Bleeding Definitions

The CEC adjudicated bleeding events using three bleeding classifications including TIMI, International Society on Thrombosis and Haemostasis (ISTH), and GUSTO defined below.

The primary safety endpoint was TIMI Major Non-CABG Surgery-Related bleeding events.

5.3.1.8.2.1 TIMI Bleeding Event Classification Scale

TIMI bleeding was classified as follows:

• TIMI Major Bleeding Event o Non-CABG-Related

A Non-CABG-Related TIMI major bleeding event was defined as

o Any symptomatic intracranial hemorrhage, or

o Clinically overt signs of hemorrhage (including imaging) associated with a

drop in hemoglobin of ≥ 5 g/dL (or when the hemoglobin concentration was not available, an absolute drop in hematocrit of ≥ 15%)

o CABG-Related* (included in CEC Charter only)

A CABG-Related TIMI major bleeding event was defined as

o CABG-related fatal bleeding (i.e., bleeding that directly resulted in death) o Perioperative intracranial bleeding

o Reoperation following closure of the sternotomy incision to control bleeding o Transfusion of greater than or equal to 5 units of whole blood or packed red

blood cells (PRBCs) within a 48 hour period (cell saver transfusion was not counted in calculations of blood products), or chest tube output > 2 L within a 24 hour period.

*Per the CEC Charter, for the TIMI scale, bleeding that occurred in the setting of CABG was classified as a CABG-Related TIMI major bleed, or as not a CABG- related TIMI Major Bleed. Events associated with CABG, were not classified as TIMI minor bleeding or bleeding requiring medical attention.

• TIMI Minor Bleeding Event

A TIMI minor bleeding event was defined as any clinically overt sign of hemorrhage (including imaging) that was associated with a fall in hemoglobin concentration of 3 to < 5 g/dL (or, when hemoglobin concentration was not available, a fall in

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• Bleeding Events Requiring Medical Attention

A bleeding event requiring medical attention was defined as any bleeding event that required medical treatment, surgical treatment, or laboratory evaluation and did not meet criteria for a major or minor bleeding event, as defined above.

Examples of medical treatment, surgical treatment, or laboratory evaluation included the following: laboratory evaluation; CT or MRI; nasal packing; endoscopy;

colonoscopy; cystoscopy; bronchoscopy; compression; ultrasound-guided closure of an aneurysm; coil embolization; pericardiocentesis; inotropin support; reducing or removing antiplatelet therapies; stopping the study medication (either temporarily or permanently); surgery.

• Insignificant Bleeding Events

An insignificant bleeding event was defined as a reported blood loss or bleeding event episode not meeting any of the above criteria

• Clinically Significant Bleeding Events (included in protocol only)

The composite endpoint of TIMI major bleeding event, TIMI minor bleeding event, or bleeding event requiring medical attention was considered clinically significant for the TIMI scale.

• Life-Threatening Bleeding Events (definition included in CEC Charter only)

TIMI bleeding events were further classified as life-threatening if any of the following features were present:

o Fatal;

o Led to hypotension requiring treatment with intravenous inotropic agents; o Required surgical intervention for ongoing bleeding

o Necessitated the transfusion of 4 or more units of blood (whole blood or packed

red blood cells) over a 48-hour period;

o Symptomatic intracranial hemorrhage

5.3.1.8.2.2 International Society on Thrombosis and Haemostasis (ISTH) Event Classification Scale

International Society on Thrombosis and Haemostasis (ISTH) bleeding was classified as follows:

• ISTH Major Bleeding Event

A major bleeding event was defined using ISTH criteria as clinically overt bleeding that was associated with

o A fall in hemoglobin of 2 g/dL or more, or

o A transfusion of 2 or more units of packed red blood cells or whole blood, or

o A critical site: intracranial, intraspinal, intraocular, pericardial, intra-articular,

intramuscular with compartment syndrome, retroperitoneal, or

o A fatal outcome

• Clinically Relevant Nonmajor Bleeding Events

A clinically-relevant nonmajor bleeding event was defined as an overt bleeding event not meeting the criteria for a major bleeding event, but associated with medical intervention, unscheduled contact (visit or telephone call) with a physician,

(temporary) cessation of study drug treatment, or associated with discomfort for the subject such as pain or impairment of activities of daily life.

Examples of nonmajor clinically relevant bleeding events were:

o Unscheduled contact (visit or telephone call) with a physician (included in CEC

Charter only)

o Study drug temporarily discontinued o Study drug permanently discontinued

o Epistaxis if it lasted for more than 5 minutes, if it was repetitive (i.e., 2 or more

episodes of true bleeding, i.e., no spots on a handkerchief, within 24 hours), or led to an intervention (packing, electrocautery, etc.)

o Gingival bleeding if it occurred spontaneously (i.e., unrelated to tooth brushing or

eating), or if it lasted for more than 5 minutes

o Hematuria if it was macroscopic, and either spontaneous or lasted for more than

24 hours after instrumentation (e.g., catheter placement or surgery) of the urogenital tract

o Macroscopic gastrointestinal hemorrhage: at least 1 episode of melena or

hematemesis, if clinically apparent

o Rectal blood loss, if more than a few spots

o Hemoptysis, if more than a few speckles in the sputum, or

o Intramuscular hematoma

o Subcutaneous hematoma if the size was larger than 25 cm2 or larger than 100

cm2 if provoked

o Multiple source bleeding events o Surgery (CEC Charter only) • Minimal Bleeding Events

All other overt bleeding events not meeting the criteria for major or clinically-relevant nonmajor bleeding events were classified as minimal bleeding events.

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5.3.1.8.2.3 GUSTO Bleeding Event Classification Scale

There were three classes of GUSTO bleeding as follows:

• Severe or Life Threatening

Severe or life-threatening was defined as either an intracranial hemorrhage or bleeding that caused hemodynamic compromise and required intervention

CEC definition was for Severe Bleeding Event as follows: “clinically overt bleeding that was fatal, intracranial, or that caused hemodynamic compromise requiring intervention (e.g., systolic blood pressure < 90 mm Hg that required blood or fluid replacement, or vasopressor/inotropic support,* or surgical intervention)

*Need for vasopressor/inotropic support for hemodynamic compromise, even if blood pressure was > 90 mm Hg with treatment.”

• Moderate

Moderate bleeding was defined as bleeding that required blood transfusion but did not result in hemodynamic compromise

• Mild

Mild bleeding was defined as bleeding that did not meet criteria for either severe or moderate bleeding