Online Figure 1
Flow diagram of the selection process according to the PRISMA (Preferred Reporting Items for Systematic
reviews and Meta-Analyses) statement.
Online Figure 2
Publication bias assessment for 30-day outcomes.
Online Figure 3
Individual and summary odds ratios with 95% confidence intervals (CI) for 30-day ischemia-driven
revascularization in ACS patients treated with bivalirudin vs heparins stratified by protocol use of GP
inhibitors.
ACUITY, Acute Catheterization and Urgent Intervention Triage Strategy trial; BRIGHT, Bivalirudin versus
Heparin Monotherapy and Glycoprotein IIb/IIIa Plus Heparin for Patients with AMI Undergoing Coronary
Stenting; HORIZONS-AMI, Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial
Infarction Trial; ISAR-REACT 4, Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for
Coronary Treatment 4; REPLACE-2, the Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical
Events-2; BAT, Bivalirudin Angioplasty Trial (aka. HAS, Hirulog Angioplasty Study); BRAVE-4, The Bavarian
Reperfusion Alternatives Evaluation 4 Trial; EUROMAX, European Ambulance Acute Coronary Syndrome
Angiography HEAT-PPCI, How Effective are Antithrombotic Therapies in Primary PCI; M-H, Mantel-Haenszel
method.
Online Table 1. Outcomes definitions
Study
ACUITY*
ARMYDA-7-BIVALVE
BRAVE-4*
Major bleeding
(1) Intracranial or intraocular bleeding unrelated to CABG;
(2) Haemorrhage at the access site requiring intervention;
(3) Access site haematoma Ø ≥5 cm;
(4) Any decrease in the haemoglobin level of ≥4 g/dl;
(5) Overt bleeding with a decrease in the haemoglobin level ≥3 g/dl;
(6) Reoperation for bleeding;
(7) Transfusion.
(1) Intracranial bleeding;
(2) Overt bleeding with a decrease in the haemoglobin level ≥5 g/dl;
(3) TIMI major bleeding.
HORIZONS-AMI definition:
(1) Intracranial or intraocular bleeding;
(2) Access site haematoma Ø ≥5 cm or requiring intervention
(3) Any decrease in the haemoglobin level of ≥4 g/dl;
(4) Overt bleeding with a decrease in the haemoglobin level ≥3 g/dl;
(5) Reoperation for bleeding;
(6) Transfusion.
BRIGHT
Type 3 or 5 bleeding as per BARC definitions †
EUROMAX*
(1) Intracranial, retroperitoneal, or intraocular bleeding unrelated to
CABG surgery;
(2) Access-site haemorrhage requiring radiologic or surgical
intervention;
(3) Any decrease in the hemoglobin level of ≥4 g/dl
(4) Overt bleeding with a decrease in the hemoglobin level ≥3 g/dl;
(5) Reintervention for bleeding;
(6) Transfusion.
Type 3-5 bleeding as per BARC definitions †
(1) Intracranial or intraocular bleeding;
(2) Access site hematoma Ø ≥5 cm or requiring intervention;
(3) Any decrease in the haemoglobin level of ≥4 g/dl;
(4) Overt bleeding with a decrease in the haemoglobin level ≥3 g/dl;
(5) Reoperation for bleeding;
(6) Transfusion.
REPLACE 2 definition:
(1) Retroperitoneal, intraocular, or intracranial haemorrhage;
(2) Any decrease in the haemoglobin level of ≥4 g/dl;
(3) Overt bleeding with a decrease in the haemoglobin level ≥3 g/dl;
(4) Blood transfusion (≥2 units of packed red blood cells or whole
blood).
REPLACE 2 definition:
(1) Retroperitoneal, intraocular, or intracranial haemorrhage;
(2) Any decrease in the haemoglobin level of ≥4 g/dl;
(3) Overt bleeding with a decrease in the haemoglobin level ≥3 g/dl;
(4) Blood transfusion (≥2 units of packed red blood cells or whole
blood).
TIMI major bleeding.
NA
REPLACE 2 definition:
(1) Retroperitoneal, intraocular, or intracranial haemorrhage;
(2) Any decrease in the haemoglobin level of ≥4 g/dl;
(3) Overt bleeding with a decrease in the haemoglobin level ≥3 g/dl;
(4) Blood transfusion (≥2 units of packed red blood cells or whole
blood).
(1) Retroperitoneal, or intracranial haemorrhage;
(2) Overt bleeding with a decrease in the haemoglobin level ≥3 g/dl;
(3) Transfusion of ≥3 units of blood.
HEAT-PPCI
HORIZONS-AMI*
ISAR-REACT 3
ISAR-REACT 4*
PROTECT-TIMI 30*
Ray et al.
REPLACE-2*
TIMI-8
NACE
Composite of:
(1) All-cause death;
(2) MI;
(3) Unplanned revascularization for ischemia;
(4) Major bleeding.
NA
Composite of:
(1) All-cause death;
(2) Recurrent MI;
(3) Unplanned revascularization of the infarct related
artery;
(4) Definite ST;
(5) Stroke;
(6) Major bleeding
Composite of:
(1) All-cause death;
(2) Re-infarction;
(3) TVR;
(4) Ischemic stroke.
(5) Bleeding events.
Composite of:
(1) Death;
(2) Re-infarction;
(3) Ischemia-driven revascularization;
(4) Stroke.
(5) Non-CABG major bleeding.
NA
Composite of:
(1) All-cause death;
(2) MI;
(3) Unplanned revascularisation for ischemia;
(4) Non-CABG major bleeding.
Composite of:
(1) All-cause death;
(2) MI;
(3) Urgent TVR;
(4) In-hospital major bleeding.
Composite of:
(1) All-cause death;
(2) Large recurrent MI;
(3) Urgent TVR;
(4) Major bleeding.
NA
NA
Composite of:
(1) All-cause death;
(2) MI;
(3) Urgent repeat revascularization;
(4) Major bleeding.
Composite of:
(1) All-cause death;
(2) Nonfatal recurrent MI;
(3) Major haemorrhage.
* studies assessing separate major bleeding outcome according to the criteria of the Thrombolysis in Myocardial Infarction (TIMI) study group:
(1) intracranial, or (2) clinically significant overt signs of hemorrhage associated with a drop in hemoglobin of > 5 g/dL (or, when hemoglobin is not
available, an absolute drop in hematocrit of > 15%; (3) if CABG related: fatal bleeding or perioperative intracranial bleeding or reoperation following
closure of the sternotomy incision for the purpose of controlling bleeding or transfusion of > 5 units of whole blood or PRBCs within a 48 hour period (cell
saver transfusion will not be counted in calculations of blood products) or chest tube output > 2 L within a 24 hour period.
† The Bleeding Academic Research Consortium (BARC): Type 0: no bleeding; Type 1: bleeding without need for hospitalization or treatment; Type 2:
bleeding requiring diagnostic studies, hospitalization, or treatment by a healthcare professional; Type 3a: bleeding includes any transfusion with overt
bleeding and overt bleeding plus a hemoglobin drop of ≥3 to <5 g/dL (provided the hemoglobin drop is related to bleeding); Type 3b: bleeding includes
overt bleeding plus a hemoglobin drop of ≥5 g/dL (provided the hemoglobin drop is related to bleeding), cardiac tamponade, bleeding requiring surgical
intervention for control (excluding dental/nasal/skin/hemorrhoid), and bleeding requiring intravenous vasoactive drugs; Type 3c: bleeding includes
intracranial hemorrhage and intraocular bleeding compromising vision; Type 4: bleeding is coronary artery bypass grafting (CABG)–related (within 48
hours); Type 5: fatal bleeding.
MACE, major adverse cardiac events; NACE, net adverse clinical events; ACUITY, Acute Catheterization and Urgent Intervention Triage Strategy trial;
CABG, coronary artery by-pass grafting; MI, myocardial infarction; ARMYDA-7-BIVALVE, Anti-Thrombotic Strategy for Reduction of Myocardial Damage
During Angioplasty–Bivalirudin vs Heparin Study; TVR, target vessel revascularisation; ST, stent thrombosis; BRAVE-4, The Bavarian Reperfusion
Alternatives Evaluation 4; HORIZONS-AMI, Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction Trial; BRIGHT,
Bivalirudin versus Heparin Monotherapy and Glycoprotein IIb/IIIa Plus Heparin for Patients with AMI Undergoing Coronary Stenting; EUROMAX, European
Ambulance Acute Coronary Syndrome Angiography; HEAT-PPCI, How Effective are Antithrombotic Therapies in Primary PCI; ISAR-REACT 3, Intracoronary
Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 3; REPLACE-2, the Randomized Evaluation of PCI Linking Angiomax to
Reduced Clinical Events-2; PCI, percutaneous coronary intervention; ISAR-REACT 4, Intracoronary Stenting and Antithrombotic Regimen: Rapid Early
Action for Coronary Treatment 4; PROTECT-TIMI 30, A Randomized Trial to Evaluate the Relative Protection Against Post-Percutaneous Coronary
Intervention Microvascular Dysfunction, Ischemia, and Inflammation Among Antiplatelet and Antithrombotic Agents-Thrombolysis in Myocardial
Infarction 30; TIMI-8, The Thrombolysis in Myocardial Infarction 8 Trial; NA, not assessed.
Online Table 2. Bias assessment
Table 2. Risk of bias of included randomized controlled trials.
STUDY
MULTICENTER
ADEQUATE
ALLOCATION
TRIAL
SEQUENCE
CONCEALMENT
GENERATION
ACUITY
Y
Y
N
ARMYDA-7Y
Y
UNCLEAR
BIVALVE
BRAVE-4
Y
UNCLEAR, 1:1
N
BRIGHT
Y
UNCLEAR, 1:1:1
N
EUROMAX
Y
Y, 1:1
N
HEAT-PPCI
N
UNCLEAR
UNCLEAR
HORIZONSY
Y, 1:1
UNCLEAR
AMI
ISAR-REACT 3
Y
Y
Y
ISAR-REACT 4
Y
Y
Y
PROTECT-TIMI Y
Y, 1:1:1
N
30
RAY MJ ET AL. N
UNCLEAR
UNCLEAR
REPLACE-2
Y
Y
Y
TIMI-8
Y
UNCLEAR
UNCLEAR
PATIENT
BLINDING
PHYSICIAN
BLINDING
N
N
N
N
ADJUDICATION OF
OUTCOMES
BLINDING
Y
Y
INCOMPLETE DATA
OUTCOME
ADDRESSED?
SELECTIVE
OUTCOME
REPORTING
FREE OF
OTHER
BIAS
N
N
N
N
N
N
N
N
N
N
Y
UNCLEAR
Y
Y
Y
UNCLEAR
Y
Y
Y
Y
UNCLEAR
N
N
N
N
Y
Y
Y
Y
Y
Y
Y
N
Y
Y
N
Y
Y
Y
Y
Y
Y
N
N
N
Y
Y
Y
N
Y
Y
N
Y
Y
UNCLEAR
Y
Y
Y
Y
Y
N
N
N
Y
Y
Y
Y
Y
N
N
Y
Y