EURHEARTJ-D-12-02594
ADDITIONAL INFORMATION FOR FIGURE LEGENDS
Figures 1 and 2 in the published manuscript were created based on data reported in: Alexander
JH, Becker RC, Bhatt DL, Cools F, Crea F, Dellborg M, Fox KA, Goodman SG, Harrington RA,
Huber K, Husted S, Lewis BS, Lopez-Sendon J, Mohan P, Montalescot G, Ruda M, Ruzyllo W,
Verheugt F, Wallentin L. Apixaban, an oral, direct, selective factor Xa inhibitor, in combination
with antiplatelet therapy after acute coronary syndrome: results of the Apixaban for Prevention
of Acute Ischemic and Safety Events (APPRAISE) trial. Circulation 2009;119:2877-28851;
Alexander JH, Lopes RD, James S, Kilaru R, He Y, Mohan P, Bhatt DL, Goodman S, Verheugt
FW, Flather M, Huber K, Liaw D, Husted SE, Lopez-Sendon J, De CR, Jansky P, Darius H,
Vinereanu D, Cornel JH, Cools F, Atar D, Leiva-Pons JL, Keltai M, Ogawa H, Pais P,
Parkhomenko A, Ruzyllo W, Diaz R, White H, Ruda M, Geraldes M, Lawrence J, Harrington
RA, Wallentin L. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J
Med 2011;365:699-708.2; Mega JL, Braunwald E, Mohanavelu S, Burton P, Poulter R,
Misselwitz F, Hricak V, Barnathan ES, Bordes P, Witkowski A, Markov V, Oppenheimer L,
Gibson CM. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS
ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet 2009;374:29-383; Mega JL,
Braunwald E, Wiviott SD, Bassand JP, Bhatt DL, Bode C, Burton P, Cohen M, Cook-Bruns N,
Fox KA, Goto S, Murphy SA, Plotnikov AN, Schneider D, Sun X, Verheugt FW, Gibson CM.
Rivaroxaban in Patients with a Recent Acute Coronary Syndrome. N Engl J Med 2012;366:919;4 Becker RC, Moliterno DJ, Jennings LK, Pieper KS, Pei J, Niederman A, Ziada KM, Berman
G, Strony J, Joseph D, Mahaffey KW, Van de Werf F, Veltri E, Harrington RA. Safety and
tolerability of SCH 530348 in patients undergoing non-urgent percutaneous coronary
intervention: a randomised, double-blind, placebo-controlled phase II study. Lancet
1
EURHEARTJ-D-12-02594
2009;373:919-9285; Tricoci P, Huang Z, Held C, Moliterno DJ, Armstrong PW, Van de Werf F,
White HD, Aylward PE, Wallentin L, Chen E, Lokhnygina Y, Pei J, Leonardi S, Rorick TL,
Kilian AM, Jennings LH, Ambrosio G, Bode C, Cequier A, Cornel JH, Diaz R, Erkan A, Huber
K, Hudson MP, Jiang L, Jukema JW, Lewis BS, Lincoff AM, Montalescot G, Nicolau JC,
Ogawa H, Pfisterer M, Prieto JC, Ruzyllo W, Sinnaeve PR, Storey RF, Valgimigli M, Whellan
DJ, Widimsky P, Strony J, Harrington RA, Mahaffey KW. Thrombin-Receptor Antagonist
Vorapaxar in Acute Coronary Syndromes. N Engl J Med 2012;366:20-336; Wiviott SD, Antman
EM, Winters KJ, Weerakkody G, Murphy SA, Behounek BD, Carney RJ, Lazzam C, McKay
RG, McCabe CH, Braunwald E. Randomized comparison of prasugrel (CS-747, LY640315), a
novel thienopyridine P2Y12 antagonist, with clopidogrel in percutaneous coronary intervention:
results of the Joint Utilization of Medications to Block Platelets Optimally (JUMBO)-TIMI 26
trial. Circulation 2005;111:3366-33737; Wiviott SD, Braunwald E, McCabe CH, Montalescot G,
Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De SS, Murphy SA, Riesmeyer J,
Weerakkody G, Gibson CM, Antman EM. Prasugrel versus clopidogrel in patients with acute
coronary syndromes. N Engl J Med 2007;357:2001-20158; Cannon CP, Husted S, Harrington
RA, Scirica BM, Emanuelsson H, Peters G, Storey RF. Safety, tolerability, and initial efficacy of
AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, compared with
clopidogrel, in patients with non-ST-segment elevation acute coronary syndrome: primary results
of the DISPERSE-2 trial. J Am Coll Cardiol 2007;50:1844-18519; Wallentin L, Becker RC,
Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey
KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA, Freij A, Thorsen M. Ticagrelor
versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045105710
2
EURHEARTJ-D-12-02594
Online Figure 1a. Incidence of TIMI Major Bleeding, non-CABG from ATLAS ACS 2-TIMI
51, TRITON-TIMI 38, and PLATO
Created based on data reported in: Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL,
Bode C, Burton P, Cohen M, Cook-Bruns N, Fox KA, Goto S, Murphy SA, Plotnikov AN,
Schneider D, Sun X, Verheugt FW, Gibson CM. Rivaroxaban in Patients with a Recent Acute
Coronary Syndrome. N Engl J Med 2012;366:9-194; Wiviott SD, Braunwald E, McCabe CH,
Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De SS, Murphy SA,
Riesmeyer J, Weerakkody G, Gibson CM, Antman EM. Prasugrel versus clopidogrel in patients
with acute coronary syndromes. N Engl J Med 2007;357:2001-20158; and Wallentin L, Becker
RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H,
Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA, Freij A, Thorsen M.
Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med
2009;361:1045-105710.
Online Figure 1b. Composite Endpoint of Cardiovascular Death, MI, or Stroke in ATLAS ACS
2-TIMI 51, TRITON-TIMI 38, and PLATO
Created based on data reported in: Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL,
Bode C, Burton P, Cohen M, Cook-Bruns N, Fox KA, Goto S, Murphy SA, Plotnikov AN,
Schneider D, Sun X, Verheugt FW, Gibson CM. Rivaroxaban in Patients with a Recent Acute
Coronary Syndrome. N Engl J Med 2012;366:9-194; Wiviott SD, Braunwald E, McCabe CH,
Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De SS, Murphy SA,
Riesmeyer J, Weerakkody G, Gibson CM, Antman EM. Prasugrel versus clopidogrel in patients
with acute coronary syndromes. N Engl J Med 2007;357:2001-20158; and Wallentin L, Becker
3
EURHEARTJ-D-12-02594
RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H,
Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA, Freij A, Thorsen M.
Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med
2009;361:1045-105710.
4
EURHEARTJ-D-12-02594
Online Appendix. Bleeding Definitions
1. BARC
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
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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)
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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.
2. GUSTO
Severe or Life Threatening
Either intracranial hemorrhage or bleeding that causes hemodynamic compromise and requires
intervention
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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
3. 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
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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.
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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
4. 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
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Other hemorrhages that led to interruption of the study medication
5. 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.
6. 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
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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.
7. 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, intraarticular bleeding, or pericardial bleeding
Furthermore, major bleed is classified as life-threatening if they met ≥ 1 of the following criteria:
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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
8. 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
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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)
9. 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
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Reference List for Figure Legend
1. Alexander JH, Becker RC, Bhatt DL, Cools F, Crea F, Dellborg M, Fox KA, Goodman
SG, Harrington RA, Huber K, Husted S, Lewis BS, Lopez-Sendon J, Mohan P,
Montalescot G, Ruda M, Ruzyllo W, Verheugt F, Wallentin L. Apixaban, an oral, direct,
selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary
syndrome: results of the Apixaban for Prevention of Acute Ischemic and Safety Events
(APPRAISE) trial. Circulation 2009;119:2877-2885.
2. Alexander JH, Lopes RD, James S, Kilaru R, He Y, Mohan P, Bhatt DL, Goodman S,
Verheugt FW, Flather M, Huber K, Liaw D, Husted SE, Lopez-Sendon J, De CR, Jansky
P, Darius H, Vinereanu D, Cornel JH, Cools F, Atar D, Leiva-Pons JL, Keltai M, Ogawa
H, Pais P, Parkhomenko A, Ruzyllo W, Diaz R, White H, Ruda M, Geraldes M,
Lawrence J, Harrington RA, Wallentin L. Apixaban with antiplatelet therapy after acute
coronary syndrome. N Engl J Med 2011;365:699-708.
3. Mega JL, Braunwald E, Mohanavelu S, Burton P, Poulter R, Misselwitz F, Hricak V,
Barnathan ES, Bordes P, Witkowski A, Markov V, Oppenheimer L, Gibson CM.
Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACSTIMI 46): a randomised, double-blind, phase II trial. Lancet 2009;374:29-38.
4. Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL, Bode C, Burton P, Cohen M,
Cook-Bruns N, Fox KA, Goto S, Murphy SA, Plotnikov AN, Schneider D, Sun X,
Verheugt FW, Gibson CM. Rivaroxaban in Patients with a Recent Acute Coronary
Syndrome. N Engl J Med 2012;366:9-19.
15
EURHEARTJ-D-12-02594
5. Becker RC, Moliterno DJ, Jennings LK, Pieper KS, Pei J, Niederman A, Ziada KM,
Berman G, Strony J, Joseph D, Mahaffey KW, Van de Werf F, Veltri E, Harrington RA.
Safety and tolerability of SCH 530348 in patients undergoing non-urgent percutaneous
coronary intervention: a randomised, double-blind, placebo-controlled phase II study.
Lancet 2009;373:919-928.
6. Tricoci P, Huang Z, Held C, Moliterno DJ, Armstrong PW, Van de Werf F, White HD,
Aylward PE, Wallentin L, Chen E, Lokhnygina Y, Pei J, Leonardi S, Rorick TL, Kilian
AM, Jennings LH, Ambrosio G, Bode C, Cequier A, Cornel JH, Diaz R, Erkan A, Huber
K, Hudson MP, Jiang L, Jukema JW, Lewis BS, Lincoff AM, Montalescot G, Nicolau
JC, Ogawa H, Pfisterer M, Prieto JC, Ruzyllo W, Sinnaeve PR, Storey RF, Valgimigli M,
Whellan DJ, Widimsky P, Strony J, Harrington RA, Mahaffey KW. Thrombin-Receptor
Antagonist Vorapaxar in Acute Coronary Syndromes. N Engl J Med 2012;366:20-33.
7. Wiviott SD, Antman EM, Winters KJ, Weerakkody G, Murphy SA, Behounek BD,
Carney RJ, Lazzam C, McKay RG, McCabe CH, Braunwald E. Randomized comparison
of prasugrel (CS-747, LY640315), a novel thienopyridine P2Y12 antagonist, with
clopidogrel in percutaneous coronary intervention: results of the Joint Utilization of
Medications to Block Platelets Optimally (JUMBO)-TIMI 26 trial. Circulation
2005;111:3366-3373.
8. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S,
Neumann FJ, Ardissino D, De SS, Murphy SA, Riesmeyer J, Weerakkody G, Gibson
CM, Antman EM. Prasugrel versus clopidogrel in patients with acute coronary
syndromes. N Engl J Med 2007;357:2001-2015.
16
EURHEARTJ-D-12-02594
9. Cannon CP, Husted S, Harrington RA, Scirica BM, Emanuelsson H, Peters G, Storey RF.
Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral adenosine
diphosphate receptor antagonist, compared with clopidogrel, in patients with non-STsegment elevation acute coronary syndrome: primary results of the DISPERSE-2 trial. J
Am Coll Cardiol 2007;50:1844-1851.
10. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J,
Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF,
Harrington RA, Freij A, Thorsen M. Ticagrelor versus clopidogrel in patients with acute
coronary syndromes. N Engl J Med 2009;361:1045-1057.
17