JACC: CARDIOVASCULAR INTERVENTIONS
VOL. 3, NO. 12, 2010
© 2010 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 1936-8798/$36.00
PUBLISHED BY ELSEVIER INC.
DOI: 10.1016/j.jcin.2010.09.015
STATE-OF-THE-ART PAPER
The Evolving Role of Glycoprotein IIb/IIIa Inhibitors
in the Setting of Percutaneous Coronary Intervention
Strategies to Minimize Bleeding Risk and Optimize Outcomes
Elias B. Hanna, MD,* Sunil V. Rao, MD,† Steven V. Manoukian, MD‡
Jorge F. Saucedo, MD§
New Orleans, Louisiana; Durham, North Carolina; Nashville, Tennessee;
and Oklahoma City, Oklahoma
The use of glycoprotein IIb/IIIa inhibitors (GPI) reduces ischemic events in patients undergoing percutaneous coronary intervention (PCI). However, the same properties that confer this benefit lead to an
increased bleeding risk. Recent studies have shown a less robust net clinical benefit of GPI in the current era of routine thienopyridine and direct thrombin inhibitor use. To optimize the net clinical benefit of GPI, these agents need to be selectively used in patients most likely to benefit from their antiischemic effect, namely patients undergoing PCI for non–ST-segment elevation myocardial infarction,
select patients undergoing primary PCI, and select patients undergoing PCI without appropriate preloading with a thienopyridine. Moreover, strategies to minimize bleeding should be applied in these
patients and include shorter GPI infusions (in some patients), dose adjustments of heparin and GPI,
careful access site management with more frequent use of the transradial approach, use of smaller
sheaths, and identification of patients at high bleeding risk. This review provides an update of the current literature that supports these measures, an insight on the tailored use of GPI, and a potential direction for future research addressing combined antithrombotic therapies. (J Am Coll Cardiol Intv
2010;3:1209 –19) © 2010 by the American College of Cardiology Foundation
Glycoprotein IIb/IIIa inhibitors (GPI) are potent
parenteral inhibitors of platelet aggregation. Three
agents are available—abciximab, eptifibatide, and
tirofiban—and have been studied across the spec-
From the *Department of Medicine, Cardiovascular Section, Louisiana
State University, New Orleans, Louisiana; †Duke Clinical Research
Institute, Durham, North Carolina; ‡The Sarah Cannon Research
Institute and the Hospital Corporation of America, Nashville, Tennessee; and the §Department of Medicine, Cardiovascular Section, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
Dr. Hanna reports he has no relationships to disclose. Dr. Rao received
funding from Portola Pharmaceuticals, Cordis Corporation, Novartis,
and Medicure; he consults and received honoraria for The Medicines
Company, Bristol-Myers Squibb, sanofi, Terumo USA, Astra Zeneca,
and Daiichi Sankyo-Lilly. Dr. Manoukian has served as a consultant for
Bristol-Myers Squibb, Sanofi-Aventis, Daiichi Sankyo, Eli Lilly, and the
Medicines Company. Dr. Saucedo has served as a consultant for Merck,
Daiichi Sankyo-Lilly, and Medicure; he is a shareholder for Vascular
Solutions Inc., and received honoraria for Merck and Lilly/Daiichi.
Manuscript received August 2, 2010; revised manuscript received
September 13, 2010, accepted September 15, 2010.
trum of acute ischemic heart disease as well as for
elective and primary percutaneous coronary intervention (PCI) (1–12). The use of all 3 agents in the
setting of PCI has been associated with a significant reduction in both short- and long-term events
compared with unfractionated or low-molecularweight heparin alone. Indeed, a 35% to 50%
reduction in major adverse cardiovascular ischemic
events was reported in low-, intermediate-, and
high-risk patients undergoing PCI including patients with stable coronary artery disease (CAD)
(1,3,4), patients presenting with non–ST-segment
elevation acute coronary syndrome (NSTE-ACS)
(5,7,8), particularly patients with elevated troponin
levels (5,12), and patients presenting with STsegment elevation myocardial infarction (STEMI)
(9 –11) (Tables 1, 2, and 3). Notably, this reduction
in events was mainly driven by a reduction in
periprocedural myocardial infarctions, including
1210
Hanna et al.
Optimize GPI Therapy
JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 3, NO. 12, 2010
DECEMBER 2010:1209 –19
large or Q-wave myocardial infarctions, but there was no
mortality reduction. Furthermore, a meta-analysis suggested
that the use of GPI in NSTE-ACS was associated with a
mortality reduction in diabetic patients, but this was not
confirmed in a randomized trial (13). All of these studies
demonstrated that the risk of bleeding, measured in a variety
of ways, was higher with the addition of GPI to standard
therapy; however, the lack of other therapeutic options and
the high rate of adverse outcomes in both the acute coronary
syndrome (ACS) and PCI settings made for an acceptable
trade-off between the benefit of reduced ischemic events and
the risk of increased bleeding.
Stenting was not routinely performed in these early
studies, and patients were not pre-treated with thienopyridines. As the therapeutic armaAbbreviations
mentarium of ischemic heart
and Acronyms
disease has evolved, the utility of
GPI has become less clear in a
ACS ⴝ acute coronary
variety of clinical settings. The
syndrome(s)
purpose of this review is to sumACT ⴝ activated clotting
time
marize the data reducing the role
of GPI to a select population in
CAD ⴝ coronary artery
disease
the current era, review strategies
CrCl ⴝ creatinine clearance
for reducing the bleeding risk
associated with GPI, and deGPI ⴝ glycoprotein IIb/IIIa
inhibitor(s)
velop a proposal for what role
GPI should play in the modern
MI ⴝ myocardial infarction
era.
NSTE-ACS ⴝ non–STsegment elevation acute
coronary syndrome(s)
NSTEMI ⴝ non–ST-segment
elevation myocardial
infarction
Bleeding Risk Associated
With GPI
Whereas ischemic events were
strikingly reduced with abciximab in the EPIC (Evaluation of
STEMI ⴝ ST-segment
c7E3 for the Prevention of Ischelevation myocardial
emic Complications) trial, TIMI
infarction
(Thrombolysis In Myocardial
TIMI ⴝ Thrombolysis In
Infarction) major bleeding risk
Myocardial Infarction
was similarly increased (7% for
placebo vs. 14% for abciximab, p ⫽ 0.001). However, when
adjusted-dose heparin and early sheath removal were implemented, GPI use was associated with a smaller (⬃1%)
absolute increase in major bleeding in some studies (4,5,8),
and no significant increase in major bleeding in other
studies (2,3,6,7). Transfusion requirements and TIMI minor bleeding remained higher with GPI. Of note, the TIMI
scale may underestimate rates of clinically important bleeding complications, and TIMI minor bleeding has been
associated with over a 50% increase in the adjusted rate of
death or myocardial infarction (MI) (14). Thus, significant
bleeding associated with GPI may be more common than
reported in these early trials.
PCI ⴝ percutaneous
coronary intervention
As described in many PCI trials, most major bleeding
occurs at the femoral access site (1,5). In fact, groin
hematoma and retroperitoneal hemorrhage constituted 60%
to 80% and 5% to 10% of major bleeding events, respectively, whereas gastrointestinal bleeding and intracranial
bleeding constituted ⬃15% and ⬍2% of major bleeding
episodes, respectively. Thus, a safer vascular access strategy
will potentially attenuate the bleeding risk associated with
GPI.
Evolution of PCI Pharmacotherapy:
Diminishing Role of Traditional GPI Dosing
and Current Indications
As opposed to the pivotal GPI trials (1–11), studies performed in the current era of routine stenting and thienopyridine therapy have not consistently shown a net clinical
benefit with GPI, that is, a benefit on the composite of
death, MI, revascularization, and major bleeding (Table 4).
After pre-loading with 600 mg of clopidogrel at least 2 h
before elective PCI, the ISAR-REACT (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for
Coronary Treatment) trial indicated that the addition of
abciximab to unfractionated heparin in low-risk patients undergoing elective PCI did not further reduce ischemic complications (15); this was further expanded to elective PCI in
diabetic patients in the ISAR-SWEET (Is Abciximab a
Superior Way to Eliminate Elevated Thrombotic Risk in
Diabetics) trial (16). In both studies, bleeding rates were higher
with GPI, therefore shifting the traditional benefit-risk ratio
away from supporting their routine use in elective PCI.
Furthermore, in the case of STEMI, the BRAVE-3 (Bavarian
Reperfusion Alternatives Evaluation-3) trial (17) showed that
the addition of abciximab to heparin in patients undergoing
primary PCI and pre-loaded with 600 mg of clopidogrel in the
emergency department did not reduce infarct size or improve
clinical outcomes. Previously, the CADILLAC (Controlled
Abciximab and Device Investigation to Lower Late Angioplasty Complications) trial had shown that patients presenting
with STEMI and undergoing stenting did not achieve the
same marked benefit with abciximab as patients undergoing
angioplasty did (10). Accordingly, the above-mentioned data
questioned the value of GPI in both elective PCI and primary
PCI. However, in the ISAR-REACT 2 trial, the tailored use
of GPI for high-risk NSTE-ACS patients, particularly patients with elevated troponin levels, was beneficial despite
stenting and pre-loading with clopidogrel and provided a
substantial clinical benefit without significantly increasing major or minor bleeding rates (18). Thus, this trial identified a
population in which GPI use is still warranted. In addition, the
use of GPI in patients undergoing an elective PCI for stable
CAD, but not adequately pre-loaded with thienopyridines, still
seems reasonable (19).
1211
Hanna et al.
Optimize GPI Therapy
JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 3, NO. 12, 2010
DECEMBER 2010:1209 –19
Table 1. Major Studies Addressing GPI Use in Patients Undergoing PCI (Elective Indication or ACS) Before the Era of Routine Stenting and Appropriate
Thienopyridine Pre-Loading
GPI vs. Placebo
GPI
n
Routine
Stenting
(% Stent Use)
EPIC
(1994) (1)
Abciximab
2,099
No (⬍2%)
No
N/A
42%
6.6% vs. 9.6%,
p ⫽ 0.01
14% vs. 7%,
p ⫽ 0.001
EPILOG
(1997) (2)
Abciximab
2,792
No (15%)
No
N/A
46%
4% vs. 9.1%,
p ⬍ 0.001
2% vs. 3.1%,
p ⫽ NS in low-dose UFH†
4% vs. 3.7%,
p ⫽ NS in low-dose UFH†
EPISTENT
(1998) (3)
Abciximab
2,399
Yes (100%)
No
Yes
36%
5.2% vs. 10.2%,
p ⬍ 0.001
1.5% vs. 2.2%,
p ⫽ NS
2.9% vs. 1.7%,
p ⫽ NS
ESPRIT
(2000) (4)
Eptifibatide 2,064
Yes (95%)
No
Yes
13%
6.4% vs. 10.2%,
p ⫽ 0.0014
1% vs. 0.4%,
p ⫽ 0.027
2.8% vs. 1.7%,
p ⫽ NS
Study
(Year) (Ref. #)
Appropriate
Thienopyridine
Pre-Loading
Thienopyridine
Therapy After
PCI
% ACS
Death or MI
at 30 Days
TIMI Major
Bleeding*
TIMI Minor
Bleeding*
N/A
*TIMI major bleeding is defined as intracranial hemorrhage or 5 g/dl decrease in the hemoglobin concentration. TIMI minor bleeding is defined as 4 g/dl decrease in the hemoglobin concentration or 3 g/dl
decrease in the hemoglobin concentration in case of overt hemorrhage. †In EPILOG trial, patients randomized to GPI ⫹ high-dose UFH had increased minor bleeding events in comparison with placebo: 7.4%
versus 3.7%, p ⬍ 0.001.
ACS ⫽ acute coronary syndrome(s); GPI ⫽ glycoprotein IIb/IIIa inhibitor; N/A ⫽ not available; NS ⫽ nonsignificant; PCI ⫽ percutaneous coronary intervention; TIMI ⫽ Thrombolysis In Myocardial Infarction;
UFH ⫽ unfractionated heparin.
Newer oral antiplatelet therapies, such as prasugrel and
ticagrelor, have not been studied in the setting of elective
PCI, but they have shown a benefit over clopidogrel in the
setting of NSTE-ACS and STEMI managed invasively
(20,21). In the TRITON–TIMI-38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel) trial of 13,608 patients with
ACS undergoing PCI, 55% of the patients received GPI.
The benefit of prasugrel over clopidogrel was consistent
among patients who did or did not receive GPI, and the
relative increase of major or minor bleeding with prasugrel
versus clopidogrel was not significantly different in patients
who were or were not treated with GPI (22). This established the benefit of prasugrel even in the setting of potent
platelet inhibition with GPI. Similarly, the benefit and
safety of ticagrelor versus clopidogrel was not altered in
patients receiving GPI (21). However, whereas the utility of
adding the potent and prompt platelet inhibitors prasugrel
or ticagrelor to GPI has been investigated, the benefit and
safety of adding GPI therapy to prasugrel or ticagrelor have
not been evaluated yet and merit investigation.
In addition to antiplatelet therapy, anticoagulants have
also undergone significant evolution and available options
now include low-molecular-weight heparins (both subcutaneous and intravenous), synthetic indirect factor Xa inhibitors, and direct thrombin inhibitors. The agent that has
been most studied directly against a GPI-based strategy is
the direct thrombin inhibitor bivalirudin. Unlike unfractionated and low-molecular-weight heparins, bivalirudin
does not activate platelets. The REPLACE-2 (Randomized
Evaluation of PCI Linking Angiomax to Reduced Clinical
Events) trial (23) compared a strategy of bivalirudin plus
provisional GPI to a strategy of unfractionated heparin plus
routine GPI in ⬃6,000 patients undergoing elective PCI.
The primary end point of 30-day death, MI, target vessel
revascularization, and major bleeding was similar between
Table 2. Major Studies Addressing GPI Use in Patients With ACS, a Proportion of Whom Underwent PCI, Before the Era of Routine Stenting and
Appropriate Thienopyridine Pre-Loading
GPI
n
% Undergoing
PCI
Routine
Stenting in
the PCI
Subgroup
(% Stent Use)
CAPTURE
(1997) (5)
Abciximab
1,560
98%
No (⬍2%)
No
N/A
31%
4.8% vs. 9%,
p ⫽ 0.003*
3.8% vs. 1.9%,
p ⫽ 0.04
RESTORE
(1997) (6)
Tirofiban
2,212
100%
No (2.5%)
No
N/A
33%
5.1% vs. 6.3%,
p ⫽ 0.1
2.4% vs. 2.1%,
p ⫽ 0.67
N/A
PRISM-PLUS
(1998) (7)
Tirofiban
1,560
30%
No (⬍2%)
No
N/A
45%
8.7% vs. 12%,
p ⫽ 0.004
1.4% vs. 0.8%,
p ⫽ 0.23
N/A
PURSUIT
(1998) (8)
Eptifibatide
10,948
24%
(50%)
No
N/A
45%
14.2% vs. 15.7%,
p ⫽ 0.004
3% vs. 1.3%,
p ⬍ 0.001
Study
(Year) (Ref. #)
GPI vs. Placebo
Thienopyridine
Pre-Loading
Thienopyridine
Therapy After
PCI
%
Elevated
Troponin
Death or MI at
30 Days
TIMI Major
Bleeding
TIMI Minor
Bleeding
4.8% vs. 2%,
p ⫽ 0.008
11.1% vs. 4.7%,
p ⬍ 0.001
*In CAPTURE trial, the benefit of GPI was limited to patients with elevated troponin (death or MI at 30 days: 5.8% with GPI vs. 19.6% with placebo if troponin elevated; 5.2% with GPI vs. 4.9% with placebo if
troponin was not elevated).
MI ⫽ myocardial infarction; other abbreviations as in Table 1.
1212
Hanna et al.
Optimize GPI Therapy
JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 3, NO. 12, 2010
DECEMBER 2010:1209 –19
Table 3. Major Studies Addressing GPI Use in Patients Undergoing Primary PCI for STEMI
GPI vs. Placebo
Study
(Year) (Ref. #)
GPI
n
% Stent
Thienopyridine Loading
Before or Immediately
After PCI*
Death, MI, Urgent
TVR at 30 Days
Major
Bleeding†
Minor or Moderate
Bleeding†
ADMIRAL
(2001) (9)
Abciximab
300
92%
No
6.0% vs. 14.6%,
p ⫽ 0.01
0.7% vs. 0%,
p ⫽ NS
35.3% vs. 12.1%,
p ⫽ 0.004
CADILLAC
angioplasty
arms (2002) (10)
Abciximab
1,046
0%
Yes
4.8% vs. 8.3%,
p ⫽ 0.02
0.4% vs. 0.6%,
p ⫽ NS
2.3% vs. 2.5%,
p ⫽ NS
CADILLAC stent
arms (2002) (10)
Abciximab
1,036
100%
Yes
4.4% vs. 5.7%,
p ⫽ NS
0.8% vs. 0.2%,
p ⫽ NS
4.3% vs. 2.5%,
p ⫽ NS
ON-TIME 2
(2008) (11)
Tirofiban
984
90%
Yes
7% vs. 8.2%,
p ⫽ NS‡
4% vs. 2.9%,
p ⫽ NS
6.1% vs.4.4%,
p ⫽ NS
* In the ON-TIME 2 trial, patients were pre-loaded with 600 mg of clopidogrel before arrival to the cardiac catheterization laboratory. In CADILLAC trial, 300 mg of clopidogrel or 500 mg of ticlopidine were given
before cardiac catheterization. No loading dose of thienopyridine was administered in the ADMIRAL trial. †TIMI criteria were used to defined major and minor bleeding in ADMIRAL and ON-TIME 2 trials, and
GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) trial criteria were used to define major and moderate bleeding in CADILLAC trial. ‡In the ON-TIME 2 trial, the high-bolus dose of tirofiban
reduced the primary end point of residual ST-segment deviation 1 h after PCI but did not improve TIMI flow grade or clinical outcomes.
TVR ⫽ target vessel revascularization; other abbreviations as in Tables 1 and 2.
the 2 strategies. This noninferiority was driven by a significant reduction in major and minor bleeding with bivalirudin that came at the expense of a slight and nonsignificant
increase in periprocedural MI rate. Similarly, in the open
label ACUITY (Acute Catheterization and Urgent Intervention Strategy) trial of patients with intermediate-to
high-risk NSTE-ACS randomized to bivalirudin alone,
bivalirudin plus GPI, or heparin (either unfractionated or
low-molecular-weight) plus GPI, there was a trend toward
a reduction of ischemic events in the GPI arms, particularly
in the absence of thienopyridine pre-loading (24). Again, an
increased risk of major bleeding counterbalanced the antiischemic benefit of GPI therapy. This pattern held also in
the HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction)
trial that compared bivalirudin to heparin plus GPI in the
setting of primary PCI after preloading with 300 to 600 mg
of clopidogrel in the emergency department; patients in the
bivalirudin arm had significantly less bleeding, but a significantly higher rate of acute stent thrombosis (25). Interestingly however, in the HORIZONS-AMI trial, the rate of
stent thrombosis at 30 days was not significantly different
between the 2 arms and bivalirudin was associated with a
lower 30-day and 1-year mortality that may have been
related to the bleeding reduction (25,26). Thus, although
the role of GPI has been questioned in patients presenting
with STEMI and receiving heparin (17), this role is further
reduced in patients receiving bivalirudin. The American
College of Cardiology guidelines currently give a Class IIa
recommendation for the use of GPI at the time of primary PCI
in select patients with STEMI, particularly patients with a
large thrombus burden or those who have not received adequate thienopyridine loading (27).
Table 4. Randomized Trials of GPI Therapy During PCI in the Context of Routine Stenting and Adequate Thienopyridine Pre-Loading
GPI vs. Placebo
Study
(Year) (Ref. #)
% Complex
(Type B2/C)
Coronary
Lesions
%
Diabetes
Stable CAD
65%
21%
68%
n
Study Population
ISAR-REACT
(2004) (15)
2,159
ISAR-SWEET
(2004) (16)
701
Stable CAD diabetes
BRAVE-3
(2009) (17)
800
STEMI
ISAR-REACT 2
(2006) (18)
2,022
ACS 1 troponin in 51%
Death/MI/Urgent
Vessel
Revascularization at
30 Days
TIMI Major
Bleeding*
TIMI Minor
Bleeding*
% Patients
Requiring
Transfusion
4% vs. 4%,
p ⫽ NS
1% vs. 1%,
p ⫽ NS
2% vs. 2%,
p ⫽ NS
2% vs. 1%,
p ⫽ 0.007
100%
5.7% vs. 4.3%,
p ⫽ 0.39
1.1% vs. 0.9%,
p ⫽ NS
3.4% vs. 1.4%,
p ⫽ 0.09
2.3% vs. 0.6%,
p ⫽ 0.11
—
19%
4.7% vs. 3.5%,
p ⫽ NS†
1.8% vs. 1.8%,
p ⫽ NS
3.7% vs. 1.8%,
p ⫽ 0.06
3% vs. 3.3%,
p ⫽ NS
80%
25%
8.9% vs. 11.9%,
p ⫽ 0.03‡
1.4% vs. 1.4%,
p ⫽ NS
4.2% vs. 3.3%,
p ⫽ NS
2.5% vs. 2%,
p ⫽ NS
*See TIMI bleeding definition in Table 1. †In the BRAVE-3 trial, abciximab was not associated with a reduction in infarct size (the primary end point). Patients were pre-loaded with 600 mg of clopidogrel in the
emergency department. ‡In patients with elevated troponin values, event rates with GPI versus placebo: 13.1% versus 18.3%, p ⫽ 0.02. In patients without troponin elevation, event rates with GPI versus
placebo: 4.6% versus 4.6%, p ⫽ 0.99.
CAD ⫽ coronary artery disease; STEMI ⫽ ST-segment elevation myocardial infarction; other abbreviations as in Tables 1, 2, and 3.
Hanna et al.
Optimize GPI Therapy
JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 3, NO. 12, 2010
DECEMBER 2010:1209 –19
1213
Table 5. Measures That Reduce Bleeding Risk With GPI
Dosage and infusion
●
Bolus-only strategy or reduction of infusion duration
●
Careful selection of upstream therapy in acute coronary syndromes limited to patients who have not received thienopyridine loading
and who are at the highest spectrum of risk
●
Heparin dose adjustment to obtain ACT ⬍250 s during PCI (starting bolus ⱕ50 U/kg)
●
Eptifibatide and tirofiban infusion dose adjustment in patients with creatinine clearance ⱕ50 and ⱕ30 ml/min, respectively
Patient selection
●
Avoidance of GPI in patients older than 75 years and in patients at high bleeding risk
●
Targeting patients with NSTEMI undergoing PCI (particularly if not receiving bivalirudin or if receiving bivalirudin but not adequately pre-loaded with a thienopyridine)
Access selection and management
●
Use of transradial approach
●
Use of smaller sheath size
●
Prompt sheath removal
●
Avoidance of venous sheath placement in case of femoral access
●
Use of vascular closure devices (possibly)
ACT ⫽ activating clotting time; other abbreviations as in Tables 1, 2, 3, and 4.
Current indications for GPI use. In summary, the antiischemic value of GPI seems currently limited to 4 subgroups of patients: 1) patients with non–ST-segment elevation myocardial infarction (NSTEMI) undergoing PCI
(18), particularly if they are not receiving bivalirudin, or if
they are receiving bivalirudin but are not adequately preloaded with a thienopyridine, as recommended by the
American College of Cardiology guidelines (24,28); 2)
patients having thrombotic complications or large sidebranch closure or unsealed dissection during any PCI
performed for stable or unstable CAD, whether bivalirudin
is used or not (GPI were used for bailout in 7% and 9% of
patients randomized to bivalirudin in the REPLACE-2 and
ACUITY trials, respectively); 3) select patients with
STEMI, particularly those not pre-loaded with a thienopyridine in the emergency department or those with a large
thrombus burden; 4) patients undergoing ad hoc PCI for
stable or unstable CAD and not adequately pre-loaded with
a thienopyridine (19). In fact, studies that did not show a
benefit of GPI in elective PCI had mandated appropriate
clopidogrel pre-loading and there is currently not enough
evidence that supports omitting GPI in patients receiving
heparin and not adequately pre-loaded with a thienopyridine (15,16,19). However, if bivalirudin is the anticoagulant
used in elective PCI, GPI may be omitted regardless of
thienopyridine pre-loading (29); as opposed to ACS, the
comparable effectiveness of bivalirudin and heparin plus
GPI in elective PCI was not influenced by clopidogrel
pre-treatment (29). Also, GPI may be omitted in ad hoc
elective PCI if a rapid-onset and potent oral P2Y12 receptor
antagonist is loaded during PCI, but this strategy has yet to
be tested.
On the other hand, if hyporesponsiveness to clopidogrel
or aspirin is suspected clinically or on the basis of platelet
function or genetic testing, GPI may have a role even in
patients undergoing PCI for stable CAD. In the 3T/2R
(Tailoring Treatment With Tirofiban in Patients Showing
Resistance to Aspirin and/or Resistance to Clopidogrel)
study, patients undergoing PCI who were poor responders
to aspirin, clopidogrel, or both who were treated with
tirofiban compared to placebo had a significant reduction in
the 30-day risk of major adverse cardiovascular events (3.8%
vs. 10.7%, p ⫽ 0.031), without an increase in bleeding (30).
With further study, expanded use of bedside and laboratory
platelet function testing, and wider use of genetic testing,
the role of GPI in these situations will become better
defined.
Because a robust relationship between major bleeding and
increased mortality and morbidity has been reported in
several analyses, the reduction of bleeding risk has become a
primary target for improving PCI outcomes (31,32). Therefore, it is reasonable to better define strategies of GPI
administration that would reduce bleeding risk in the 4
subgroups of patients who benefit from GPI, particularly
patients with NSTEMI. Several potential options are available and are discussed herein (Table 5).
Duration of Infusion of GPI After PCI:
The Appropriateness of Bolus-Only or
Short-Infusion Strategy
Currently, on the basis of the EPIC and ESPRIT (Novel
Dosing Regimen of Eptifibatide in Planned Coronary Stent
Implantation) trials, it is recommended to administer a 12-h
infusion of abciximab and an 18- to 24-h infusion of
eptifibatide, respectively, after PCI. In the EPIC trial, an
abciximab bolus followed by a 12-h infusion resulted in a
35% reduction in the rate of death, MI, or unplanned
revascularization at 30 days compared with unfractionated
heparin alone (1). By contrast, patients receiving bolus-only
were protected for the first 6 h only; end points measured at
1214
Hanna et al.
Optimize GPI Therapy
JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 3, NO. 12, 2010
DECEMBER 2010:1209 –19
Table 6. Studies Comparing a Bolus-Only Strategy or a Short Infusion of GPI With Long Standard Infusions
Study
(Year) (Ref. #)
Study Type
GPI Type
Study
Population
B2/C Coronary
Lesion*
(%)
Duration of
Infusion
Adequate
Clopidogrel
Load
Before PCI†
(%)
Bolus-Only or Short Infusion
vs. Prolonged Infusion
Death/MI/
Urgent TVR
at 30 Days
Major
Bleeding
Risk‡
Minor
Bleeding
Risk‡
BRIEF PCI
(2009) (33)
RCT, 624
patients
Eptifbatide
ACS (53%) or
stable CAD;
32% positive
troponin
63%
⬍2 h vs. 18 h
70%
4.8% vs. 4.5%,
p ⫽ 1.0
1% vs. 4.2%,
p ⫽ 0.02
17.6% vs. 21.2%,
p ⫽ 0.31
EASY
(2006) (34)
RCT, 1,005
patients
Abciximab
ACS or stable
CAD;
20% positive
troponin
47%
Bolus-only vs.
12 h
92%
1.4% vs. 1.8%,
p ⫽ NS
0.8% vs. 0.2%,
p ⫽ NS
N/A
Kini et al.
(2008) (35)
Retrospective
analysis,
2,629
patients
Eptifibatide
(72%)
or abciximab
(28%)
ACS (39%) or
stable CAD;
14% positive
troponin
80%
Bolus-only vs.
12–18 h
54%
3.2% vs. 3%,
p ⫽ 0.73
0.8% vs. 1.6%,
p ⫽ 0.09
1.1% vs. 2.2%,
p ⫽ 0.03
*Coronary lesions defined according to lesion classification of American College of Cardiology/American Heart Association. †The definition of appropriate clopidogrel load before PCI varied between studies
(600 mg ⬎2 h or 300 mg ⬎6 h or 75 mg ⬎4 days before PCI [33]; 300 mg ⬎12 h before PCI [34] ; 300 mg ⬎ 3 h before PCI (35)). ‡Major and minor bleeding risks were defined according to REPLACE-2 study
criteria. Major bleeding ⫽ intracranial, intraocular, or retroperitoneal hemorrhage; clinically overt blood loss resulting in a decrease in hemoglobin ⱖ3 g/dl; any decrease in hemoglobin ⱖ4 g/dl; or transfusion
of at least 2 U of packed red blood cells or whole blood. Minor bleeding ⫽ clinically overt bleeding that did not meet major bleeding criteria.
RCT ⫽ randomized controlled trial; other abbreviations as in Tables 1, 2, 3, 4, and 5.
30 days demonstrated no difference between bolus-only and
placebo because of ongoing ischemic events beyond 6 h,
mainly driven by acute vessel closure. However, in the EPIC
trial, thienopyridine therapy was not used and only balloon
angioplasty was performed. Routine stenting with optimal
deployment technique and coverage of dissection planes
reduces the prothrombotic stimuli and may obviate the need
for prolonged GPI infusion. However, due to the concern
raised by the EPIC trial, subsequent trials of abciximab in
PCI generally used bolus and 12-h infusion regimens
despite routine stenting and thienopyridine therapy. Similarly, large trials of eptifibatide did not attempt to reduce or
eliminate the infusion.
Few studies have specifically addressed the issue of the
infusion duration in the modern era (Table 6) (33–35). The
BRIEF-PCI (Brief Infusion of Eptifibatide Following Percutaneous Coronary Intervention) trial randomized patients
who received eptifibatide bolus therapy and underwent
successful PCI with stenting to either a standard (18 h) or
shorter (ⱕ2 h) infusion of eptifibatide (33). All patients
received appropriate clopidogrel therapy before or at the
conclusion of PCI. Whereas 32% of patients had ACS with
elevated troponin level, most patients had stable CAD.
Moreover, patients with visible thrombus, unsealed dissection, coronary slow flow, or loss of major side branches were
excluded. Compared with the standard infusion, the shorter
infusion was associated with a similar incidence of periprocedural myonecrosis and adverse ischemic events at 30 days
and a significantly lower incidence of major bleeding (1% vs.
4.2%, p ⫽ 0.02).
In the EASY (Early Discharge After Transradial Stenting
of Coronary Arteries) trial by Bertrand et al. (34), 1,005
patients who received a bolus of abciximab during an uncomplicated transradial PCI were randomly allocated to either an
abciximab bolus-only strategy and same-day discharge, or to a
standard 12-h abciximab infusion and overnight hospitalization. Only 20% of patients had an elevated troponin level at the
time of the procedure. The bolus-only strategy was noninferior
with respect to the 30-day occurrence of death or adverse
ischemic events. Major bleeding was low in both groups, likely
related to the use of the radial access site. Of note, more than
90% of patients in the EASY trial had received clopidogrel
⬎12 h before the procedure.
These findings are similar to those reported in a large
retrospective single-center analysis (35). A major limitation of
these studies is that they compared short-length with fulllength regimens of GPI, rather than a short-length regimen of
GPI with placebo. Because most of these patients were
undergoing elective PCI for stable CAD and because in the
current era, GPI are mainly beneficial in NSTEMI, there was
a questionable need for GPI in most of these patients. Thus,
this strategy needs to be adequately studied in NSTEMI and
potentially in patients with stable CAD undergoing ad hoc
PCI without clopidogrel pre-loading, where a bolus of GPI
with a truncated infusion may be enough to bridge the gap
between PCI and the 2-to-8-h time it takes clopidogrel to
reach an adequate antiplatelet effect (this theory is yet unproven). The newer P2Y12 receptor antagonists, prasugrel or
ticagrelor, which induce a much higher and consistent inhibition of platelet activity coupled with a prompt onset of activity
within 30 min of administration, may further influence any
need for GPI, more so prolonged GPI infusions, but this needs
to be tested prospectively (36,37).
JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 3, NO. 12, 2010
DECEMBER 2010:1209 –19
GPI Dose Adjustment
Being renally cleared, eptifibatide and tirofiban infusion
rates should be reduced by 50% if creatinine clearance
(CrCl) is ⱕ50 or ⱕ30 ml/min, respectively, while maintaining the same bolus dose (38). In addition, eptifibatide
is contraindicated in patients on dialysis (39). By contrast, abciximab does not require dose adjustment with
renal failure. Data from moderate-to high-risk PCI
patients with NSTE-ACS treated with eptifibatide in the
PROTECT-TIMI 30 (Randomized Trial to Evaluate
the Relative Protection Against Post-PCI Microvascular
Dysfunction and Post-PCI Ischemia Among AntiPlatelet and Anti-Thrombotic Agents) trial showed that
the lack of adjustment of the maintenance infusion
occurred in 45% of patients with CrCl ⱕ50 ml/min and
was associated with a high rate of bleeding complications
(20%); in fact, no major or minor bleeding event occurred
among patients with reduced CrCl who received the
reduced-dose infusion (40). Consistent with these findings, data from the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse
Outcomes With Early Implementation of the ACC/
AHA Guidelines) registry showed that excess dosing of
eptifibatide and tirofiban occurs in 27% of patients
treated with GPI, mainly in women, older patients, small
patients, or patients with renal insufficiency (38). Excess
dosing was associated with a 17.5% rate of major bleeding, a 36% increase in the adjusted rate of major bleeding,
and a 50% increase in mortality. Furthermore, data from
the National Cardiovascular Data Registry (NCDR)-CathPCI
registry indicated that the use of eptifibatide in dialysis
patients was associated with increased in-hospital bleeding
and mortality risk (39). By contrast, abciximab seems
relatively safe in advanced renal failure (41).
In aggregate, these data suggest that the risks associated
with GPI can be mitigated in patients with chronic kidney
disease. All patients undergoing PCI need to have CrCl
assessed, and, if eptifibatide or tirofiban are used, their
dosages need to be adjusted accordingly.
Impact of age and sex. Several analyses have shown that
older patients have an increased bleeding risk with GPI.
In a meta-analysis by Boersma et al. (12), the benefit of
GPI decreased with advancing age, with a nonsignificant
treatment effect in patients ⱖ60 years of age. Additionally, in a pre-specified subgroup analysis of ACUITY
trial, the benefit of bivalirudin monotherapy over combined therapy with GPI in terms of the number needed to
treat to prevent 1 bleeding event was particularly high in
patients older than 75 years of age (42). These data
suggest that the risk may outweigh the benefit in most
patients older than 75 years of age, and, if used, the GPI
dose should be adjusted and the infusion shortened or
eliminated.
Hanna et al.
Optimize GPI Therapy
1215
Results from the CRUSADE initiative indicate that
women with ACS had higher rates of major bleeding than
men among patients treated with GPI (15.7% vs. 7.3%,
p ⬍ 0.0001) and among patients not treated with GPI
(8.5% vs. 5.4%, p ⬍ 0.0001) (43). Treated women were also
more likely to receive excess dosing of GPI than men
(46.4% vs. 17.2%, p ⬍ 0.0001) were, and bleeding risk
attributable to excess dosing was much higher in women
(25.0% vs. 4.4%).
Anticoagulation Dose Adjustment
The EPILOG (Evaluation of PTCA to Improve LongTerm Outcome by c7E3 GP IIb/IIIa Receptor [abciximab]
Blockade) trial randomly assigned 2,799 low-risk patients to
placebo plus standard-dose, weight-adjusted heparin (100
U/kg); abciximab plus standard-dose, weight-adjusted heparin; or abciximab plus a reduced-dose, weight-adjusted
heparin (70 U/kg bolus, activated clotting time [ACT] goal
200 to 300 s) regimens. Although rates of 30-day composite
ischemic events were reduced by 56% in both abciximab
groups, bleeding was increased only in the abciximab plus
standard-dose heparin group (2). In the ESPRIT trial,
TIMI major bleeding was overall increased with eptifibatide
therapy, but not in the tertile of patients with ACT ⬍244 s
(44). Later trials using low-dose heparin, early sheath
removal, avoidance of routine placement of venous sheaths,
and target ACT levels of 200 to 250 s reported no difference
in major or minor bleeding for patients treated with abciximab versus placebo (3,7). This highlights the efficacy and
safety of GPI when used in conjunction with a reduced-dose
heparin regimen and a target ACT of 200 s.
Upstream Versus Downstream Administration
of GPI in ACS
Early GPI studies have suggested that the upstream use of
GPI in ACS reduces the risk of MI in the pre-procedural
period compared with therapy with heparin only (5,7,8).
Recently, however, in the EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Non–ST-Segment Elevation
Acute Coronary Syndromes) trial, the routine upstream
addition of eptifibatide to the therapy of intermediate- and
high-risk NSTE-ACS patients managed with an intended
invasive strategy did not prove superior to their provisional
downstream addition during PCI and was associated with
an increase in bleeding (45). This may be in part explained
by the fact that any anti-ischemic benefit conferred during
the time interval preceding PCI is offset by a 2.4% increase
in TIMI major or minor bleeding, and that patients
assigned an invasive strategy did not always undergo PCI. In
fact, the upstream use of GPI significantly reduced the
absolute risk of ischemic events by 2.4% in patients who
underwent PCI. Furthermore, in the FINESSE (Facilitated
1216
Hanna et al.
Optimize GPI Therapy
JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 3, NO. 12, 2010
DECEMBER 2010:1209 –19
Figure 1. Recommended Strategy of GPI Use in Patients Undergoing PCI and Routinely Treated With Stenting and Thienopyridines
Flow chart of the recommended strategy for glycoprotein IIb/IIIa inhibitor use in patients undergoing percutaneous coronary intervention and who are routinely
treated with stenting and thienopyridines. *Non–ST-segment elevation myocardial infarction (18). #The presence of 1 and particularly 2 or more of the following
factors is associated with an increased bleeding risk: age ⬎ 75 years, female, chronic kidney disease stage 3 or worse, baseline anemia, history of prior bleeding,
cardiogenic shock, or class IV heart failure. Also, adjust unfractionated heparin dose during percutaneous coronary intervention: use a starting bolus dose of ⱕ50
U/kg and achieve a target activated clotting time of low 200 s. †The need for a short infusion after percutaneous coronary intervention (ⱕ2 h) depends on the
timing of thienopyridine load. Adjust infusion dose to renal function. GPI ⫽ glycoprotein IIb/IIIa inhibitor(s); PCI ⫽ percutaneous coronary intervention; thieno ⫽
thienopyridine.
Intervention With Enhanced Reperfusion Speed to Stop
Events) trial, the early (“facilitated”) use of abciximab in
ST-segment elevation MI before primary PCI, as opposed
to its use during PCI, did not translate into clinical benefit,
but did increase major bleeding (46). Thus, in the current
era of thienopyridine therapy, the upstream administration
of GPI in NSTE-ACS and STEMI is associated with
increased bleeding risk and may not be warranted on a
routine basis. However, GPI may still be used upstream in
patients with positive cardiac markers who are not loaded
with clopidogrel and who are judged clinically to be at high
risk of thrombotic events relative to bleeding risk (i.e.,
refractory or recurrent ischemic chest pain), as proposed by
the American College of Cardiology guidelines (27). Further analysis of the EARLY ACS trial could help determine
subgroups of patients that may benefit from upstream use of
GPI.
Radial Versus Femoral Approach:
Access Management
Femoral access site bleeding complications constitute over
one-half of the major bleeding that occurs after PCI (as
demonstrated in the EPIC, CAPTURE [Chimeric 7E3
Antiplatelet Therapy in Unstable Angina Refractory to
Standard Treatment], REPLACE-2, and ACUITY trials)
(1,5,23,24). Recent data from the NCDR-CathPCI registry
indicates that, although used in a small minority of PCI
procedures, the radial artery access site, compared with the
femoral artery access site, is associated with a 58% reduction
of bleeding and vascular complications (47). This benefit is
more pronounced in elderly patients and in women. These
findings have been replicated in several registry analyses, 1
of which suggests that the radial approach is associated with
a significant reduction in mortality (48). An ongoing
multicenter randomized trial that is an extension of the
CURRENT–OASIS 7 (Clopidogrel Optimal Loading
Dose Usage to Reduce Recurrent Events–Organization
to Assess Strategies in Ischemic Syndromes) study is
comparing the transradial and the transfemoral access
sites in patients with ACS undergoing PCI.
Importantly, this reduction in access site bleeding may
attenuate the increase in bleeding risk associated with GPI.
A recent analysis from the ACUITY trial reported that the
use of bivalirudin monotherapy was associated with significantly less 30-day major bleeding than heparin plus GPI
after femoral access (3.0% vs. 5.8%, p ⬍ 0.0001), but not
Hanna et al.
Optimize GPI Therapy
JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 3, NO. 12, 2010
DECEMBER 2010:1209 –19
after radial access (4.2% vs. 2.2%, p ⫽ 0.19) (49). In a large
Italian registry of patients who underwent PCI for ACS
utilizing GPI, the transradial approach, in comparison with
the transfemoral approach, was associated with low bleeding
rates and a 6.6⫻ lower odds of major/minor bleeding (50).
These results confirm the findings of an analysis of 150
patients undergoing PCI and receiving GPI: no major
access site bleeding complications occurred in the radial
group (51). The radial approach may be particularly useful
in women or high-bleeding risk patients receiving GPI.
Furthermore, as opposed to transfemoral PCI, female sex
was not a predictor of adverse clinical outcomes after
transradial PCI performed under maximal antiplatelet therapy, including GPI (52).
If, by contrast, transfemoral access is used, early sheath
removal within 4 to 6 h of the procedure seems fundamental
in reducing bleeding risk (1,2,5). Though the reduction of
vascular complications with vascular closure devices remains
questionable, early sheath removal allowed by these devices
may prove beneficial. A multivariate analysis from the
NCDR-CathPCI registry showed that closure devices were
significantly associated with less bleeding and vascular
access complications (53). In addition, closure devices have
been reported to be safe in patients receiving GPI (54). A
recent analysis of the ACUITY trial data showed that
vascular closure devices independently reduce access site
bleeding by 22%; this benefit extended to patients receiving
GPI (55). It is important to point out that these analyses are
observational and that the safety and potential benefit may
be driven by the operator’s experience with these devices.
Collectively, available data support the use of the radial
access site, smaller sheaths (irrespective of the access site),
prompt sheath removal, and possibly vascular closure devices to minimize bleeding risk, although additional prospective and/or randomized data are needed in some of
these areas.
In summary, we suggest a strategy of GPI use that takes
into account the patient’s baseline ischemic and bleeding
risk and the above-described measures limiting hemorrhagic
events (Fig. 1). Many ischemic risk factors are also bleeding
risk factors (56,57), hence the importance of a careful use of
GPI with the strategies outlined in Table 5.
Conclusions and Final Recommendations
• Early studies have shown a reduction of ischemic events
with GPI, yet more recent studies performed in the era of
routine thienopyridine therapy show an increase in
bleeding risk and a less consistent net clinical benefit of
GPI administration.
• To use GPI safely, one should:
1217
X Target high-risk patients, particularly NSTEMI patients or patients undergoing PCI without adequate
clopidogrel pre-loading.
X Avoid the routine upstream use of GPI in ACS,
particularly if thienopyridines are used early on.
X Appropriately adjust dose for patients with renal
failure.
X Reduce or eliminate the infusion.
X Use radial approach, particularly in patients with
NSTEMI who otherwise have an indication to receive GPI.
X Select lower bleeding risk patients, which is challenging because ACS patients who are likely to benefit
from GPI have a higher bleeding risk than stable
patients (56,57).
Reprint requests and correspondence: Dr. Elias B. Hanna,
Department of Medicine, Cardiovascular Section, Louisiana State
University, 1542 Tulane Avenue, Room 323, New Orleans,
Louisiana 70112. E-mail: [email protected].
REFERENCES
1. The EPIC Investigators. Use of a monoclonal antibody directed against
the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med 1994;330:956 – 61.
2. The EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor
blockade and low-dose heparin during percutaneous coronary revascularization. N Engl J Med 1997;336:1689 –96.
3. The EPISTENT Investigators. Randomised placebo-controlled and
balloon-angioplasty-controlled trial to assess safety of coronary stenting
with use of platelet glycoprotein IIb/IIIa blockade. Lancet 1998;352:
87–92.
4. The ESPRIT Investigators. Novel dosing regimen of eptifibatide in
planned coronary stent implantation (ESPRIT): a randomised,
placebo-controlled trial. Lancet 2000;356:2037– 44.
5. Hamm CW, Heeschen C, Goldmann B, et al., for CAPTURE
Investigators. Benefit of abciximab in patients with refractory unstable
angina in relation to serum troponin T levels. N Engl J Med 1999;
340:1623–9.
6. The RESTORE Investigators. Effects of platelet glycoprotein IIb/IIIa
blockade with tirofiban on adverse cardiac events in patients with unstable
angina or acute myocardial infarction undergoing coronary angioplasty.
Randomized Efficacy Study of Tirofiban for Outcomes and REstenosis.
Circulation 1997;96:1445-53.
7. The PRISM-PLUS Investigators. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non–
Q-wave myocardial infarction. N Engl J Med 1998;338:1488-97.
8. The PURSUIT Trial Investigators. Inhibition of platelet glycoprotein
IIb/IIIa with eptifibatide in patients with acute coronary syndromes.
Platelet glycoprotein IIb/IIIa in unstable angina: receptor suppression
using Integrilin therapy. N Engl J Med 1998;339:436-43.
9. Montalescot G, Barragan P, Wittenberg O, et al., for the ADMIRAL
Investigators. Platelet glycoprotein IIb/IIIa inhibition with coronary
stenting for acute myocardial infarction. N Engl J Med 2001;344:
1895–903.
10. Stone GW, Grines CL, Cox DA, et al., for the CADILLAC
Investigators. Comparison of angioplasty with stenting, with or without abciximab, in acute myocardial infarction. N Engl J Med 2002;
346:957– 66.
11. Van’t Hof AW, Ten Berg J, Heestermans T, et al., for the On-TIME
2 Study Group. Prehospital initiation of tirofiban in patients with
ST-elevation myocardial infarction undergoing primary angioplasty
1218
Hanna et al.
Optimize GPI Therapy
(On-TIME 2): a multicentre, double-blind, randomised controlled
trial. Lancet 2008;372:537– 46.
12. Boersma E, Harrington RA, Moliterno DJ, et al. Platelet glycoprotein
IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all
major randomised clinical trials (correction in Lancet 2002;359:2120).
Lancet 2002;359:189 –98.
13. Roffi M, Chew DP, Mukherjee D, et al. Platelet glycoprotein IIb/IIIa
inhibitors reduce mortality in diabetic patients with non-ST-segmentelevation acute coronary syndromes. Circulation 2001;104:2767–71.
14. Rao SV, O’Grady K, Pieper KS, et al. A comparison of the clinical
impact of bleeding measured by two different classifications among
patients with acute coronary syndromes. J Am Coll Cardiol 2006;47:
809 –16.
15. Kastrati A, Mehilli J, Schühlen H, et al., for the Intracoronary Stenting
and Antithrombotic Regimen–Rapid Early Action for Coronary Treatment Study Investigators. A clinical trial of abciximab in elective
percutaneous coronary intervention after pretreatment with clopidogrel. N Engl J Med 2004;350:232– 8.
16. Mehilli J, Kastrati A, Schuhlen H, et al., for the ISAR-SWEET Study
Investigators. Randomized clinical trial of abciximab in diabetic patients undergoing elective percutaneous coronary interventions after
treatment with a high loading dose of clopidogrel. Circulation 2004;
110:3627–35.
17. Mehilli J, Kastrati A, Schulz S, et al., for the BRAVE-3 Study
Investigators. Abciximab in patients with acute ST-segment-elevation
myocardial infarction undergoing primary percutaneous coronary intervention after clopidogrel loading: a randomized double-blind trial.
Circulation 2009;119:1933– 40.
18. Kastrati A, Mehilli J, Neumann FJ, et al., for the ISAR-REACT 2
Trial Investigators. Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: the ISAR-REACT 2 randomized trial. JAMA
2006;295:1531– 8.
19. Gurbel PA, Bliden KP, Zaman KA, Yoho JA, Hayes KM, Tantry US.
Clopidogrel loading with eptifibatide to arrest the reactivity of platelets:
results of the Clopidogrel Loading With Eptifibatide to Arrest the
Reactivity of Platelets (CLEAR PLATELETS) study. Circulation
2005;111:1153–9.
20. Wiviott SD, Braunwald E, McCabe CH, et al., for the TRITONTIMI 38 Investigators. Prasugrel versus clopidogrel in patients with
acute coronary syndromes. N Engl J Med 2007;357:2001–15.
21. Wallentin L, Becker RC, Budaj A, et al., for the PLATO Investigators.
Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045–57.
22. O’Donoghue M, Antman EM, Braunwald E, et al., for the TIMI
Study Group. The efficacy and safety of prasugrel with and without a
glycoprotein IIb/IIIa inhibitor in patients with acute coronary syndromes undergoing percutaneous intervention: a TRITON–TIMI 38
(Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition With Prasugrel–Thrombolysis In Myocardial Infarction 38) analysis. J Am Coll Cardiol 2009;54:678 – 85.
23. Lincoff AM, Bittl JA, Harrington RA, et al., for the REPLACE 2
Investigators. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade
during percutaneous coronary intervention: the REPLACE-2 randomized trial. JAMA 2003;289:853– 63.
24. Stone GW, McLaurin BT, Cox DA, et al., for the ACUITY
Investigators. Bivalirudin for patients with acute coronary syndromes.
N Engl J Med 2006;355:2203–16.
25. Stone GW, Witzenbichler B, Guagliumi G, et al., for the HORIZONSAMI Trial Investigators. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008;358:2218 –30.
26. Mehran R, Lansky AJ, Witzenbichler B, et al., for the HORIZONSAMI Trial Investigators. Bivalirudin in patients undergoing primary
angioplasty for acute myocardial infarction (HORIZONS-AMI): 1-year
results of a randomised controlled trial. Lancet 2009;374:1149 –59.
27. Kushner FG, Hand M, Smith SC Jr., et al. 2009 focused updates:
ACC/AHA guidelines for the management of patients with STelevation myocardial infarction (updating the 2004 guideline and 2007
focused update) and ACC/AHA/SCAI guidelines on percutaneous
coronary intervention (updating the 2005 guideline and 2007 focused
JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 3, NO. 12, 2010
DECEMBER 2010:1209 –19
update): a report of the American College of Cardiology
Foundation/American Heart Association Task Force on Practice
Guidelines. J Am Coll Cardiol 2009;54:2205– 41.
28. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non–ST
elevation myocardial infarction. J Am Coll Cardiol 2007;50:1–157.
29. Saw J, Lincoff AM, DeSmet W, et al., for REPLACE-2 Investigators.
Lack of clopidogrel pretreatment effect on the relative efficacy of
bivalirudin with provisional glycoprotein IIb/IIIa blockade compared to
heparin with routine glycoprotein IIb/IIIa blockade: a REPLACE-2
substudy. J Am Coll Cardiol 2004;44:1194 –9.
30. Valgimigli M, Campo G, de Cesare N, et al. Intensifying platelet
inhibition with tirofiban in poor responders to aspirin, clopidogrel, or
both agents undergoing elective coronary intervention. Circulation
2009;119:3215–22.
31. Manoukian SV, Feit F, Mehran R, et al. Impact of major bleeding on
30-day mortality and clinical outcomes in patients with acute coronary
syndromes: an analysis from the ACUITY trial. J Am Coll Cardiol
2007;47:1362– 8.
32. Feit F, Voeltz MD, Attubato MJ, et al. Predictors and impact of major
hemorrhage on mortality following percutaneous coronary intervention
from the REPLACE-2 trial. Am J Cardiol 2007;100:1364 –9.
33. Fung AY, Saw J, Starovoytov A, et al. Abbreviated infusion of
eptifibatide after successful coronary intervention: the BRIEF PCI
(Brief Infusion of Eptifibatide Following Percutaneous Coronary
Intervention) randomized trial. J Am Coll Cardiol 2009;53:837– 45.
34. Bertrand OF, De Larochelliere R, Rodes-Cabau J, et al., for the Early
Discharge After Transradial Stenting of Coronary Arteries Study
Investigators. A randomized study comparing same-day home discharge and abciximab bolus only to overnight hospitalization and
abciximab bolus and infusion after transradial coronary stent implantation. Circulation 2006;114:2636 – 43.
35. Kini AS, Chen VHT, Krishnan P, et al. Bolus-only versus bolus ⫹
infusion of glycoprotein IIb/IIIa inhibitors during percutaneous coronary intervention. Am Heart J 2008;156:513–9.
36. Gurbel PA, Bliden KP, Butler K, et al. Randomized double-blind
assessment of the ONSET and OFFSET of the antiplatelet effects of
ticagrelor versus clopidogrel in patients with stable coronary artery
disease: the ONSET/OFFSET study. Circulation 2009;120:2577– 85.
37. Wiviott SD, Trenk D, Frelinger AL, et al., for the PRINCIPLETIMI 44 Investigators. Prasugrel compared with high loading- and
maintenance-dose clopidogrel in patients with planned percutaneous
coronary intervention: the Prasugrel in Comparison to Clopidogrel for
Inhibition of Platelet Activation and Aggregation-Thrombolysis In
Myocardial Infarction 44 trial. Circulation 2007;116:2923–32.
38. Alexander KP, Chen AY, Roe MT, et al., for the CRUSADE
Investigators. Excess dosing of antiplatelet and antithrombin agents in
the treatment of non-ST-segment elevation acute coronary syndromes.
JAMA 2005;294:3108 –16.
39. Tsai TT, Maddox TM, Roe MT, et al., for the National Cardiovascular Data Registry. Contraindicated medication use in dialysis patients
undergoing percutaneous coronary intervention. JAMA 2009;302:
2458 – 64.
40. Kirtane AJ, Piazza G, Murphy SA, et al., for the TIMI Study Group.
Correlates of bleeding events among moderate- to high-risk patients
undergoing percutaneous coronary intervention and treated with eptifibatide: observations from the PROTECT-TIMI-30 trial. J Am Coll
Cardiol 2006;47:2374 –9.
41. Best PJ, Lennon R, Gersh BJ, et al. Safety of abciximab in patients with
chronic renal insufficiency who are undergoing percutaneous coronary
interventions. Am Heart J 2003;146:345–50.
42. Lopes RD, Alexander KP, Manoukian SV, et al. Advanced age,
antithrombotic strategy, and bleeding in non-ST-segment elevation
acute coronary syndrome: results from the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial. J Am Coll
Cardiol 2009;53:1021–30.
43. Alexander KP, Chen AY, Newby LK, et al., for the CRUSADE
Investigators. Sex differences in major bleeding with glycoprotein
IIb/IIIa inhibitors: results from the CRUSADE (Can Rapid risk
stratification of Unstable angina patients Suppress ADverse outcomes
JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 3, NO. 12, 2010
DECEMBER 2010:1209 –19
with Early implementation of the ACC/AHA guidelines) initiative.
Circulation 2006 ;114:1380 –7.
44. Tolleson TR, O’Shea JC, Bittl JA, et al. Relationship between heparin
anticoagulation and clinical outcomes in coronary stent intervention:
observations from the ESPRIT trial. J Am Coll Cardiol 2003;41:386 –93.
45. Giugliano RP, White JA, Bode C, et al., for the EARLY ACS
Investigators. Early versus delayed, provisional eptifibatide in acute
coronary syndromes. N Engl J Med 2009;360:2176 –90.
46. Ellis SG, Tendera M, de Belder MA, et al., for the FINESSE
Investigators. Facilitated PCI in patients with ST-elevation myocardial
infarction. N Engl J Med 2008;358:2205–17.
47. Rao SV, Ou FS, Wang TY, et al. Trends in the prevalence and
outcomes of radial and femoral approaches to percutaneous coronary
intervention. J Am Coll Cardiol Intv 2008;1:379 – 86.
48. Chase AJ, Fretz EB, Warburton WP, et al. The association of arterial
access site at angioplasty with transfusion and mortality: the M.O.R.
T.A.L. study (Mortality benefit Of Reduced Transfusion after percutaneous coronary intervention via the Arm or Leg). Heart 2008;94:
1019 –25.
49. Hamon M, Rasmussen LH, Manoukian SV, et al. Choice of arterial
access site and outcomes in patients with acute coronary syndromes
managed with an early invasive strategy: the ACUITY trial. EuroIntervention 2009;5:115–20.
50. De Carlo M, Borelli G, Gistri R, et al. Effectiveness of the transradial
approach to reduce bleedings in patients undergoing urgent coronary
angioplasty with GPIIb/IIIa inhibitors for acute coronary syndromes.
Catheter Cardiovasc Interv 2009;74:408 –15.
51. Choussat R, Black A, Bossi I, Fajadet J, Marco J. Vascular complications and clinical outcome after coronary angioplasty with platelet
IIb/IIIa receptor blockade. Comparison of transradial vs transfemoral
arterial access. Eur Heart J 2000;21:662–7.
Hanna et al.
Optimize GPI Therapy
1219
52. Tizón-Marcos H, Bertrand OF, Rodés-Cabau J, et al. Impact of female
gender and transradial coronary stenting with maximal antiplatelet
therapy on bleeding and ischemic outcomes. Am Heart J 2009;157:
740 –5.
53. Tavris DR, Dey S, Albrecht-Gallauresi B, et al. Risk of local adverse
events following cardiac catheterization by hemostasis device use—
phase II. J Invasive Cardiol 2005;17:644 –50.
54. Applegate RJ, Grabarczyk MA, Little WC, et al. Vascular closure
devices in patients treated with anticoagulation and IIb/IIIa receptor
inhibitors during percutaneous revascularization. J Am Coll Cardiol
2002;40:78 – 83.
55. Sanborn TA, Ebrahimi R, Manoukian SV, et al. Impact of femoral
vascular closure devices and antithrombotic therapy on access site
bleeding in acute coronary syndromes: the Acute Catheterization and
Urgent Intervention Triage Strategy (ACUITY) trial. Circ Cardiovasc
Interv 2010;3:57– 62.
56. Mehta SK, Frutkin AD, Lindsey JB, et al., for the National Cardiovascular Data Registry. Bleeding in patients undergoing percutaneous
coronary intervention: the development of a clinical risk algorithm from
the National Cardiovascular Data Registry. Circ Cardiovasc Interv
2009;2:222–9.
57. Nikolsky E, Mehran R, Dangas G, et al. Development and validation
of a prognostic risk score for major bleeding in patients undergoing
percutaneous coronary intervention via the femoral approach. Eur
Heart J 2007;28:1936 – 45.
Key Words: acute coronary syndrome(s) 䡲 bleeding risk 䡲
dose adjustment 䡲 glycoprotein IIb/IIIa inhibitor 䡲 percutaneous coronary intervention.