 * Intracranial hemorrhage (does not include microbleeds; does include intraspinal). Subcategories; Confirmed by autopsy or imaging or LP
 * Intra-ocular compromising vision (even temporarily)
 * Overt bleeding plus hemoglobin drop > 5 g/dL (provided hemoglobin drop is related to bleed)
 * Tamponade
 * Bleeding requiring surgical or percutaneous intervention for control (exclude dental/nose/skin/hemorrhoids) or inotropes


 * b. BARC Type 3b Bleeding
 * Any transfusion with overt bleeding
 * Overt bleeding plus hemoglobin drop 3 to 5 g/dL

Type 4 (CABG)

 * 1) BARC CABG-related bleeding definitions must include the same criteria for fatal bleeding, intracranial hemorrhage, need for intervention to control bleeding and the number of transfusions as for BARC non-CABG related bleeding,
 * 2) Specific criteria for the amount of chest tube drainage need to be included,
 * 3) If bleeding is not defined as BARC Type 3, it will not be counted as an event,
 * 4) Specific time intervals will need to apply for CABG-related events: up to 48 hours for transfusions and intracranial bleeding. It is appropriate that there will be no time window for the occurrence of fatal bleeding.

Type 5 (Fatal)
Fatal bleeding is bleeding that directly causes death with no other explainable cause. BARC Fatal Bleeding is categorized as either definite or probable as follows:
 * 1) Definite fatal bleeding is bleeding that is directly observed or confirmed on autopsy or imaging.
 * 2) Probable fatal bleeding is bleeding that is clinically suspicious as the cause of death, but the bleeding is not directly observed and there is no autopsy or confirmatory imaging. The site of fatal bleeding is specified as intracranial, GI, retroperitoneal, pulmonary, pericardial, GU, or other.

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2. GUSTO

 * Severe or Life Threatening Either intracranial hemorrhage or bleeding that causes hemodynamic compromise and requires intervention
 * Moderate Bleeding that requires blood transfusion but does not result in hemodynamic compromise
 * Mild Bleeding that does not meet the criteria for severe or moderate

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1. Major

 * Any intracranial bleeding OR
 * Clinically overt signs of hemorrhage associated with a drop in hemoglobin (Hgb) of ≥ 5 g/dL.

2. Minor
Any clinically overt signs of hemorrhage (including imaging) that is associated with a fall in Hgb of 3 to < 5 g/dL

3. Medical Attention
Any overt sign of hemorrhage that requires medical evaluation, medical treatment (including discontinuation of medications), or surgical treatment, and that does not meet criteria for a major or minor bleeding event, as defined above.

4. Minimal
Any overt bleeding event that does not meet the criteria above NOTE: To account for transfusions, Hgb measurements will be adjusted for any packed red blood cells (PRBCs) or whole blood given between baseline and post-transfusion measurements. A transfusion of one unit of blood will be assumed to result in an increase by 1 gm/dL in Hgb. Thus, to calculate the true change in hemoglobin, if there has been an intervening transfusion between two blood measurements, the following calculations should be performed: ∆ Hgb = [Baseline Hgb – Post transfusion Hgb] + [# transfused units].

1.	Fatal Bleeding
Death in which a bleeding event directly led to death within 7 days. Examples of fatal bleeding events are an intracranial hemorrhage that led to herniation of the brain and death within 24 hours, and a massive gastrointestinal hemorrhage that results in shock, hemodynamic collapse, and death. If a bleeding event is considered fatal, then the cause of death must be either intracranial or non-intracranial bleeding.

2.	Bleeding Contributed to Death
Death in which a bleeding event was part of a causal chain of medical events that ultimately led to death within 30 days of the bleed, but bleeding was not directly and/or immediately related to the subject’s death. An example of bleeding contributing to death is a large retroperitoneal bleed that leads to surgical evacuation, development of a subsequent abscess in the area of bleeding that leads to sepsis, multiorgan failure, and death 10 days after the onset of bleeding. If bleeding has contributed to death (but the bleeding was not categorized as “fatal”), then the cause of death must be recorded as something other than intracranial / non-intracranial bleeding.

c.	Bleeding in the Setting of Coronary Artery Bypass Graft Surgery (CABG)
Minor and minimal bleeding are not adjudicated in the setting of CABG. As a drop in hemoglobin and transfusions are commonplace in routine CABG cases, one of the following criteria must be met to qualify for major bleeding in any of the preceding definitions:
 * 1) Fatal bleeding (i.e., bleeding that directly results in death)
 * 2) Perioperative intracranial bleeding
 * 3) Reoperation following closure of the sternotomy incision for the purpose of controlling bleeding
 * 4) Transfusion of ≥ 5 units of packed red blood cells (PRBCs) or whole blood within a 48 hour period.  Cell saver transfusion will not be counted in calculations of blood products
 * 5) Chest tube output > 2 L within a 24 hour period

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a.	Major Bleeding episodes are those which are:

 * 1) Substantially disabling
 * 2) Intraocular bleeds leading to loss of vision
 * 3) Require at least 2 units of blood transfusion

b. Major bleeds are to be classified as life-threatening if they meet one or more of the following criteria:

 * 1) Fatal, symptomatic intracranial bleed
 * 2) Reduction in hemoglobin of at least 5 g/dL
 * 3) Transfusion of at least 4 units of blood or packed cells, associated with substantial hypotension requiring the use of intravenous inotropic agents
 * 4) Necessitated surgical intervention

c. Minor Bleeding

 * Other hemorrhages that led to interruption of the study medication

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a. Major Bleeding is defined as

 * 1) Intracranial bleeding
 * 2) Intraocular bleeding
 * 3) Access site hemorrhage requiring intervention
 * 4) ≥ 5 cm diameter hematoma
 * 5) Reduction in hemoglobin concentration of ≥ 4 g/dL without an overt source of bleeding
 * 6) Reduction in hemoglobin concentration of ≥ 3 g/dL with an overt source of bleeding
 * 7) Reoperation for bleeding
 * 8) Use of any blood product transfusion

b. Minor bleeding
Clinically overt bleeding that did not meet criteria for major bleeding.

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a. Major Bleed—Fatal/life-threatening bleeding is defined as any one of the following:

 * 1) Fatal
 * 2) Intracranial
 * 3) Intrapericardial bleed with cardiac tamponade
 * 4) Hypovolemic shock or severe hypotension due to bleeding requiring pressors or surgery
 * 5) Clinically overt or apparent bleeding associated with a decrease in Hgb of more than 50 g/L
 * 6) Transfusion of 4 or more units (whole blood or packed red blood cells (PRBCs)) for bleeding

b. Major Bleed—Other is defined as any one of the following:

 * 1) Significantly disabling (e.g., intraocular with permanent vision loss)
 * 2) Clinically overt or apparent bleeding associated with a decrease in hemoglobin of 30 g/L (tetramer: 1.9 mmol/L, monomer:  0.465 mmol/L) to 50 g/L (3.1 mmol/L; 0.775 mmol/L)
 * 3) Transfusion of 2-3 units (whole blood or PRBCs) for bleeding

c. Minor Bleed
Requires medical intervention to stop or treat bleeding (e.g., epistaxis requiring visit to medical facility for packing)

d. Minimal Bleed
All others (e.g., bruising, bleeding gums, oozing from injection sites, etc.) not requiring intervention or treatment.

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a. Major bleeding is defined by ≥ 1 of the following criteria:
Furthermore, major bleed is classified as life-threatening if they met ≥ 1 of the following criteria:
 * 1) Bleeding associated with reduction in hemoglobin level of at least 2.0 g/L
 * 2) Leading to transfusion of at least 2 units of blood or packed cells; or
 * 3) Symptomatic bleeding in a critical area or organ such as intraocular, intracranial, intraspinal or intramuscular with compartment syndrome, retroperitoneal bleeding, intra-articular bleeding, or pericardial bleeding
 * 1) Fatal, symptomatic intracranial bleed;
 * 2) Reduction in hemoglobin level of at least 5.0 g/L;
 * 3) Transfusion of at least 4 U of blood or packed cells;
 * 4) Associated with hypotension requiring the use of intravenous inotropic agents; or
 * 5) Necessitated surgical intervention

b. Minor bleeds
Clinical bleeds that do not fulfill the criteria for major bleeds

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a. Major Bleed

 * Fatal bleed and/or
 * Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome and/or
 * Bleeding causing a fall in hemoglobin level of 2 g/dL (1.24 mmol/L) or leading to transfusion of two or more units of whole blood or red cells

b. Minor Bleed
All non major bleeds will be considered minor bleeds. Minor bleeds will be further divided to those that are clinically relevant and those that are not

c. Clinically Relevant Minor Bleed
A clinically relevant minor bleed is an acute or subacute clinically overt bleed that does not meet the criteria for a major bleed but prompts a clinical response, in that it leads to at least one of the following:
 * A hospital admission for bleeding
 * OR a physician guided medical or surgical treatment for bleeding
 * OR a change in antithrombotic therapy (including interruption or discontinuation of study drug)

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a. Major Bleeding must satisfy one or more of the following criteria:

 * Fatal
 * Clinically overt bleeding associated with a reduction in hemoglobin of at least 2 g/dL or leading to a transfusion of at least 2 units of blood or packed red blood cells
 * Bleeding in areas of special concern such as: intraocular, intracranial, intraspinal, retroperitoneal, pericardial or atraumatic intra-articular bleeding

b. Minor bleeds must satisfy either

 * Minor bleeds causing permanent stop of medication or
 * Other minor bleeds such as epistaxis, gingival bleeds, and microscopic hematuria