Current opinion:
Challenges in the adjudication of major bleeding events in acute coronary syndrome.
A plea for a standardized approach and guidance to adjudication
Wouter J. Kikkert, MD, PhD, Jan G. P. Tijssen, PhD, Jan J. Piek, MD, PhD, José P. S. Henriques, MD, PhD
Department of Cardiology, Academic Medical Center – University of Amsterdam
1
Supplementary table 1. Bleeding definitions used in cardiovascular trials
Definition
ACUITY1
HORIZONS-AMI2
Major
Criteria
-
Intracranial or intraocular hemorrhage
Access-site hemorrhage requiring intervention
≥5-cm hematoma
Retroperitoneal
Reduction in hemoglobin concentration of ≥4 g/dL without an overt source of bleeding
Reduction in hemoglobin concentration of ≥3 g/dL with an overt source of bleeding
Reoperation for bleeding
Use of any blood product transfusion
Type 0
Type 1
-
No bleeding
Bleeding that is not actionable and does not cause the patient to seek unscheduled performance of studies,
hospitalization, or treatment by a healthcare professional; may include episodes leading to self-discontinuation of medical
therapy by the patient without consulting a healthcare professional.
Type 2
-
Any overt, actionable sign of hemorrhage (eg, 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 healthcare professional, (2) leading to
hospitalization or increased level of care, or (3) prompting evaluation.
-
Overt bleeding plus hemoglobin drop of 3 to <5 g/dL* (provided hemoglobin drop is related to bleed)
Any transfusion with overt bleeding.
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 include intraspinal).
Subcategories confirmed by autopsy or imaging or lumbar puncture.
Intraocular bleed compromising vision.
Perioperative intracranial bleeding within 48 h
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-h period.
Chest tube output ≥2L within a 24-h period.
BARC3
Type 3
Type 3a
Type 3b
Type 3c
Type 4: CABG-related
bleeding
2
Type 5: fatal bleeding
Type 5a
Type 5b
-
Definite fatal bleeding; overt bleeding or autopsy or imaging confirmation.
Probable fatal bleeding; no autopsy or imaging confirmation but clinically suspicious.
-
Fatal
Symptomatic intracranial hemorrhage requiring surgical intervention, and/or
Resulting in substantial hypotension requiring the use of intravenous inotropic agents and/or
Hemoglobin decrease ≥5 g/dL, and/or
Requiring ≥4 units of blood
Substantially disabling bleeding, and/or
Intraocular bleeding leading to the loss of vision, and/or
Transfusion of 2–3 units of blood
-
Led to discontinuation of study drug
-
Clinically overt bleeding that was fatal (bleeding reported to cause death),
Symptomatic intracranial haemorrhage,
Retroperitoneal haemorrhage,
Intraocular haemorrhage leading to significant vision loss,
A decrease in haemoglobin of at least 3.0 g/dL (with each blood transfusion unit counting for 1.0 g/dL of haemoglobin), or
Bleeding requiring transfusion of two or more units of red blood cells or equivalent of whole blood.
All other clinically significant bleeding not meeting the definition for major bleeding and that led to interruption of the
study
CURE4
Major
Life-threatening
Other major
bleeding
Minor
CURRENT-OASIS 75
Severe
Other
major
Minor
Other
ESSENCE6
Major
Minor
Fatal or
Leading to a drop in hemoglobin of 5 g/dl, or
Significant hypotension with the need for inotropes, or
Requiring surgery (other than vascular site repair), or
Symptomatic intracranial hemorrhage, or
Requiring ≥4 units of blood or equivalent whole blood.
Significantly disabling, or
Intraocular bleeding leading to significant loss of vision or
Bleeding requiring transfusion of two or three units of red blood cells or equivalent whole blood.
Other bleeding that leads to modification of drug regimen
Bleeding not meeting criteria for major or minor
3
GRACE7
Major
GUSTO8
Severe
Moderate
Mild
ISTH9
Major
PLATO10
Major
-
Requiring a transfusion of ≥2 U PRBCs
Resulting in a decrease in hematocrit of ≥10%
Occurring intracerebrally
Resulting in stroke or death
-
Either intracranial hemorrhage or bleeding that causes hemodynamic compromise and requires intervention
Bleeding that requires blood transfusion but does not result in hemodynamic compromise
Bleeding that does not meet the criteria for GUSTO severe or moderate bleeding
-
Fatal bleeding, 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 20 g/L (1.24 mmol/L) or more, or leading to transfusion of two
or more units of whole blood or red cells.
Life threatening
Minor
Minimal
REPLACE-211/
ISAR-REACT 312
Major
-
Fatal bleeding,
Intracranial bleeding,
Intrapericardial bleeding with cardiac tamponade,
Hypovolemic shock or severe hypotension due to bleeding and requiring pressors or surgery,
A decline in the hemoglobin level of 5.0 g per deciliter or more, or the need for transfusion of at least 4 units of red cells.
Bleeding that led to clinically significant disability (e.g., intraocular bleeding with permanent vision loss) or
Bleeding either associated with a drop in the hemoglobin level of at least 3.0 g per deciliter but less than 5.0 g per deciliter
or requiring transfusion of 2 to 3 units of red cells
Requiring medical intervention to stop or treat bleeding (eg, epistaxis requiring visit to medical facility for packing)
All others (eg, bruising, bleeding gums, oozing from injection sites) not requiring intervention or treatment
-
Intracranial, intraocular, or retroperitoneal
Overt blood loss with hemoglobin decrease >3 g/dl
Any hemoglobin decrease >4 g/dL
Transfusion of ≥2 U blood products
Minor
STEEPLE13
-
Overt bleeding not meeting criteria for major bleeding
Other major
-
4
Major
-
Minor
TIMI14, 15
Major
Minor
Minimal
CABG related
-
Fatal bleeding
Retroperitoneal, intracranial, or intraocular bleeding
Bleeding that causes hemodynamic compromise requiring specific treatment
Bleeding that requires intervention (surgical or endoscopic) or decompression of a closed space to stop or control the
event
Clinically overt bleeding, requiring any transfusion of ≥1 unit of packed red cells or whole blood
Clinically overt bleeding, causing a decrease in hemoglobin of ≥3 g/dl (or, if hemoglobin level not available, a decrease in
hematocrit of ≥10%)
Gross hematuria not associated with trauma (e.g., from instrumentation)
Epistaxis that is prolonged, repeated, or requires plugging or intervention
Gastrointestinal hemorrhage
Hemoptysis
Subconjunctival hemorrhage Hematoma >5 cm or leading to prolonged or new hospitalization
Clinically overt bleeding, causing a decrease in hemoglobin of 2 to 3 g/dl
Uncontrolled bleeding requiring protamine sulfate administration
-
Intracranial or clinically significant overt signs of hemorrhage associated with a hemoglobin decrease greater than 5g/L
(Corrected for transfusion (1 U packed red blood cells or 1 U whole blood=1 g/dL hemoglobin)
- The diagnosis of intracranial bleeding required confirmation by computed tomography or magnetic resonance imaging of
the head.
- Observed blood loss and a decrease in hemoglobin level of 3 to 5 g/dL *
- Any overt bleeding event that does not meet the criteria for TIMI major or minor bleeding
- Fatal bleeding
- Perioperative intracranial bleeding
- Reoperation after closure of the sternotomy incision for the purpose of controlling bleeding
- Transfusion 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 period
5
Supplementary figure 1. Flow Chart of Search Strategy. Flow chart demonstrating the search strategy and selection of eligible studies
for table 1 and figure 1 through 3.
6
Supplementary table 2. General recommendations regarding data collection
Example
One-year follow-up of a patient participating in a trial is obtained
by the investigator in the PCI center by means of a telephone call.
When asked for hospital admissions, the patient reports 2
hospital admissions in the regional non-PCI hospital: one with
pneumonia, and one for nephrectomy. The investigator does not
acquire discharge letters of the admissions. It turns out the
patient was in fact admitted 3 times: 1) pneumonia, 2)
nephrectomy complicated by retroperitoneal bleeding requiring
additional surgery, and 3) a one day-admission for colonoscopy
because of red blood loss per anum.
A patient is discharged after a 4 day admission to the hospital
because of ACS. In the discharge letter an uneventful clinical
course is reported, while in fact the patient suffered a TIMI
minor/BARC 3A/GUSTO moderate bleeding during the admission.
The local investigator only obtains the discharge letter and
reports no bleeding in the case report form.
Issue
1. Missed bleeding events and underreporting of
bleeding by not adequately ascertaining follow-up
information in both the PCI center as well as
regional hospital(s).
2. Patients when asked for hospital admissions and
the occurrence of primary or secondary endpoints
on occasion cannot reproduce their hospital
admissions and the course of events correctly.
Recommendation
Adequate and systematic follow-up of bleeding events requires full
documentation of bleeding and proof of the absence of bleeding events.
This requires at least a telephone call to the patient and preferably an outpatient visit, in addition to discharge letters and laboratory results of all
hospital admissions.
Differences in bleeding rates may arise because of
differences in detail of source documentation and
quality in monitoring.
In a RCT the 30 day bleeding rate is reported to be 3.6% for a
novel antiplatelet agent X. In another RCT the bleeding rate of
another antiplatelet agent Y is reported to be 2.4%. It is difficult to
compare these bleeding rates because baseline bleeding risk for
the 2 trial populations is not reported.
Differences in bleeding rates across trials are
difficult to interpret because baseline bleeding risk
for a given population cannot be estimated and
compared across trials.
Source documentation of all hospital admissions should contain at least
the following:
Discharge letter
Case history
Laboratory measurements
Source documentation of the index admission and all hospital admissions
potentially concerning bleeding events should contain at least the
following:
Discharge letter
Case history
Nurse reports
Laboratory measurements
Imaging studies
Mandatory reporting of the mean bleeding risk of a study population
using a validated bleeding risk score such as the HAS-BLED risk score or
the Mehran risk score.16, 17
7
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