Clinical event adjudication: Bleeding

Editors-in-Chief: C. Michael Gibson, M.S., M.D. [1]

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Bleeding

This chapter presents bleeding definitions used in the Clinical Event Committee adjudication processes. These definitions are current as of 3/26/10.

1. 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

2. TIMI

a. Types of TIMI Bleeding

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].

b. Relationship of Bleeding to Death

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

3. CURE

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

4. ACUITY

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.

5. PLATO

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.

6. RELY

a. Major bleeding is defined by ≥ 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

Furthermore, major bleed is classified as life-threatening if they met ≥ 1 of the following criteria:

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

7. ISTH

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)

8. ESTEEM

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

References

1. ACC/AHA 2007 Guidelines for the Management of Patients with Unstable Angina/Non ST-Elevation Myocardial Infarction: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction): Developed in Collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons: Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine, Circulation, 2007, 116:803-877.
   
2. Campeau L, Grading of angina pectoris (letter), Circulation, 1976, 54:522-23.
   
3. Cutlip DE, S Windecker, R Mehran, A Boam, DJ Cohen, G-A van Es, PG Steg, M-A Morel, L Mauri, P Vranckx, E McFadden, A Lansky, M Hamon, MW Krucoff, PW Serruys and on behalf of the Academic Research Consortium, Clinical End Points in Coronary Stent Trials: A Case for Standardized Definitions, Circulation, 2007, 115:2344-2351.
   
4. Easton JD, Saver JL, Albers GW, Alberts MJ, Chaturvedi S, Feldmann E, Hatsukami TS, Higashida RT, Johnston SC, Kidwell CS, Lutsep HL, Miller E, Sacco RL; Definition and Evaluation of Transient Ischemic Attack, A Scientific Statement for Healthcare Professionals from the American Heart Association; American Stroke Association Stroke Council; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Nursing; and the Interdisciplinary Council on Peripheral Vascular Disease, Stroke, 2009 Jun; 40(6):2276-93. Epub 2009 May 7. Review.
   
5. Thygesen, Kristian, Alpert JS, White HD on behalf of the Joint ESC/ACCF/AHA/WHF Task Force for the Redefinition of Myocardial Infarction. Universal Definition of Myocardial Infarction, Circulation, 2007, 116:1-20.