GP IIb-IIIa Inhibitors

GP IIb/IIIa Inhibitors
A Pocket Guide to the Studies

Involving GP IIb/IIIa Inhibitors in
Acute Coronary Syndrome and
Cardiovascular Disease
2010
INTRODUCTION
Glycoprotein IIb/IIIa inhibitors (GPIs) play an important role in the
current treatment of acute coronary syndrome (ACS) and have played
a significant role in increasing patient survival.
This pocket guide contains the abstracts of nearly 50 of the major

studies involving the 3 currently marketed GPIs—Aggrastat® (tirofiban),
Integrilin® (eptifibatide), and ReoPro® (abciximab)—in the treatment of
ACS. The key endpoint data from each study are shown.
Also included are several of the major studies that utilized the
antithrombin Angiomax®/Angiox® (bivalirudin), which is used with and
without GPIs in the treatment of patients with ACS.
Finally, key product information for Aggrastat, Integrilin, ReoPro, and

Angiomax/Angiox is included in the Appendix.
1
Table of Contents
GPI Studies
Aggrastat® (tirofiban) Year* Page
ADVANCE 2004 3
EVEREST 2006 4
FATA 2008 5
FATA [LVF] 2009 6
MR PCI 2007 7
MULTISTRATEGY 2008 8
On-TIME 2 2008 9
On-TIME 2 [1 year] 2009 10
PRISM-PLUS 1998 11
PRISM-PLUS [Renal] 2002 12
PRISM-PLUS [Age] 2003 13
PRISM-PLUS [Diabetes] 2000 14
PRISM-PLUS [Troponins] 2000 15
RESTORE 1997 16
TACTICS-TIMI 18 2001 17
TACTICS-TIMI 18 [Troponins] 2001 18
TACTICS-TIMI 18 [Diabetes] 2007 19
TARGET 2001 20
TENACITY 2005 21
3T/2R 2009 22
Integrilin® (eptifibatide) Year* Page

ASSIST 2008 23
BRIEF-PCI 2009 24
CLEAR PLATELETS 2005 25
CLEAR PLATELETS-2 2009 26
EARLY ACS 2009 27
ESPRIT 2000 28
ESPRIT [Diabetes] 2002 29
ESPRIT [High risk] 2006 30
EVA-AMI 2007 31
PROTECT–TIMI-30 2006 32
PURSUIT 1998 33
ReoPro® (abciximab) Year* Page

ADMIRAL 2001 34
BRAVE-3 2009 35
CADILLAC 2002 36
CAPTURE 1997 37
EPIC 1994 38
EPILOG 1997 39
EPISTENT 1998 40
FINESSE 2008 41
GUSTO IV-ACS 2003 42
GUSTO V 2001 43
ISAR-REACT 2004 44
ISAR-REACT 2 2006 45
ISAR-REACT 2 [1 year] 2008 46
ISAR-REACT 2 [Age] 2006 47
ISAR-REACT 2 [Troponins] 2008 48
Antithrombin Studies
Angiomax®/Angiox® (bivalirudin) Year* Page
ACUITY 2006 49
ACUITY [PCI] 2007 50
ACUITY [Timing] 2007 51
ACUITY [1 year] 2007 52
ACUITY [1-year PCI] 2008 53
ACUITY [Diabetes] 2008 54
HORIZONS-AMI 2008 55
ISAR-REACT 3 2008 56
Meta-analyses Year* Page

Meta-analysis [Diabetes] 2001 57
Meta-analysis [High-dose tirofiban] 2006 58
Meta-analysis [Tirofiban] 2009 59
Guidelines Page
ESC NSTEMI 2007 60
ESC STEMI 2008 61
ACC/AHA STEMI 2004 62
Appendix: Important Product Information Page

Aggrastat® 63
Angiomax®/ Angiox® 64
Integrilin® 65
ReoPro® 66
2
*Year of primary publication or major meeting presentation.
ADVANCE Aggrastat
Valgimigli M, Percoco G, Barbieri D, et al. The additive value of
tirofiban administered with the high-dose bolus in the prevention of
ischaemic complications during high-risk coronary angioplasty: the
ADVANCE Trial. J Am Coll Cardiol. 2004;44(1):14-19.
Background
High-dose bolus (HDB) tirofiban use in the catheterisation laboratory is
controversial. Specifically, in patients with acute coronary syndromes
undergoing percutaneous coronary intervention (PCI), no evidence
exists to show that tirofiban administered in the catheterisation
laboratory is superior to heparin alone. This finding may reflect
suboptimal platelet inhibition when tirofiban is employed with the
RESTORE (Randomised Efficacy Study of Tirofiban for Outcomes and
Restenosis) regimen.
Objectives
The aim of this study was to investigate whether HDB tirofiban was
safe and effective for high-risk patients undergoing PCI.
Methods
Two hundred two patients (mean age 69 ± 8 years; 137 males [68%])
who were pretreated with thienopyridines and undergoing high-risk
PCI were consecutively randomised to HDB tirofiban (25 μg/kg/3
min and an infusion of 0.15 μg/kg/min for 24 to 48 hours) or placebo
just before the procedure. They were then observed for a median
of 185 days (range: 45 to 324 days) for the incidence of the primary
composite endpoint of death, myocardial infarction (MI), target vessel
revascularisation (TVR), and bailout use of glycoprotein IIb/IIIa
inhibitors (GPIs).
Results
The cumulative primary endpoint rates were 35% and 20% in the
placebo group and HDB tirofiban group, respectively (hazard ratio:
0.51; 95% confidence interval, 0.29-0.88; P=.01). This difference
mainly reflects reduced MI and bailout use of GPIs. However, there
was no significant effect on TVR or death. Similar safety profiles were
noted for tirofiban and placebo.
1.0
HDB Tirofiban
0.8
Survival Probability
0.6
0.4 Placebo
P=0.01
0.2
0.0
0 100 200 300 400
Days
Kaplan-Meier survival analysis: plot of proportion of cumulative survival free from primary
endpoint events in patients treated with high-dose bolus (HDB) tirofiban (dashed line) and
placebo (solid line). The difference in the incidence of events emerged soon after the procedure.
At month 6, the hazard ratio was 0.51 (95% CI, 0.29-0.88; P=0.01 by the log-rank test).
Abstract and figure adapted from Valgimigli M et al. J Am Coll Cardiol. 2004;44(1):14-19.
Conclusions
HDB tirofiban is safe and causes a significant reduction of ischaemic/
thrombotic complications during high-risk PCI.
3
Please see Important Product Information in the Appendix.
EVEREST Aggrastat
Bolognese L, Falsini G, Liistro F, et al. Randomised comparison of
upstream tirofiban versus downstream high bolus dose tirofiban or
abciximab on tissue-level perfusion and troponin release in high-
risk acute coronary syndromes treated with percutaneous coronary
interventions: the EVEREST trial. J Am Coll Cardiol. 2006;47(3):522-
528.
Background
Optimal timing and dosage of glycoprotein IIb/IIIa inhibitors for acute
coronary syndrome (ACS) are not known.
Objectives
This study was conducted to compare the effects of upstream tirofiban
versus downstream high-dose bolus (HDB) tirofiban and abciximab
on tissue-level perfusion and troponin I release in high-risk patients
with non–ST-segment elevation ACS (NSTE-ACS) treated with
percutaneous coronary intervention (PCI).
Methods
Ninety-three high-risk patients with ACS undergoing PCI were
randomised to receive upstream (in the coronary care unit) tirofiban,
downstream (just prior to PCI) HDB tirofiban, or downstream
abciximab. The effects of the 3 drug regimens on tissue-level perfusion
using the corrected Thrombolysis in Myocardial Infarction (TIMI) frame
count, the TIMI myocardial perfusion grade (TMPG), and intracoronary
myocardial contrast echocardiography (MCE) were analysed before
and just after PCI and after cardiac troponin I (cTnI).
Results
Upstream tirofiban treatment compared with HDB tirofiban and
abciximab resulted in significantly less frequent TMPG 0/1 perfusion
both before (28.1% vs 66.7% vs 71%, respectively; P=.0009) and after
PCI (6.2% vs 20% vs 35.5%, respectively; P=.015). A significantly
higher MCE score index was noted with upstream tirofiban (0.88 ±
0.18 vs 0.77 ± 0.32 vs 0.71 ± 0.30, respectively; P<.05). Patients in the
upstream tirofiban group compared with those in the HDB tirofiban and
abciximab groups had significantly less frequent postprocedural cTnI
elevation (9.4% vs 30% vs 38.7%, respectively; P=.018). Significantly
reduced cTnI levels after PCI were seen with upstream tirofiban
compared with HDB tirofiban (3.8 ± 4.1 vs 7.2 ± 12; P=.015) and
abciximab (3.8 ± 4.1 vs 9 ± 13.8; P=.0002).
A B
100 50
P=0.0009 P=0.015
80 71 40 35.5
TMPG 0/1, %
TMPG 0/1, %
66.7
60 30
20
40 20
28.1
20 10 6.2
0 0
HDB Upstream Abciximab HDB Upstream Abciximab
Tirofiban Tirofiban Tirofiban Tirofiban
Pre-PCI Post-PCI
Rate of TIMI TMPG 0/1 flow stratified by glycoprotein IIb/IIIa inhibitor treatment pre-PCI (A)
and post-PCI (B). P=0.0009 by Fisher exact test upstream tirofiban vs HDB vs abciximab before
PCI. P=0.015 by Fisher exact test upstream tirofiban vs HDB vs abciximab after PCI.
Abstract and figure adapted from Bolognese L et al. J Am Coll Cardiol. 2006;47(3):522-528.
Conclusions
Improved tissue-level perfusion and attenuated myocardial damage
with upstream tirofiban occurred in high-risk patients with NSTE-ACS
treated with an early invasive strategy.
4
FATA Aggrastat
Marzocchi A, Manari A, Piovaccari G, et al. Randomised comparison
between tirofiban and abciximab to promote complete ST-resolution in
primary angioplasty: results of the facilitated angioplasty with tirofiban
or abciximab (FATA) in ST-elevation myocardial infarction trial. Eur
Heart J. 2008;29(24):2972-2980.
Objectives
This study evaluated whether high-dose bolus (HDB) tirofiban was
equivalent to the standard dose of abciximab for patients undergoing
primary percutaneous coronary intervention (PPCI), as measured by
ST-segment resolution (STR).
Methods
The FATA trial (Facilitated Angioplasty With Tirofiban or Abciximab)
was a prospective, multicentre, open-label trial of patients with ST-
segment elevation myocardial infarction (STEMI) undergoing PPCI.
Six hundred ninety-two patients were enrolled and randomised 1:1 to
receive either a standard dose of abciximab (n=341) or HDB tirofiban
(n=351). The primary endpoint was the rate of complete (at least
70%) STR 90 minutes after the first balloon inflation. Major bleedings,
death, reinfarction, and new revascularisations at 30 days were also
evaluated.
Results
Baseline characteristics of the 2 groups were well balanced, with only
minor differences observed between the study groups; specifically,
the incidence of previous MI rates (tirofiban 6% vs abciximab 2.6%;
P=.03). The procedure was successful in 96.7% of the patients in
the abciximab group and in 96.6% of the patients in the tirofiban
group (P=.94). Of the patients treated with tirofiban, 67.05% reached
the primary endpoint of complete STR at 90 minutes compared
with 70.45% of the patients in the abciximab group (Δ –3.4%, 95%
confidence interval, –10.35 to 3.56), which lies beyond the predefined
Δ ± 10% equivalence boundaries. Both groups had similar rates of
secondary endpoints
100
9.85
Rate of ST-Segment Resolution, %
ST-resolution
14.45
Absent
Partial
80 18.50 Complete
19.70
60 67.05 70.45
40
20
0
Tirofiban Abciximab
Rates of complete (≥70%), partial (30%-70%), and absent (<30%) ST-segment
resolution 90 minutes after primary angioplasty in both study groups.
Abstract and figure adapted from Marzocchi A et al. Eur Heart J. 2008;29(24):2972-2980.
Conclusions
The FATA trial demonstrated that HDB tirofiban was not equivalent to
abciximab as an adjunctive therapy for PPCI.
5
FATA (Left Ventricular Function) Aggrastat
Taglieri N, Saia F, Guiducci V, et al. Left ventricular function after
ST-elevation myocardial infarction in patients treated with primary
percutaneous coronary intervention and abciximab or tirofiban (from
the Facilitated Angioplasty with Tirofiban or Abciximab [FATA] Trial).
Am J Cardiol. 2009;103(6):785-790.
Background
For patients with ST-elevation myocardial infarction, left ventricular
(LV) function recovery is ameliorated with abciximab therapy during
primary percutaneous coronary intervention (PPCI). A similar effect of
high-dose bolus (HDB) tirofiban is seen on platelet inhibition. It is not
clear if this is related to comparable efficacy on LV function recovery.
Objectives
The objective of this study was to investigate the impact of HDB
tirofiban or abciximab on patients undergoing PPCI on LV function,
along with the predictors of favourable (at least 50%) LV ejection
fraction (EF) and LV function recovery at 30 days.
Methods
Three hundred fourteen patients (abciximab, n=154; tirofiban, n=160)
undergoing PPCI in the randomised Facilitated Angioplasty With
Tirofiban or Abciximab (FATA) trial were studied. LVEF was evaluated
within 48 hours and at 30 days following PPCI. For patients with
systolic dysfunction at baseline, LV function recovery was defined by
either an increase of LVEF of at least 10% compared with baseline or
LVEF of at least 50%.
Results
No difference in LVEF was seen between the 2 groups postprocedure
(abciximab 49.7 ± 10.1% vs tirofiban 49.3 ± 10.1%; P=.9) and at
30 days (abciximab 53.1 ± 9.8% vs tirofiban 52.5 ± 10.2%; P=.6).
Preprocedure Thrombolysis in Myocardial Infarction (TIMI) flow class
greater than 0 (odds ratio [OR], 2.4; 95% confidence interval [CI], 1.32-
4.34), anterior location (OR, 0.25; 95% CI, 0.15-0.42), and age (OR,
0.97; 95% CI, 0.95-0.99) were the independent predictors of 30-day
LVEF of at least 50%. The lone predictor of LV function recovery was
preprocedure TIMI flow grade greater than 0 (OR, 6.73; 95% CI, 2.69-
16.88).
55 P=0.6
54
P=0.000
53 53.1%
52.5%
52
P=0.7
51
LVEF, %
50
49.7% 49.3%
49
P=0.000
48
47
Tirofiban
Abciximab
46
45
Post-PCI 30 Day
Comparison of LVEF with abciximab and tirofiban after primary PCI (post-PCI)
and 30 days. Squares indicate the mean values and bars the 95% CI boundaries.
Abstract and figure adapted from Taglieri N et al. Am J Cardiol. 2009;103(6):785-790.
Conclusions
In patients undergoing PPCI, treatment with either abciximab or HDB
tirofiban resulted in similar LV function recovery. The most important
predictor of favourable LVEF and LV function recovery at 30 days
seemed to be preprocedure TIMI flow grade greater than 0.
6
MR PCI Aggrastat
Mardikar HM, Hiremath MS, Moliterno DJ, et al. Optimal platelet
inhibition in patients undergoing PCI: data from the Multicentre
Registry of High-Risk Percutaneous Coronary Intervention
and Adequate Platelet Inhibition (MR PCI) study. Am Heart J.
2007;154(2):344.e1-344.e5.
Background
Greater protection against ischaemic events during percutaneous
coronary intervention (PCI) may result from optimal inhibition of
platelet aggregation (IPA).
Objectives
The goal of this study was to compare different combinations of
glycoprotein IIb/IIIa inhibitors (GPIs) and clopidogrel to facilitate the
evaluation of several antiplatelet regimens in elective high-risk patients
undergoing PCI.
Methods
This was a randomised open-label study at 3 heart centres in India.
One hundred twenty patients were enrolled between July 2006 and
September 2006 and were randomised to 1 of the 4 groups: group A,
tirofiban; group B, eptifibatide; group C, tirofiban plus clopidogrel
600-mg loading dose; and group D, eptifibatide plus clopidogrel
600-mg loading dose. A clopidogrel maintenance dose after PCI was
administered to all patients. The IPA assessed at 10 minutes, at 6 to 8
hours, and at 24 hours was the primary outcome measure.
Results
High-dose tirofiban versus eptifibatide resulted in higher IPA at 10
minutes (95.88 ± 5.85% vs 91.22 ± 7.52%; P=.003) and at 6 to 8
hours (93.11 ± 7.6% vs 85.45 ± 11.03; P<.001). Greater than 95% IPA
was achieved in significantly more patients treated with the high-dose
tirofiban regimen.
High-dose Double-bolus
tirofiban eptifibatide
(group A + group C) (group B + group D)
IPA, 10 min (%) 95.88 ± 5.85* 91.22 ± 7.52*

IPA, 6-8 h (%) 93.11 ± 7.60† 85.45 ± 11.03†
IPA, 24 h (%) 20.25 ± 36.82‡ 21.09 ± 45.04‡
*P = .004; †P < .001; ‡P = .173
Abstract and figure adapted from Mardikar HM et al. Am Heart J. 2007;154(2):344.e1-344.e5.
Conclusions
In patients undergoing elective high-risk PCI, a higher degree of
platelet inhibition was noted with high-dose tirofiban at 10 minutes
and at 6 to 8 hours in this head-to-head study comparing high-dose
tirofiban with double-bolus eptifibatide. Clopidogrel addition did not
acutely prolong the IPA from intravenous GPIs, but did do so at 24
hours.
7
MULTISTRATEGY Aggrastat
Valgimigli M, Campo G, Percoco G, et al. Comparison of angioplasty
with infusion of tirofiban or abciximab and with implantation of
sirolimus-eluting or uncoated stents for acute myocardial infarction: the
MULTISTRATEGY randomised trial. JAMA. 2008;299(15):1788-1799.
Background
In patients undergoing angioplasty for ST-segment elevation
myocardial infarction (STEMI), abciximab infusion and uncoated-stent
implantation is a complementary treatment strategy for the reduction of
major adverse cardiac events (MACE). It is unclear if the replacement
of abciximab with high-dose bolus (HDB) tirofiban results in similar
benefits. This study compared the effects of HDB tirofiban and
sirolimus-eluting stents versus abciximab infusion and uncoated-stent
implantation in patients with STEMI undergoing percutaneous coronary
intervention (PCI).
Methods and Results
This was an open-label 2-by-2 factorial trial at 16 referral centres in
Italy, Spain, and Argentina between October 2004 and April 2007. It
consisted of 745 patients presenting with STEMI or new left bundle–
branch block. HDB tirofiban versus abciximab infusion, as well as
sirolimus-eluting stent versus uncoated-stent implantation, were the
interventions used. For drug comparison, the main outcome measure
was at least 50% ST-segment elevation resolution at 90 minutes
postintervention with a prespecified noninferiority margin of 9%
difference (relative risk [RR], 0.89). For stent comparison, the rate of
MACE, defined as the composite of death from any cause, reinfarction,
and clinically driven target-vessel revascularisation within 8 months
was the main outcome measure. Three hundred and two of the 361
patients (83.6%) who had received abciximab infusion and 308 of the
361 patients (85.3%) who had received tirofiban infusion (RR, 1.020;
97.5% confidence interval, 0.958-1.086; P<.001 for noninferiority)
displayed ST-segment resolution. No difference was observed in
ischaemic and hemorrhaegic outcomes in the tirofiban and abciximab
groups. MACE at 8 months were reported in 54 patients (14.5%) with
uncoated stents and in 29 patients (7.8%) with sirolimus-eluting stents
(P=.004), predominantly reflecting a reduction of revascularisation
rates (10.2% vs 3.2%). There were no differences in the incidence of
stent thrombosis between the 2 stent groups.
20
Uncoated stent
Primary Endpoint, %
plus abciximab
Uncoated stent
plus tirofiban
10 Sirolimus-eluting
stent plus
abciximab
Sirolimus-eluting
stent plus
tirofiban
0
0 40 80 120 160 200 240
Days After Randomisation
Abstract and figure adapted from Valgimigli M et al. JAMA. 2008;299(15):1788-1799.
Conclusions
For patients with STEMI undergoing PCI, tirofiban compared with
abciximab resulted in noninferior resolution of ST-segment elevation
at 90 minutes following coronary intervention. By contrast, sirolimus-
eluting stent implantation resulted in a significantly reduced risk
of MACE compared with uncoated stents within 8 months after
intervention.
8
On-TIME 2 Aggrastat
Van’t Hof AW, Ten Berg J, Heestermans T, et al. Prehospital initiation of
tirofiban in patients with ST-elevation myocardial infarction undergoing
primary angioplasty (On-TIME 2): a multicentre, double-blind,
randomised controlled trial. Lancet. 2008;372(9638):537-546.
Background
The most effective magnitude and timing of antiplatelet therapy is
important for patients with acute ST-elevation myocardial infarction
(STEMI).
Objectives
This study investigated whether the early administration of the
glycoprotein IIb/IIIa–blocker tirofiban at first medical contact in the
ambulance or referral centre can improve the results of primary
coronary angioplasty (PCI).
Methods
The On-TIME 2 trial was a double-blind, randomised, placebo-
controlled trial in 24 centres in the Netherlands, Germany, and
Belgium. Nine hundred eighty-four patients with STEMI who were
candidates to undergo PCI were randomised to either high-bolus dose
(HDB) tirofiban (n=491) or placebo (n=493), in addition to aspirin 500
mg, heparin 5000 IU, and clopidogrel 600 mg from June 29, 2006 to
November 13, 2007. Randomisation was by blinded sealed kits, with
the study drug in blocks of 4. The primary endpoint was the extent
of residual ST-segment deviation 1 hour after PCI. Analysis was by
intention to treat.
Results
A total of 936 (95%) patients were included and randomised to
treatment after a prehospital diagnosis of myocardial infarction in the
ambulance. Median time from onset of symptoms to diagnosis was
76 minutes (interquartile range, 35-150). Mean residual ST deviation
before PCI (10.9 mm [SD 9.2] vs 12.1 mm [SD 9.4], respectively;
P=.028) and 1 hour after PCI (3.6 mm [SD 4.6] vs 4.8 mm [SD 6.3],
respectively; P=.003) was significantly lower for patients pretreated
with HDB tirofiban than for those who received placebo. The major
bleeding rate was not significantly different between the HDB tirofiban
group and the placebo group (19% [SD 4%] vs 14% [SD 3%],
respectively; P=.36).
Residual ST Deviation >3 mm 1 Hour
After Angiography/PCI
50
45.1% P=0.035
45
38.1%
40
35
Patients, %
30
25
20
15
10 n=205/455 n=172/451
5
0
Placebo Tirofiban
Abstract and figure adapted from Van’t Hof AW et al. Lancet. 2008;372(9638):537-546.
Conclusions
Prehospital initiation of HDB tirofiban improved ST-segment resolution
and clinical outcome after PCI. This suggests that further platelet
aggregation inhibition in addition to high-dose clopidogrel is necessary
for patients with STEMI undergoing PCI.
9
On-TIME 2 (1-Year Outcomes) Aggrastat
Hamm C. on behalf of the On-TIME 2 investigators. Prehospital
Tirofiban in ST-Elevation Myocardial Infarction: One Year Outcome
of ON-TIME-2. Presented at: American College of Cardiology’s 58th
Annual Scientific Session; March 29-31, 2009; Orlando, FL.
Background
The On-TIME 2 trial was a double-blind, randomised, placebo-
controlled trial in 24 centres in the Netherlands, Germany, and
Belgium.
Methods and Results
Nine hundred eighty-four patients with ST-segment elevation
myocardial infarction (STEMI) who were candidates to undergo
percutaneous coronary intervention (PCI) were randomised to either
high-dose bolus tirofiban or placebo in the ambulance or other
prehospital setting. An additional 414 patients received either tirofiban
or no tirofiban in an open-label design. Aspirin and a 600-mg loading
dose of clopidogrel were also administered to all patients. Patients
were then transferred for primary PCI (PPCI). The primary endpoint
was residual ST-segment deviation (greater than 3 mm) 1 hour after
PCI. The key secondary endpoints included the combined occurrence
of death, recurrent MI, urgent target vessel revascularisation or
thrombotic bailout at 30 days, major bleeding, and death at 1-year
follow-up. Patients treated with tirofiban had significantly better
ST-segment resolution 1 hour after undergoing PPCI (the primary
endpoint) compared with the group of patients who did not receive
tirofiban. There was a reduction in the secondary composite clinical
endpoint at 30 days in patients treated with tirofiban. The strong
trend toward mortality benefit at 30 days was sustained at 1 year in
the tirofiban group (double blind, 3.4% with tirofiban versus 5.3%
with placebo; relative risk [RR] 0.78; 95% confidence interval [CI],
0.53-1.14; P=.157; open label: 4.4% with tirofiban versus 7.0% with
placebo; RR, 0.77; 95% CI, 0.46-1.29; P=.276). Patients who received
PPCI (84% of the study population) had a significant reduction in
mortality with tirofiban versus placebo (P=.007). The greatest efficacy
of tirofiban was observed in the elderly population (patients over 65
years of age), patients with Killip class 2 or higher, and in patients who
were early presenters.
1-Year Survival: Patients With Primary PCI
Event-Free Survival, %
100
P=0.009
95
90
Tirofiban
Placebo double blind, n=826
85
0 90 180 270 360
Abstract and figure adapted from Hamm C. Presention at: American College of Cardiology’s
58th Annual Scientific Session; March 29-31, 2009; Orlando, FL.
Conclusions
Early administration of tirofiban showed a strong trend of reduction in
mortality, which continued over a 1-year follow-up in both the open-
label and double-blind cohorts. In patients undergoing PPCI (84% of
the study population), there was a significant reduction in mortality. The
highest efficacy of tirofiban was noted in elderly patients (those over 65
years of age), patients with Killip class 2 or higher, and in patients who
were early presenters.
10
PRISM-PLUS Aggrastat
Platelet Receptor Inhibition in Ischaemic Syndrome Management in
Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS)
Study 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(21):1488-1497.
Background
Although antithrombotic therapy improves the prognosis of patients
with acute coronary syndromes (ACS), the syndromes still remain a
therapeutic challenge.
Objectives
The aim of this study was to investigate tirofiban, a specific inhibitor of
the platelet glycoprotein IIb/IIIa receptor, in the treatment of unstable
angina and non–Q-wave myocardial infarction (MI).
Methods
A total of 1915 patients were randomised in a double-blind manner
to receive tirofiban, heparin, or tirofiban plus heparin. Aspirin was
administered to patients if its use was not contraindicated. The study
drugs were infused for a mean of 71.3 ± 20 hours, during this period,
coronary angiography and angioplasty were performed when indicated
after 48 hours. Death, MI, or refractory ischaemia within 7 days after
randomisation constituted the composite primary endpoint.
Results
Excess mortality at 7 days in the group receiving tirofiban alone (4.6%
vs 1.1% for the patients treated with heparin alone) resulted in the
study being halted prematurely for this group. At 7 days, reduced
frequency of the composite primary endpoint was observed in patients
who received tirofiban plus heparin versus those who received heparin
alone (12.9% vs 17.9%; risk ratio, 0.68; 95% confidence interval,
0.53-0.88; P=.004). Reduced composite endpoint rates were noted in
the tirofiban plus heparin group at 30 days (18.5% vs 22.3%; P=.03)
and at 6 months (27.7% vs 32.1%; P=.02). At 7 days, the death or
MI rate was 4.9% in the tirofiban plus heparin group versus 8.3% in
the heparin only group (P=.006). The comparable figures at 30 days
were 8.7% and 11.9% (P=.03), respectively. Those at 6 months were
12.3% and 15.3% (P=.06), respectively. Beneficial effects persisted in
various subgroups of patients, including those treated medically and
those treated with angioplasty. The major bleeding rates were 3.0%
in the heparin only group and 4.0% in the combination therapy group
(P=.34).
0.40
Infarction, or Refractory Ischaemia
Probability of Death, Myocardial
P=0.02
0.30
0.20
0.10
Heparin
Tirofiban plus heparin
0.00
0 15 30 45 60 75 90 105 120 135 150 165 180
Kaplan-Meier curves showing the cumulative incidence of events among patients
randomly assigned to receive tirofiban plus heparin or heparin alone.
Abstract and figure adapted from PRISM-PLUS Study Investigators. N Engl J Med.
1998;338(21):1488-1497.
Conclusions
The platelet glycoprotein IIb/IIIa receptor inhibitor tirofiban
administered in combination with heparin and aspirin versus treatment
with only heparin and aspirin reduced the incidence of ischaemic
events in patients with ACS.
11
PRISM-PLUS (Renal) Aggrastat
Januzzi JL Jr, Snapinn SM, DiBattiste PM, et al. Benefits and safety
of tirofiban among acute coronary syndrome patients with mild to
moderate renal insufficiency: results from the Platelet Receptor
Inhibition in Ischaemic Syndrome Management in Patients Limited
by Unstable Signs and Symptoms (PRISM-PLUS) trial. Circulation.
2002;105(20):2361-2366.
Background
The role of glycoprotein IIb/IIIa receptor antagonists for the treatment
of patients with acute coronary syndrome and renal insufficiency (RI)
remains undefined.
Methods And Results
Participants enrolled in the PRISM-PLUS trial were stratified by
creatinine clearance (CrCl). Based on treatment assignment to
tirofiban/heparin or heparin alone, they were assessed for the risk
of adverse outcomes and bleeding. Patients with severe RI (serum
creatinine of at least 2.5 mg/dL) were excluded from the PRISM-
PLUS study. High-risk clinical features were more likely to be seen
in patients with the lowest CrCl (less than 30 mL/min). There was a
strong association between decreasing renal function and adverse
outcomes, which increased the risk for ischaemic complications at
all examined time points (P<.002 for all time points). Treatment with
tirofiban, irrespective of CrCl, resulted in a reduction in the odds of the
composite endpoint of death, myocardial infarction (MI), or refractory
ischaemia at 48 hours (odds ratio [OR], 0.68; 95% confidence interval
[CI], 0.46-1.0; P=.05), 7 days (OR, 0.68; 95% CI, 0.52-0.88; P=.003),
30 days (OR, 0.78; 95% CI, 0.63-0.98; P=.03), and 6 months (OR,
0.81; 95% CI, 0.68-0.98; P=.03). A similar magnitude of significant
reduction in the risk of MI/death was noted at all time points. No
evidence of treatment by CrCl interaction was seen. Declining renal
function (and treatment with tirofiban) independently increased the
risk for bleeding (OR, 1.57; P<.001 for the trend across categories).
Treatment with tirofiban did not result in unexpected incremental risk of
bleeding, even among the lowest CrCl categories.
Combination
OR=1.57 Heparin
Bleeding Odds
OR=1.80
OR=1.61
20 40 60 80 100
Creatinine Clearance, mL/min
Proportional odds for any severity of bleeding among patients in
PRISM-PLUS treated with tirofiban and heparin (combination)
versus heparin, expressed as a function of CrCl (in mL/min).
Declining renal function was significantly associated with haemorrhage,
irrespective of treatment assignment (P<0.001), as was the addition
of tirofiban to heparin (P<0.001). However, although each of these was
associated with significant increases in the risk for mild to moderate
bleeding, the addition of tirofiban in the presence of renal insufficiency
was not accompanied by an incremental increase in risk for haemorrhage
(incremental risk of bleeding from adding tirofiban to heparin from
lowest to highest category of CrCl: OR, 1.80 vs 1.61; P=NS).
Abstract and figure adapted from Januzzi JL Jr et al. Circulation. 2002;105(20):2361-2366.
Conclusions
Patients with mild to moderate impairment in renal function in
the PRISM-PLUS trial were treated safely and effectively with a
combination of tirofiban and heparin to reduce their risk for adverse
ischaemic cardiovascular events.
12
PRISM-PLUS (Age) Aggrastat
Januzzi JL Jr, Sabatine MS, Wan Y, et al. Interactions between age,
outcome of acute coronary syndromes, and tirofiban therapy. Am J
Cardiol. 2003;91(4):457-461.
Background
The interaction between non–ST-elevation acute coronary syndrome
(NSTE-ACS), age, and the effect on outcomes from treatment with
glycoprotein IIb/IIIa receptor antagonists remains relatively undefined.
Objectives
The objective of this study was to identify the interactions between
age, prognosis, and bleeding risk in patients with NSTE-ACS in the
PRISM-PLUS study.
Methods
In this analysis, age was considered to be a continuous and categoric
(up to 60 years of age, 61 to 70 years of age, and 71 years of age
or older) variable. The beneficial effects of treatment with tirofiban
on ischaemic endpoints were investigated. Assessment of the effect
of age and treatment assignment was based on bleeding risk,
which followed the same classification scheme as the PRISM-PLUS
study. The interactions between age as a continuous variable and
dichotomous baseline patient characteristics were evaluated; bleeding
events were also analysed.
Results
There was an increase in the odds of a 7-day composite endpoint by a
factor of 1.46 for every 10 years of age (95% confidence interval [CI],
1.21-1.77), while the odds of death and/or acute myocardial infarction
at the same time point increased by a factor of 1.42 for every 10 years
of increasing age (95% CI, 0.99-2.02). Treatment with tirofiban resulted
in significant decreases in ischaemic complications, with a relatively
similar magnitude across age ranges. All bleeding rates increased with
age (odds ratio [OR], 1.29 per decade increase in age, 95% CI, 1.19-
1.40; P<.0001). Treatment with tirofiban also increased bleeding risk
irrespective of age, but these risks were not incrementally amplified in
older patients.
Combination
Bleeding Log Odds
OR=1.29
OR=1.34
Heparin
OR=1.32
40 45 50 55 60 65 70 75 80
Age, Years
Proportional odds for bleeding among patients in the
PRISM-PLUS study who were treated with tirofiban and heparin
(combination) versus heparin alone, expressed as a function of age.
Advanced age was significantly associated with haemorrhage,
irrespective of treatment assignments (P<0.0001), as was treatment
with tirofiban (P<0.0001). However, the addition of tirofiban in the
presence of advancing age was not accompanied by an increment
in the expected increase in risk for haemorrhage (incremental risk of
bleeding from adding tirofiban to heparin from the lowest to highest
category of age OR, 1.33 vs 1.34; P=NS).
Abstract and figure adapted from Januzzi JL Jr et al. Am J Cardiol. 2003;91(4):457-461.
Conclusions
The benefits of tirofiban treatment were preserved across the age
groups studied, with an acceptable age-related risk for bleeding.
13
PRISM-PLUS (Diabetes) Aggrastat
Théroux P, Alexander J Jr, Pharand C, et al. Glycoprotein IIb/IIIa
receptor blockade improves outcomes in diabetic patients presenting
with unstable angina/non-ST-elevation myocardial infarction:
results from the Platelet Receptor Inhibition in Ischaemic Syndrome
Management in Patients Limited by Unstable Signs and Symptoms
(PRISM-PLUS) study. Circulation. 2000;102(20):2466-2472.
Background
A substantial increase in the incidence of infarction or death is
observed in diabetic patients who initially present with unstable angina
(UA) or non–ST-elevation myocardial infarction (NSTEMI) compared
with patients without diabetes.
Objectives
The objective of this study was to investigate the benefit of platelet
glycoprotein IIb/IIIa receptor–mediated inhibition of platelet aggregation
by tirofiban in diabetic patients in the Platelet Receptor Inhibition in
Ischaemic Syndrome Management in Patients Limited by Unstable
Signs and Symptoms (PRISM-PLUS) study.
Methods and Results
Of the 1570 PRISM-PLUS patients treated with either tirofiban plus
heparin (n=773) or heparin alone (n=797), approximately 23% in each
treatment group were diabetic. In the diabetic subgroup, treatment with
tirofiban plus heparin versus heparin alone resulted in reductions in the
incidence of the composite primary endpoint of death, MI, or refractory
ischaemia at 2, 7, 30, and 180 days (7.7% vs 8.3%, 14. 8% vs 21.8%,
20.1% vs 29.0%, and 32.0% vs 39.9%, respectively; P=not significant)
and in the incidence of MI or death (0.0% vs 3.1%; P=.03; 1.2% vs
9.3%; P=.005; 4.7% vs 15.5%; P=.002; and 11.2% vs 19.2%; P=.03).
Tests for quantitative interaction between tirofiban therapy and diabetic
status were significant.
T+H, % H, % CI
Composite 32.0 39.9 (0.53, 1.06)

180 days
MI/death 11.2 19.2 (0.31, 0.95)
30 days Composite 20.1 29.0 (0.44, 1.03)

MI/death* 4.7 15.5 (0.13, 0.62)
Composite 14.8 21.8 (0.41, 1.10)

7 days
MI/death* 1.2 9.3 (0.03, 0.52)
Composite 7.7 8.3 (0.45, 1.97)

48 hours
MI/death 0.0 3.1 ND†
0.1 1.0 10.0

Diabetic Patients Risk Ratio (95% CI)
Non-Diabetic Patients
*Statistically significant (P<0.05) interactions were found between tirofiban therapy and diabetic
status for these endpoints, suggesting that tirofiban was more efficacious among diabetic patients
than among non-diabetic patients.
†
Not defined.
Effect of treatment with tirofiban plus heparin (T+H) or heparin alone (H) on composite primary
endpoint of MI or death in diabetic and nondiabetic patients at various time points after randomisation.
Abstract and figure adapted from Théroux P et al. Circulation. 2000;102(20):2466-2472.
Conclusions
The present study reveals that adding tirofiban to heparin and aspirin
may be beneficial to diabetic patients presenting with UA and NSTEMI
in the prevention of ischaemic complications, particularly MI or death.
14
PRISM-PLUS (Troponins) Aggrastat
Januzzi JL, Hahn SS, Chae CU, et al. Effects of tirofiban plus heparin
versus heparin alone on troponin I levels in patients with acute
coronary syndromes. Am J Cardiol. 2000;86(7):713-717.
Background
Following an acute coronary syndrome (ACS), elevations in serum
troponins predict poor clinical outcomes. The use of glycoprotein IIb/
IIIa inhibitors (GPIs) reduces adverse clinical outcomes in patients with
ACS. However, their effect on serum troponin I (TnI) in this setting has
been undefined.
Objectives
The goal of this study was to investigate the effects of the GPI tirofiban
on serum TnI levels in a group of patients in the Platelet Inhibition in
Ischaemic Syndrome Management in Patients Limited by Unstable
Signs and Symptoms (PRISM-PLUS) trial.
Methods and Results
Serial blood samples of patients receiving the combination therapy
of tirofiban/heparin (n=53) and receiving heparin alone (n=52) were
obtained and analysed for baseline, peak, and mean concentrations
of TnI. Baseline TnI levels were similar in the combination therapy
group and heparin monotherapy group (1.6 ± 3.0 vs 3.1 ± 6.7 ng/
mL, respectively; P=.15). A significantly reduced peak TnI level was
observed in the combination therapy group versus the heparin only
group (5.2 ± 8.3 vs 15.5 ± 29.1 ng/mL, respectively; P=.017). Also,
significantly reduced mean TnI levels over the initial 24-hour period
were noted in the combination therapy group (3.2 ± 5.0 vs 8.5 ± 14.8
ng/mL, respectively; P=.016). Combination therapy was associated
with reduced TnI levels in univariate analysis. In multivariate analysis,
the lower peak and mean TnI levels due to combination therapy
were significant compared with heparin monotherapy (peak, P=.029;
mean, P=.035). Significantly lower peak (2.5 ± 5.4 vs 14.6 ± 32.8 ng/
mL, respectively; P=.024) and mean (1.2 ± 2.6 vs 6.9 ± 15.8 ng/mL,
respectively; P=.029) TnI levels were seen in patients with negative
TnI at baseline treated with the combination of tirofiban and heparin
compared with heparin monotherapy.
P=0.017
45
25 P=0.016
Troponin I, ng/mL
20
15
P=NS
10
0
H C H C H C
Baseline Mean Peak
Baseline, peak, and mean Tnl levels in subjects treated with combination
therapy of tirofiban/heparin (C) versus heparin monotherapy (H).
Abstract and figure adapted from Januzzi JL et al. Am J Cardiol. 2000;86(7):713-717.
Conclusions
Patients with ACS treated with tirofiban and heparin versus heparin
alone displayed lower serum TnI levels, implying reduced myocardial
injury.
15
RESTORE Aggrastat
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. Circulation. 1997;96(5):1445-1453.
Background
Following coronary angioplasty, 4% to 12.8% of patients experience
adverse cardiovascular events associated with thrombotic occlusion.
Tirofiban, a GP IIb/IIIa inhibitor, inhibits ex vivo platelet aggregation in
response to a variety of agonists.
Methods and Results
The RESTORE trial (Randomised Efficacy Study of Tirofiban for
Outcomes and REstenosis) was a randomised, double-blind, placebo-
controlled trial of tirofiban in patients undergoing coronary interventions
(balloon angioplasty or directional atherectomy) within 72 hours of
presentation with an acute coronary syndrome (ACS), defined as an
unstable angina pectoris or acute myocardial infarction (MI). Death
from any cause, MI, coronary bypass surgery due to angioplasty failure
or recurrent ischaemia, repeat target vessel angioplasty for recurrent
ischaemia, and insertion of a stent due to actual or threatened abrupt
closure of the dilated artery were the study endpoints; the primary
endpoint was a composite of any of those events. A total of 2139
patients were randomised to receive tirofiban or placebo; they were
already receiving treatment with aspirin and heparin. There was a
reduction in the rate of the primary composite endpoint at 30 days from
12.2% in the placebo group to 10.3% in the tirofiban group, which was
a 16% relative reduction (P=.160). However, 2 days after angioplasty,
there was a 38% relative reduction in the composite endpoint (P≤.005)
with tirofiban and at 7 days, there was a 27% relative reduction
(P=.022), mainly because of reduced incidence of nonfatal MI and
the need for repeat angioplasty. When repeat angioplasty or coronary
artery bypass surgery procedures were included in the composite
(only if performed on an urgent or emergency basis), the 30-day
composite event rates were 10.5% for the placebo group and 8.0% for
the tirofiban group, a relative reduction of 24% (P=.052). No significant
differences in major bleeding, including transfusion, were seen
between the 2 groups (3.7% in the placebo group and 5.3% in the
tirofiban group; P=.096). The incidence of Thrombolysis In Myocardial
Infarction major bleeding was 2.1% in the placebo group versus 2.4%
in the tirofiban group (P=.662). Similar rates of thrombocytopaenia
were observed for the placebo and tirofiban groups (0.9% for the
placebo group vs 1.1% for the tirofiban group; P=.709).
Placebo
Proportion With Composite Endpoint
0.12
Tirofiban
0.09
P=0.160
(Day 30)
0.06
P=0.022
(Day 7)
0.03
P=0.005
(Day 2)
0.00
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
Day
Time to composite endpoint: primary analysis. The Kaplan-Meier curves show the proportion
of patients treated with placebo and tirofiban who experienced an adverse event of the
composite endpoint (death, MI, CABG, or repeat PTCA for ischaemia or stent placement for
abrupt closure) during the 30-day study period. The probability values (log-rank test) for the
risk reduction attributable to tirofiban at days 2, 7, and 30 are shown. The majority of events
occurred shortly after the angioplasty procedure.
Abstract and figure adapted from RESTORE Investigators. Circulation. 1997;96(5):1445-1453.
Conclusions
Tirofiban was protective against early adverse cardiac events related
to thrombotic closure in patients undergoing coronary angioplasty for
ACS. However, the reduction in adverse cardiac events at 30 days was
no longer statistically significant.
16
TACTICS-TIMI 18 Aggrastat
Cannon CP, Weintraub WS, Demopoulos LA, et al. Comparison of
early invasive and conservative strategies in patients with unstable
coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor
tirofiban. N Engl J Med. 2001;344(25):1879-1887.
Background
Whether a routine early invasive strategy is superior to a conservative
strategy for the management of unstable angina (UA) and myocardial
infarction (MI) without ST-segment elevation is a matter of continued
debate.
Methods
A total of 2220 patients with UA and MI without ST-segment elevation
were enrolled. They had electrocardiographic evidence of changes
in the ST-segment or T wave, elevated levels of cardiac markers, a
history of coronary artery disease, or all 3 findings. Aspirin, heparin,
and the glycoprotein IIb/IIIa inhibitor (GPI) tirofiban were administered
to all patients. Patients were randomised to either an early invasive
strategy, which included routine catheterisation within 4 to 48 hours
and revascularisation as appropriate, or to a more conservative
(selectively invasive) strategy in which catheterisation was performed
only if the patient had objective evidence of recurrent ischaemia or an
abnormal stress test. The composite primary endpoint included death,
nonfatal MI, and rehospitalisation for an acute coronary syndrome at
6 months.
Results
At 6 months, the primary endpoint rates were 15.9% in the early
invasive strategy group and 19.4% in the conservative strategy
group (odds ratio [OR], 0.78; 95% confidence interval [CI], 0.62-0.97;
P=.025). There was a similar reduction in the rate of death or nonfatal
MI at 6 months (7.3% vs 9.5%; OR, 0.74; 95% CI, 0.54-1.00; P<.05).
20
18
16
14
Patients, %
12 P=0.025
10
8
6
4 Conservative strategy
2 Invasive strategy
0
0 2 4 6
Day
Cumulative incidence of the primary endpoint of death, nonfatal myocardial infarction,
or rehospitalisation for an acute coronary syndrome during the 6-month follow-up period.
The rate of the primary endpoint was lower in the invasive-strategy group than
in the conservative-strategy group (15.9% vs 19.4%; OR, 0.78; 95% confidence interval,
0.62-0.97; P=0.025).
Abstract and figure adapted from Cannon CP et al. N Engl J Med. 2001;344(25):1879-1887.
Conclusions
In patients with UA and MI without ST-segment elevation who were
treated with the GPI tirofiban, an early invasive strategy resulted in a
significant reduction in the incidence of major cardiac events. A policy
involving the broader use of the early inhibition of glycoprotein IIb/
IIIa in combination with an early invasive strategy in such patients is
supported by these data.
17
TACTICS-TIMI 18 (Troponins) Aggrastat
Morrow DA, Cannon CP, Rifai N, et al. Ability of minor elevations of
troponins I and T to predict benefit from an early invasive strategy
in patients with unstable angina and non-ST elevation myocardial
infarction: results from a randomised trial. JAMA. 2001;286(19):2405-
2412.
Background
Cardiac troponins I (cTnI) and T (cTnT) are useful for assessing
prognosis in patients with unstable angina and non–ST-segment
elevation myocardial infarction (UA/NSTEMI). However, it is unclear
whether cardiac troponins are useful for predicting the benefit of an
invasive versus conservative strategy in this setting.
Objectives
The aim of this study was to prospectively evaluate whether an early
invasive strategy was more beneficial than a conservative strategy for
patients with acute coronary syndrome (ACS) with elevated baseline
troponin levels.
Methods
This was a prospective, randomised trial conducted from December
1997 to June 2000 consisting of 169 community and tertiary care
hospitals in 9 countries. A total of 2220 patients with ACS were enrolled
in the study. Baseline troponin level data were available for analysis
in 1821 patients; 1780 patients completed the 6-month follow-up.
Patients were randomised to receive either an early invasive strategy
of coronary angiography between 4 to 48 hours after randomisation
and revascularisation when feasible, based on coronary anatomy
(n=1114) or a conservative strategy of medical treatment and, if stable,
predischarge exercise tolerance testing (n=1106). If conservative-
strategy patients had recurrent ischaemia at rest or on provocative
testing, only then were they assigned to coronary angiography and
revascularisation. The composite endpoint was comprised of death,
MI, or rehospitalisation for ACS at 6 months.
Results
There was a significant decrease in the primary endpoint with the
invasive versus conservative strategy (15.3% vs 25.0%; odds ratio
[OR], 0.54; 95% confidence interval [CI], 0.40-0.73), in patients with a
cTnI level of 0.1 ng/mL or higher (n=1087). No detectable benefit was
observed with early invasive treatment (16.0% vs 12.4%; OR, 1.4;
95% CI, 0.89-2.05; P<.001 for interaction) in patients with cTnI levels
of less than 0.1 ng/mL. Patients with even low-level (0.1-0.4 ng/mL)
cTnI elevation displayed benefit from invasive versus conservative
management through 30 days (4.4% vs 16.5%; OR, 0.24; 95% CI,
0.08-0.69). Directionally similar results were observed with cTnT.
Outcomes Stratified by Treatment Group and Cardiac Troponin (cTnl) Levels
Early Early
Outcome Invasive, % Conservative, % P Valuea OR (95% CI)b
6 Months
cTnl ≥0.1 ng/mL, No. 555 532

Primary endpoint 15.3 25.0 <0.001 0.54 (0.40-0.73)
cTnl <0.1 ng/mL, No. 362 372

Primary endpoint 16.0 12.4 0.16 1.4 (0.89-2.05)
a
P<0.001 at 6 months for interaction between treatment group and cTnl level with respect to
the primary endpoint; P=0.15 at 6 months for interaction with respect to death or MI.
b
Odds ratio compares early invasive vs early conservative strategy.
Abstract and figure adapted from Morrow DA et al. JAMA. 2001;286(19):2405-2412.

Conclusions
In patients with ACS treated with glycoprotein IIb/IIIa inhibitors, even
minor elevations in cTnI and cTnT help identify high-risk patients who
derive immense clinical benefit from an early invasive strategy.
18
TACTICS-TIMI 18 (Diabetes ) Aggrastat
Ray KK, Cannon CP, Morrow DA, et al. Synergistic relationship
between hyperglycaemia and inflammation with respect to
clinical outcomes in non-ST-elevation acute coronary syndromes:
analyses from OPUS-TIMI 16 and TACTICS-TIMI 18. Eur Heart J.
2007;28(7):806-813.
Objectives
The objective of this study was to explore the relationship between
diabetes and inflammation and the possibly synergistic relationship
between hyperglycaemia and inflammation on clinical outcomes in
non–ST-elevation acute coronary syndromes (NSTE-ACS).
Methods and Results
The main analysis was done on the OPUS-TIMI 16 trial (n=2200) with
C-reactive protein data. Data validation was done in the invasive arm
of TACTICS-TIMI 18 (n=929). Additionally, 2 inflammatory markers
(monocyte chemoattractant protein-1 [MCP-1] and von Willebrand
factor [vWF]) were analysed in OPUS-TIMI 16. Diabetic patients
had higher C-reactive protein and MCP-1 levels compared with
nondiabetic patients in OPUS-TIMI 16 (9 vs 7.8 mg/L; P=.002, and
190.6 vs 170.8 pg/mL; P=.04, respectively), higher C-reactive protein
levels in TACTICS-TIMI 18 (6.6 vs 5.2 mg/L; P=.0005), and higher
glucose levels in both trials, as expected. In the OPUS-TIMI 16 trial,
stratification by the median C-reactive protein and diabetes revealed
that diabetic patients with C-reactive protein greater than or equal to
the median were the highest risk group versus nondiabetic patients
with C-reactive protein less than the median (adjusted hazard ratio
[HR]: 1.63; 95% CI, 1.20-2.23; P=.002). Directionally, similar findings
were noted for MCP-1 and vWF in OPUS-TIMI 16 and for C-reactive
protein in TACTICS-TIMI 18. Following adjustment for diabetes, the
risk associated with a 1 mmol/L increase in glucose was higher in
those with a C-reactive protein greater than or equal to the median
(HR: 1.07; 95% CI, 1.03-1.11) compared with those with a C-reactive
protein less than the median (HR: 1.02; 95% CI, 0.97-1.06). The
synergistic relationship between glucose and C-reactive protein
and clinical outcomes was statistically significant (P=.01) following
multivariable adjustment. TACTICS-TIMI 18 displayed a similar pattern.
CRP
DM P=0.02
High CRP HR=2.17
CI, 1.12-4.18
P=0.28
DM HR=1.53
Low CRP CI, 0.71-3.28
P=0.76
Non-DM HR=1.10
High CRP CI, 0.58-2.08
Non-DM
Low CRP (Reference)
0.5 1.0 1.5 2.0 2.5 3.0

HR of Death or MI
CRP=C-reactive protein. DM=diabetes mellitus.

Unadjusted hazard of death or MI stratified by prior history of diabetes and biomarker
level above or below the median.
Abstract and figure adapted from Ray KK et al. Eur Heart J. 2007;28(7):806-813.
Conclusions
Diabetes was associated with increased inflammation and higher
glucose levels in patients with ACS; patients with both hyperglycaemia
and inflammation had worse outcomes. To reduce cardiovascular
risk among diabetic patients, improved control of inflammation and
hyperglycaemia should be analysed in future ACS trials.
19
TARGET Aggrastat
Topol EJ, Moliterno DJ, Herrmann HC, et al. Comparison of two
platelet glycoprotein IIb/IIIa inhibitors, tirofiban and abciximab, for
the prevention of ischaemic events with percutaneous coronary
revascularisation. N Engl J Med. 2001;344(25):1888-1894.
Background
Platelet glycoprotein IIb/IIIa inhibitors have caused a significant
reduction in the incidence of death or nonfatal myocardial
infarction (MI) at 30 days in the setting of percutaneous coronary
revascularisation.
Objectives
The objective of this study was to evaluate whether there are
differences in safety or efficacy between 2 such inhibitors, tirofiban and
abciximab.
Methods
This trial used a double-blind, double-dummy design at 149 hospitals
in 18 countries to randomise patients to receive either tirofiban or
abciximab before undergoing percutaneous coronary revascularisation
with the intent to perform stenting. The composite primary endpoint
included death, nonfatal MI, or urgent target vessel revascularisation
(uTVR) at 30 days. The trial was designed and statistically powered to
demonstrate the noninferiority of tirofiban compared with abciximab.
Results
The occurrence of the primary endpoint was more frequent among the
2398 patients in the tirofiban group than among the 2411 patients in
the abciximab group (7.6% vs 6.0%; hazard ratio [HR]: 1.26; 1-sided
95% confidence interval [CI], 1.51, demonstrating lack of equivalence;
2-sided 95% CI, 1.01-1.57, demonstrating the superiority of abciximab
over tirofiban; P=.038). The magnitude and the direction of the effect
were similar for each component of the composite endpoint (HR
for death: 1.21; HR for MI: 1.27; HR for uTVR: 1.26). A significant
difference was observed in the incidence of MI between the tirofiban
group and the abciximab group (6.9% and 5.4%, respectively; P=.04).
The relative benefit of abciximab stayed consistent irrespective of
factors such as age, sex, the presence or absence of diabetes, or the
presence or absence of pretreatment with clopidogrel. No significant
differences were observed in the rates of major bleeding complications
or transfusions, but a reduced rate of minor bleeding episodes and
thrombocytopaenia was observed with tirofiban.
8
7
6
Patients, %
5
4
3
2 Tirofiban (N=2398)
1 Abciximab (N=2411)
P=0.038
0
0 10 20 30
Days
Incidence of the primary endpoint, a composite of death, nonfatal myocardial infarction,
or urgent target vessel revascularisation, in the first 30 days after enrolment.
After 30 days, the incidence of the primary endpoint was 7.6% in the tirofiban group and
6.0% in the abciximab group (hazard ratio, 1.26; 95% confidence interval, 1.01-1.57; P=0.038).
Abstract and figure adapted from Topol EJ et al. N Engl J Med. 2001;344(25):1888-1894.
Conclusions
The trial was intended to evaluate the noninferiority of tirofiban versus
abciximab. However, the results demonstrate that tirofiban offered
reduced protection from major ischaemic events compared with
abciximab.
20
TENACITY Aggrastat
Moliterno DJ, Topol E, Califf R, et al. Tirofiban Evaluation of Novel
Dosing vs Abciximab with Clopidogrel and Inhibition of Thrombin
Study. Presented at: Transcatheter Cardiovascular Therapeutics (TCT)
annual meeting; October 16-21, 2005; Washington, DC.
Background
TENACITY is a multicentre, double-blind, randomised comparison of
tirofiban and abciximab that enrolled 383 patients with moderate- to
high-risk characteristics for adverse events during percutaneous
coronary intervention (PCI). The primary objective was to determine
whether the 30-day efficacy of a single high-dose bolus regimen of
tirofiban is noninferior to abciximab for patients with ST-elevation acute
myocardial infarction (STEMI) undergoing PCI with coronary stent
placement. In addition, TENACITY evaluated the 30-day safety and
efficacy of bivalirudin versus heparin among patients receiving tirofiban
or abciximab.
Methods and Results
Patients were randomised to either tirofiban 25 μg/kg bolus and
0.15 μg/kg/min 12-hour infusion or abciximab 0.25 mg/kg bolus
and 0.125 μg/kg/min for 12 hours and then separately randomised
to receive either heparin or bivalirudin. All patients were eligible
to receive aspirin and clopidogrel. Patients receiving a bare-metal
stent also received at least 1 month of clopidogrel and consideration
for treatment to 1 year. For patients receiving a drug-eluting stent,
individuals were eligible to receive a minimum of 3 months of
clopidogrel, with consideration for therapy to 3 years. The primary
study endpoint was a composite of death, MI, and urgent target vessel
revascularisation (uTVR). The study was stopped early solely for
financial reasons after 189 patients receiving tirofiban and 194 patients
receiving abciximab had completed randomisation and treatment.
For the primary endpoint, the 30-day event rates were 6.9% for
tirofiban and 8.8% for abciximab (odds ratio, 0.77; 95% confidence
interval, 0.37-1.64). Major TIMI bleeding was 0.5% for both tirofiban
and abciximab; minor bleeding was 1.1% and 1.5% for tirofiban and
abciximab, respectively. For the combined endpoint of death, MI,
uTVR, and major bleeding, event rates were lower for the tirofiban
plus bivalirudin combination (5.6%) than for the tirofiban plus heparin
(10.1%), abciximab plus bivalirudin (10.5%), and abciximab plus
heparin (9.1%) combinations.
30-Day Clinical Outcome
OR=0.77
10% (0.37, 1.64)
OR=0.74
OR=0.69
(0.31, 1.53)
(0.33, 1.66)
8.8
8% 8.2
7.7
6.9
6% 5.9 5.9
4% OR=3.13
(0.32, 30.36)
OR=0.20
2% (0.01, 4.28)
0.5 1.6
1.0 0
0
Composite Death MI Death/MI Urgent TVR
Abciximab (n=194) Tirofiban (n=189)
Abstract and figure developed from Moliterno DJ et al. Presentation at: Transcatheter
Cardiovascular Therapeutics (TCT) annual meeting; October 16-21, 2005; Washington, DC.
Conclusions
The TENACITY study successfully enrolled a cohort at higher risk for
death, MI, and uTVR (7.8% event rate). A very small percentage of
patients (3.2%) required tirofiban infusion beyond 12 hours. The low
rate of death, MI, uTVR, and major bleeding with the tirofiban plus
bivalirudin combination is provocative and warrants further study.
21
3T/2R Aggrastat
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: results from
the double-blind, prospective, randomised Tailoring Treatment with
Tirofiban in Patients Showing Resistance to Aspirin and/or Resistance
to Clopidogrel study. Circulation. 2009;119(25):3215-3222.
Background
There is great variation in the inhibition of platelet aggregation after
aspirin or clopidogrel intake by patients. Previous studies have
suggested that an increase in the risk of thrombotic events, especially
after coronary angioplasty, may be due to the poor response to oral
antiplatelet agents. It is unknown whether this reflects suboptimal
platelet inhibition that may therefore benefit from more potent
antiplatelet agents such as tirofiban.
Methods and Results

Out of a total of 1277 patients screened, 93 aspirin, 147 clopidogrel,
and 23 dual poor responders who underwent elective coronary
angioplasty at 10 European sites for stable or low-risk unstable
coronary artery disease were enrolled based on a point-of-care assay.
In addition to the standard therapy of aspirin and clopidogrel, patients
were randomised in a double-blind manner to receive either tirofiban
(n=132) or placebo (n=131). The primary endpoint was defined as
troponin I/T elevation at least 3 times the upper limit of normal and was
reached in 20.4% of the patients (n=27) in the tirofiban group versus
35.1% of the patients (n=46) in the placebo group (relative risk, 0.58;
95% confidence interval, 0.39-0.88; P=.009). The tirofiban group also
showed a reduced rate of major adverse cardiovascular events within
30 days compared with the placebo group (3.8% vs 10.7%; P=.031).
The rates of overall incidence of bleeding were low—likely explained
by a substantial use of the transradial approach—and similar between
the 2 groups.
Patients With Troponin I/T >3x Elevation, %
RR, 0.58; 95% CI, 0.39-0.88;

40 P=0.009
30
20
10
0
Tirofiban Placebo
Rates of periprocedural MI according to the primary
endpoint definition. RR indicates relative risk.
Abstract and figure adapted from Valgimigli M et al. Circulation. 2009;119(25):3215-3222.
Conclusions
Intensified platelet inhibition with tirofiban reduced the incidence
of myocardial infarction after elective coronary intervention in low-
risk patients who were, by clinical presentation, poor responders to
standard oral platelet inhibitors via a point-of-care assay.
22
ASSIST Integrilin
Le May MR on behalf of ASSIST trial investigators. A Safety and
Efficacy Study of Integrilin Facilitated PCI versus Primary PCI in
ST Elevation Myocardial Infarction. Presented at: Transcatheter
Cardiovascular Therapeutics 20th Annual Scientific Symposium;
October 12-17, 2008; Washington DC.
Background
Abciximab is a useful adjunct for patients referred for primary
percutaneous coronary intervention (PPCI), as demonstrated by
randomised trials. It has been shown in observational studies that
eptifibatide yields similar results to abciximab. Evaluation of clinical
outcomes by a direct comparison of eptifibatide to a control group has
not yet been examined. Also, there are a limited number of studies
utilising a high loading dose of clopidogrel in PPCI.
Methods
The ASSIST trial was an open-label randomised trial. Four hundred
patients with ST-elevation myocardial infarction (STEMI) and symptom
onset up to 12 hours were enrolled in the study from August 2005
to March 2008. Aspirin 160 mg (chewable), clopidogrel 600 mg, and
heparin 60 units/kg (max 4,000) were administered to all patients.
Patients were randomised to 2 groups: 201 patients were assigned to
PCI with heparin plus eptifibatide; 199 patients were assigned to PCI
with heparin alone. Both groups were included in the 30-day follow-up
and intention-to-treat analysis. The primary endpoint included death,
reinfarction, or recurrent severe ischaemia at 30 days.
Results
No differences were observed in the clinical and procedural
characteristics, including door-to-balloon time and procedural success
between the 2 groups. Eptifibatide plus heparin compared with heparin
alone provided no benefit in the occurrence of the primary composite
endpoint (6.5% vs 5.5%, respectively; P=.69), as well as on the
individual components of the primary endpoint. At 6-month follow-up,
no benefit of eptifibatide was observed on the incidence of death,
reinfarction, or recurrent severe ischaemia. There was an increase
in the in-hospital composite endpoint of Thrombolysis in Myocardial
Infarction major or minor bleeding in the eptifibatide plus heparin group
versus the heparin alone group (22.4% vs 14.6%; P=.04).
Patients With Primary Endpoint, %
Log-rank P=0.70
Heparin plus eptifibatide
8
6.5%
6
5.5%
4
Heparin
2
0
0 6 12 18 24 30
Days
Kaplan-Meier estimates, 30 days.
Abstract and figure adapted from Le May MR on behalf of ASSIST trial investigators.
Presentation at: Transcatheter Cardiovascular Therapeutics 20th Annual Scientific
Symposium; October 12-17, 2008; Washington DC.
Conclusions
In patients with acute STEMI pretreated with high-dose clopidogrel,
PCI with eptifibatide (versus PCI with heparin alone) initiated before
catheterisation did not provide clinical benefit and resulted in increased
bleeding.
23
BRIEF-PCI Integrilin
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) randomised trial. J Am Coll Cardiol. 2009;53(10):837-845.
Background
The recommended regimen for eptifibatide is a double bolus followed
by an infusion for 18 hours. If the percutaneous coronary intervention
(PCI) is uncomplicated, it is unknown whether the infusion can be
abbreviated.
Objectives
The objective of this study was to evaluate whether the early
discontinuation of eptifibatide infusion in nonemergent PCI was
associated with a higher frequency of periprocedural ischaemic
myonecrosis.
Methods
A total of 624 patients with stable angina, acute coronary syndrome,
or recent ST-segment elevation myocardial infarction (greater than
48 hours) who underwent successful coronary stenting and received
eptifibatide were enrolled. Patients were randomised to receive
either an 18-hour infusion or an abbreviated infusion of less than
2 hours. The incidence of periprocedural myonecrosis defined as
troponin-I elevation greater than 0.26 μg/L was the primary endpoint
of the study. Death, myocardial infarction (MI), urgent target vessel
revascularisation at 30 days, and in-hospital major bleeding based on
the REPLACE-2 (Randomised Evaluation in PCI Linking Angiomax to
Reduced Clinical Events) trial criteria were the secondary endpoints.
Results
The incidence of the primary endpoint was 30.1% in the less-than-
2-hour group versus 28.3% in the 18-hour group (mean difference,
1.8%; upper bound of 95% confidence interval, 7.8%; P<.012 for
noninferiority). Death, MI, and target vessel revascularisation rates at
30 days were similar in both groups (P=not significant). The less-than-
2-hour group reported less frequent major bleeding (1.0% vs 4.2%;
P=.02).
Primary Endpoint,
No. of Events/Total No. (%)
<2-h group 18-h group

P interaction
No clopidogrel preRx 29/89 (32.6) 33/107 (30.8)
0.95
Clopidogrel preRx 63/217 (29.0) 55/204 (27.0)
No diabetes 87/268 (32.5) 79/263 (30.0)

0.40
Diabetes 5/38 (13.2) 9/48 (18.8)
No ACS 51/143 (35.7) 45/159 (28.3)

0.16
ACS 41/163 (25.2) 43/152 (28.3)
All 92/306 (30.1) 88/311 (28.3)
-10 0 10 20
<2-h group - 18-h group, %
With 95% UCL
Frequency and effects of a less-than-2-hour (<2-h group) versus an18-hour (18-h group)
eptifbatide infusion on periprocedural myonecrosis in selected subgroups.
PreRx=pretreatment; UCL=upper confidence limit.
Abstract and figure adapted from Fung AY et al. J Am Coll Cardiol. 2009;53(10):837-845.
Conclusions
This study revealed that eptifibatide infusion can be safely shortened
to less than 2 hours after uncomplicated PCI. The abbreviated infusion
is noninferior to the standard 18-hour infusion in the prevention of
ischaemic outcomes and may be associated with reduced major
bleeding.
24
CLEAR PLATELETS Integrilin
Gurbel PA, Bliden KP, Zaman KA, et al. 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(9):1153-1159.
Background
Pretreatment is not the most common strategy practiced for clopidogrel
administration in elective coronary stenting. Moreover, the information
available on the antiplatelet pharmacodynamics of a 300-mg versus a
600-mg clopidogrel loading dose is sparse and the effect of eptifibatide
in comparison with these regimens is unclear.
Methods and Results

One hundred twenty patients undergoing elective stenting were
enrolled in a 2-by-2 factorial study of clopidogrel 300 mg with or
without eptifibatide, or clopidogrel 600 mg with or without eptifibatide.
(Clopidogrel Loading With Eptifibatide to Arrest the Reactivity of
Platelets [CLEAR PLATELETS] study.) Immediately after stenting,
patients were administered clopidogrel. Platelet reactivity was
evaluated using aggregometry and flow cytometry. A 2-fold or higher
increase in platelet inhibition was observed with the addition of
eptifibatide to clopidogrel 600 mg alone at 3, 8, and 18 to 24 hours
after stenting based on the measurement by 5 μmol/L adenosine
diphosphate–induced aggregation (P<.001). Clopidogrel 600 mg
resulted in better inhibition than clopidogrel 300 mg at all time points
(P<.001) without eptifibatide. Reduced cardiac marker release was
related to glycoprotein IIb/IIIa blockade. The groups treated with
eptifibatide reported the most inhibition of active glycoprotein IIb/IIIa
expression (P<.05).
120
110
Relative inhibition
100
Group D
90 Group C
80
(Percent)
70 *
60 *
50 * Group B
40
30 Group A
20
10
0
3h 8h 18 - 24 h
Time (Post-stenting)
Abstract and figure adapted from Gurbel PA et al. Circulation. 2005;111(9):1153-1159.
Conclusions
In elective stenting without clopidogrel pretreatment, administration of
a glycoprotein IIb/IIIa inhibitor resulted in superior platelet inhibition
and reduced myocardial necrosis compared with high-dose (600 mg)
or standard-dose (300 mg) clopidogrel loading alone. Clopidogrel
600 mg was associated with better platelet inhibition than the standard
300-mg dose when a glycoprotein IIb/IIIa inhibitor was absent. A large-
scale trial would need to be conducted to confirm these results.
25
CLEAR PLATELETS-2 Integrilin
Gurbel PA, Bliden KP, Saucedo JF, et al. Bivalirudin and clopidogrel
with and without eptifibatide for elective stenting: effects on
platelet function, thrombelastographic indexes, and their relation
to periprocedural infarction results of the CLEAR PLATELETS-2
(Clopidogrel with Eptifibatide to Arrest the Reactivity of Platelets) study.
J Am Coll Cardiol. 2009;53(8):648-657.
Background
Bivalirudin is commonly administered alone to clopidogrel-naïve
patients and to patients on clopidogrel maintenance therapy (MT)
undergoing elective stenting. It is not known how the addition of
eptifibatide to bivalirudin affects platelet reactivity (PR) and thrombin-
induced platelet-fibrin clot strength (TIP-FCS) and their relation to
periprocedural infarction in these patients. The primary purpose of
this study was to compare the effect of treatment with bivalirudin
monotherapy versus treatment with bivalirudin plus eptifibatide
on PR, measured by turbidometric aggregometry, as well as TIP-
FCS, measured by thromboelastography, in patients undergoing
percutaneous coronary intervention (PCI). The secondary goal was to
investigate how platelet aggregation and TIP-FCS were related to the
occurrence of periprocedural infarction.
Methods and Results

Patients (n=200) stratified to clopidogrel treatment status were
randomised to receive bivalirudin (n=102) or bivalirudin plus
eptifibatide (n=98). Immediately after stenting, 128 clopidogrel-naïve
patients were loaded with clopidogrel 600 mg; 72 patients receiving
MT were not loaded. Serial determination of PR, TIP-FCS, and
myonecrosis markers was done. Treatment with bivalirudin plus
eptifibatide resulted in markedly reduced PR at all times (5- and 20-
μM adenosine diphosphate–induced, and 15- and 25-μM thrombin
receptor activator peptide–induced aggregation; P<.001 for all) and
lower mean TIP-FCS (P<.05) in both clopidogrel-naïve patients and
patients receiving MT. Higher mean 18-hour PR (P<.0001) and TIP-
FCS (P=.002) was observed in patients who had a periprocedural
infarction. A
80
600-mg C+B
75
TIP-FCS, mm
70
65
#
60 ++ #
+#
55
600-mg C+B+E
50
Baseline 2 6-8 18
Hours
B
80
75-mg C+B
75
TIP-FCS, mm
70
65
60
55 75-mg C+B+E
50
Baseline 2 6-8 18
Hours
TIP-FCS and R in CN and MT patients.
(A and B) Thrombin-induced platelet-fibrin clot strength (TIP-FCS).
(Part A) solid lines=600-mg C+B; dashed lines=600-mg C+B+E.
(Part B) solid lines=75-mg C+B; dashed lines=75-mg C+B+E.
B=bivalirudin; C=clopidogrel; E=eptifibitide.
+=P<0.01
++=P<0.05 versus baseline.
#=P<0.001 between groups at the same time point (Bonferroni correction).
Abstract and figure adapted from Gurbel PA et al. J Am Coll Cardiol. 2009;53(8):648-657.
Conclusions
The addition of eptifibatide to bivalirudin in elective stenting reduced
PR to multiple agonists and the tensile strength of the TIP-FCS—both
of these measurements are strongly associated with periprocedural
myonecrosis. Future studies of PR and TIP-FCS for elective stenting
may facilitate personalised antiplatelet therapy and enhance the
selection of patients for glycoprotein IIb/IIIa blockade.
26
EARLY ACS Integrilin
Giugliano RP, White JA, Bode C, et al. Early versus delayed,
provisional eptifibatide in acute coronary syndromes. N Engl J Med.
2009;360(21):2176-2190.
Background
Glycoprotein IIb/IIIa inhibitors are indicated in patients with acute
coronary syndromes (ACS) who are undergoing an invasive
procedure. The optimal timing of the initiation of such therapy is
unknown.
Methods
EARLY ACS was a comparative study of early, routine administration
of eptifibatide versus delayed, provisional administration in 9492
patients who were assigned to an invasive strategy for the treatment
of ACS without ST-segment elevation. Patients were randomised to
receive either early eptifibatide (2 boluses, each containing 180 μg/kg
of body weight administered 10 minutes apart, as well as a standard
infusion at least 12 hours before angiography) or a matching placebo
infusion with provisional use of eptifibatide after angiography (delayed
eptifibatide). The primary efficacy endpoint was a composite of death,
myocardial infarction (MI), recurrent ischaemia requiring urgent
revascularisation, or a thrombotic complication during percutaneous
coronary intervention requiring bolus therapy opposite to the initial
study group assignment (“thrombotic bailout”) at 96 hours. A composite
of death or MI within the first 30 days constituted the key secondary
endpoint. Bleeding and the need for transfusion within the first 120
hours after randomisation were the key safety endpoints.
Results
Of the patients in the early eptifibatide group, 9.3% attained the
primary endpoint. Ten percent of the patients in the delayed-
eptifibatide group attained the primary endpoint (odds ratio [OR], 0.92;
95% confidence interval [CI], 0.80-1.06; P=.23) At 30 days, 11.2% of
the patients in the early eptifibatide group, as compared with 12.3% of
the patients in the delayed-eptifibatide group (OR, 0.89; 95% CI, 0.79
to 1.01; P=.08) had incidence of death or MI. Significantly higher rates
of bleeding and red-cell transfusion were noted in patients in the early-
eptifibatide group. The rates of severe bleeding and nonhemorrhaegic
serious adverse events were not significantly different between the
2 groups.
Primary and Secondary Endpoints
Delayed-Eptifibatide Group Early-Eptifibatide Group
(n=4722) (n=4684)
14.0
12.3 P=NS
12.0 11.2
10.0 P=NS
Patients, %
10.0 9.3 P=NS

8.3
8.0 7.5
6.0
4.0
2.0
0.0
Primary Death/MI Secondary
Endpoint at 96 Hours Endpoint
at 96 Hours at 30 Days
Primary endpoint: Composite of death, MI, uR, or TBO at 96 hours.

Secondary endpoint: Death or MI at 30 days.
NS=not significant; TBO=thrombotic bailout; uR=recurrent
ischaemia requiring urgent revascularisation.
Abstract and figure adapted from Giugliano RP et al. N Engl J Med. 2009;360(21):2176-2190.
Conclusions
For patients who had ACS without ST-segment elevation, eptifibatide
administration 12 hours or more before angiography was not superior
to the provisional administration of eptifibatide after angiography.
Increased risk of non–life-threatening bleeding and need for
transfusion were noted with the early use of eptifibatide.
27
ESPIRIT Integrilin
ESPRIT Investigators. Novel dosing regimen of eptifibatide in planned
coronary stent implantation (ESPRIT): a randomised, placebo-
controlled trial. Lancet. 2000;356(9247):2037-2044.
Background
Although platelet glycoprotein IIb/IIIa inhibitors (GPIs) are effective
in reducing ischaemic complications of percutaneous coronary
intervention (PCI), they are used in few coronary stent implantation
procedures. ESPRIT (Enhanced Suppression of the Platelet IIb/IIIa
Receptor with Integrilin Therapy) is a randomised placebo-controlled
trial to evaluate whether improved outcomes of patients undergoing
coronary stenting occur with a novel, double-bolus dose of eptifibatide.
Methods
A total of 2064 patients undergoing stent implantation in a native
coronary artery were enrolled in the study. Immediately prior to PCI,
patients were randomised to receive either eptifibatide (given as two
180 μg/kg boluses 10 minutes apart) and a continuous infusion of
2 μg/kg/min for 18 to 24 hours or placebo, along with aspirin, heparin,
and a thienopyridine. The primary composite endpoint included death,
myocardial infarction (MI), urgent target vessel revascularisation
(uTVR), and thrombotic bailout GPI therapy within 48 hours after
randomisation. The composite of death, MI, or uTVR at 30 days was
the key secondary endpoint.
Results
The trial was terminated early for efficacy. There was a reduction in
the rate of the primary endpoint from 10.5% with placebo (108 of 1024
patients; 95% confidence interval [CI], 8.7%-12.4%) to 6.6% with
eptifibatide (69 of 1040 patients; 95% CI, 5.1%-8.1%). There was also
a reduction in the key 30-day secondary endpoint from 10.5% with
placebo (107 of 1024 patients; 95% CI, 8.6%-12.3%) to 6.8% with
eptifibatide (71 of 1040 patients; 95% CI, 5.3%-8.4%; P=.0034).
A consistent reduction of events across all components of the
composite endpoint and among major subgroups was reported.
Infrequent major bleeding was reported but occurred more often with
eptifibatide than with placebo (1.3% [13 of 1040 patients]; 95% CI,
0.7%-2.1% vs 0.4% [4 of 1024 patients]; 95% CI, 0.1%-1.0%; P=.027).
100
12
10.5%
Cumulative Event Rate, %
RR=0.65%
8 P=0.0030
6.8%
Placebo
0 Eptifibatide
0 5 10 15 20 25 30
Days From Randomisation
Kaplan-Meier plot of the probability of the composite endpoint of death, myocardial
infarction (upper), and urgent TVR and death and myocardial infarction (lower) to 30 days.
Abstract and figure adapted from ESPRIT Investigators. Lancet. 2000;356(9247):2037-2044.
Conclusions
There was a substantial reduction of ischaemic complications in
coronary stent intervention with routine GPI pretreatment with
eptifibatide, which was found to be better than reserving treatment to
the bailout situation.
28
ESPIRIT (Diabetes) Integrilin
Labinaz M, Madan M, O’Shea JO, et al. Comparison of one-year
outcomes following coronary artery stenting in diabetic versus
nondiabetic patients (from the Enhanced Suppression of the Platelet
IIb/IIIa Receptor With Integrilin Therapy [ESPRIT] Trial). Am J Cardiol.
2002;90(6):585-590.
Background
Glycoprotein IIb/IIIa receptor blockade with eptifibatide lowers the
incidence of ischaemic complications in patients undergoing non-
urgent coronary stent implantation. The interaction of eptifibatide with
diabetes in patients who underwent this procedure was analysed by
evaluating the 1-year outcomes of those enrolled in the Enhanced
Suppression of the Platelet IIb/IIIa Receptor With Integrilin Therapy
(ESPRIT) trial.
Methods and Results

Four hundred sixty-six diabetic patients and 1,595 nondiabetic
patients from the ESPRIT trial were enrolled in this study. Diabetic
patients had a higher 1-year composite endpoint of death, myocardial
infarction (MI), or target vessel revascularisation (TVR) compared
with nondiabetic patients (24.5% vs 18.4%; P=.008). Treatment with
eptifibatide had a similar effect on the 1-year composite endpoint of
death, MI, or TVR in diabetic patients (hazard ratio [HR]: 0.71; 95%
confidence interval [CI], 0.49-1.04) and nondiabetic patients (HR: 0.80;
95% CI, 0.63-0.99). A similar treatment effect was also seen on death
or MI in both groups. Diabetic patients who received placebo had a
1-year mortality rate of 3.5% versus 1.3% for patients treated with
eptifibatide (HR: 0.37; 95% CI, 0.10-1.41); this latter rate was similar to
the mortality rate of 1.4% observed in nondiabetic patients treated with
eptifibatide. However, treatment with eptifibatide in diabetic patients
had no significant effect on TVR (HR: 0.90; 95% CI, 0.57-1.41).
Clinical Outcomes of Diabetic Patients and Nondiabetic Patients Assigned to Epifibatide or Placebo
Nondiabetics Diabetics
Placebo, % Eptifibatide, % Placebo, % Eptifibatide, %
Time/Clinical Event (n=788) (n=807) (n=234) (n=232) P Valuea
48 hours
Death/MI/urgent TVR/thrombotic bailout 87 (11.0) 58 (7.2) 20 (8.6) 11 (4.7) 0.710
Death/MI/urgent TVR 76 (9.6) 53 (6.6) 18 (7.7) 9 (3.9) 0.503
Death/MI 75 (9.5) 48 (6.0) 18 (7.7) 9 (3.9) 0.639
Death 2 (0.3) 1 (0.1) 0 0 0.998
30 days
Death/MI/urgent TVR 84 (10.7) 58 (7.2) 22 (9.4) 13 (5.6) 0.755
Death/MI 82 (10.4) 53 (6.6) 21 (9.0) 13 (5.6) 0.990
Death 4 (0.5) 3 (0.4) 2 (0.9) 1 (0.4) 0.795
6 months
Death/MI/TVR 133 (17.1) 104 (13.1) 53 (23.2) 42 (18.6) 0.866
Death/MI 87 (11.1) 61 (7.6) 29 (12.5) 16 (6.9) 0.568
Death 8 (1.0) 6 (0.7) 6 (2.6) 2 (0.9) 0.420
TVR 67 (8.7) 57 (7.3) 29 (13.0) 31 (13.8) 0.405
1 year
Death/MI/TVR 157 (20.2) 131 (16.6) 64 (28.2) 47 (20.8) 0.639
Death/MI 94 (12.0) 65 (8.1) 31 (13.4) 18 (7.8) 0.679
Death 12 (1.5) 11 (1.4) 8 (3.5) 3 (1.3) 0.270
TVR 89 (11.6) 81 (10.4) 40 (18.1) 36 (16.1) 0.954
a
The P value is for the interaction of treatment with diabetes.
Abstract and figure adapted from Labinaz M et al. Am J Cardiol. 2002;90(6):585-590.
Conclusions
Treatment with eptifibatide in both diabetic and nondiabetic patients
undergoing coronary stent implantation resulted in a similar relative
reduction in adverse ischaemic complications. There was no evidence
of a statistical interaction in the treatment effect of eptifibatide between
patients with and without diabetes.
29
ESPRIT (High Risk) Integrilin
Puma JA, Banko LT, Pieper KS, et al. Clinical characteristics predict
benefits from eptifibatide therapy during coronary stenting: insights
from the Enhanced Suppression of the Platelet IIb/IIIa Receptor With
Integrilin Therapy (ESPRIT) trial. J Am Coll Cardiol. 2006;47(4):715-
718.
Background
Newer anticoagulant strategies during percutaneous coronary
intervention have necessitated a re-analysis of the role of intravenous
glycoprotein IIb/IIIa inhibitors. A total of 2,064 patients undergoing non-
urgent coronary stent implantation were randomised to eptifibatide or
placebo in the Enhanced Suppression of the Platelet IIb/IIIa Receptor
With Integrilin Therapy (ESPRIT) trial.
Objectives
The long-term outcome of high-risk versus low-risk patients was
compared and the survival free from death or myocardial infarction
(MI) at 1 year was evaluated to determine a differential benefit from
treatment.
Methods
Age greater than 75 years, diabetes, elevated cardiac markers, ST-
segment elevation MI within 7 days, or unstable angina within 48 hours
of randomisation were defined as high-risk characteristics, whereas,
age less than 75 years, absence of diabetes, and any other reason for
admission were defined as low-risk characteristics.
Results
The high-risk group had 1,018 patients (50.8% eptifibatide, 49.2%
placebo), while the low-risk group had 1,045 patients (50.0%
eptifibatide, 50.0% placebo). Similar baseline demographics were
observed in both groups, with the exception of more hypertension
(63% vs 55%, respectively), peripheral vascular disease (8.2% vs
5.2%, respectively), prior stroke (5.5% vs 3.2%, respectively), and
female gender (33% vs 22%, respectively) in the high-risk group
compared with the low-risk group. A total of 15.89% of the patients
receiving placebo and 7.99% of the patients receiving eptifibatide in
the high-risk group, as well as 9.02% of the patients receiving placebo
and 8.11% of the patients receiving eptifibatide in the low-risk group
attained the 1-year composite endpoint of death or MI.
Death or MI at 30 Days and 12 Months Among the 2 Risk Groups
Death or MI, 95% CI

12 Months 30 Days
Low risk (placebo) 9.02% (6.56-11.48) 8.03% (5.70-10.36)
Low risk (eptifibatide) 8.11% (5.76-10.46) 6.51% (4.40-8.63)
High risk (placebo) 15.89% (12.67-19.10) 12.38% (9.49-15.26)
High risk (eptifibatide) 7.99% (5.64-10.34) 6.19% (4.11-8.27)
Abstract and figure adapted from Puma JA et al. J Am Coll Cardiol. 2006;47(4):715-718.
Conclusions
Treatment with eptifibatide improved outcomes for all patients.
However, a subgroup of patients who may derive the greatest benefit
from its use during coronary stent placement can be defined by
preprocedural clinical characteristics.
30
EVA-AMI Integrilin
Zeymer U on behalf of the EVA-AMI Investigators. Eptifibatide versus
Abciximab in primary PCI for acute ST elevation myocardial infarction.
EVA-AMI Trial. Presented at: 2007 Scientific Sessions of the American
Heart Association; November 3-7 2007; Orlando, FL.
Background
Eptifibatide has reduced events in patients with elective PCI
comparable to abciximab. To date, there has been no head-to-head
comparison of the 2 glycoprotein IIb/IIIa inhibitors (GPIs) in PPCI. The
purpose of this study was to demonstrate noninferiority of eptifibatide
compared with abciximab as adjunctive treatment for patients
undergoing PPCI.
Methods and Results
EVA-AMI was an international, multicentre, randomised, open,
parallel-group, comparative study of eptifibatide and abciximab in
patients with ST-elevation myocardial infarction (STEMI) for less
than 12 hours treated with aspirin, clopidogrel, and unfractionated
heparin or enoxaparin scheduled for PPCI. Four hundred patients
with STEMI for less than 12 hours who were scheduled for PPCI
were enrolled in the study. The patients were randomised to receive
either eptifibatide—given as 2 boluses—and a 24-hour infusion, or
an abciximab bolus and a 12-hour infusion. The primary endpoint
of the study was complete sum ST resolution (more than 70%) at
60-minutes (range: 45 to 75 minutes) post-PCI. The key secondary
endpoints included death, reinfarction, target vessel revascularisation
(TVR), and bleedings until 7 days, 30 days, and 6 months. Eptifibatide
was noninferior for the primary endpoint (59.6% in the abciximab
group vs 63.1% in the eptifibatide group; P=not significant). In fact,
the proportion of patients with no ST resolution after 60 minutes was
statistically lower in the eptifibatide arm (5.4% in abciximab group vs
14.7% in eptifibatide group; P=.021). There were no differences in
in-hospital events between the abciximab group and the eptifibatide
group, including death (3.5% vs 3.5%, respectively), reinfarction (1.5%
vs 0%, respectively), heart failure (8.5% vs 6.4%, respectively), TVR
(4% vs 2.7%, respectively), and coronary artery bypass graft surgery
(0.5% vs 0.9%, respectively) among the 2 groups. Additionally, major-
and minor-bleeding rates were also similar between the 2 groups.
Sum ST-Resolution 60 Minutes After
PCI Intention-to-Treat Analysis
Eptifibatide, % Abciximab, % P Value
(n=225) (n=200)
Single lead
complete 46.2 41.0 NS
No 27.6 28.0 NS
Partial 22.2 24.5 NS
Complete 50.2 47.5 NS
Abstract and figure adapted from Zeymer U on behalf of the EVA-AMI Investigators. Presented
at: 2007 Scientific Sessions of the American Heart Association; November 3-7 2007;
Orlando, FL.
Conclusions
Eptifibatide double bolus was equally effective as abciximab as
adjunctive treatment to PPCI with respect to myocardial reperfusion.
There were no differences in preliminary clinical events between
the 2 agents. Therefore, eptifibatide seems to be an alternative to
abciximab for patients with STEMI undergoing PPCI.
31
PROTECT─TIMI-30 Integrilin
Gibson CM, Morrow DA, Murphy SA, et al. A randomised trial to
evaluate the relative protection against post-percutaneous coronary
intervention microvascular dysfunction, ischaemia, and inflammation
among antiplatelet and antithrombotic agents: the PROTECT–TIMI-30
trial. J Am Coll Cardiol. 2006;47(12):2364-2373.
Background
There is no certainty about the optimal combination of an antiplatelet
and antithrombin regimen to maximise efficacy and minimise
bleeding among patients with non–ST-segment elevation acute
coronary syndrome (NSTE-ACS) undergoing percutaneous coronary
intervention (PCI).
Objectives
The objective of this study was to assess glycoprotein IIb/IIIa inhibition
with eptifibatide when administered with indirect thrombin inhibition
versus direct thrombin inhibition with bivalirudin monotherapy for
patients with NSTE-ACS.
Methods
Eight hundred fifty-seven patients with NSTE-ACS were randomised to
receive eptifibatide plus reduced-dose unfractionated heparin (n=298),
eptifibatide plus reduced-dose enoxaparin (n=275), or bivalirudin
monotherapy (n=284).
Results
Among angiographically evaluable patients (n=754), significantly
greater post-PCI coronary flow reserve ([CFR] the primary endpoint)
was noted with bivalirudin (1.43 vs 1.33 for pooled eptifibatide arms;
P=.036). Eptifibatide treatment versus bivalirudin resulted in more
frequent normal rates of Thrombolysis In Myocardial Infarction (TIMI)
myocardial perfusion grade (57.9% vs 50.9%; P=.048). Significantly
longer duration of ischaemia after PCI was observed on continuous
Holter monitoring among patients treated with bivalirudin (169 minutes
vs 36 minutes; P=.013). No excess of TIMI major bleeding was noted
among patients treated with eptifibatide compared with bivalirudin
(0.7%, n=4 vs 0%; P=not significant), but there was an increase in the
TIMI minor bleeding rates (2.5% vs 0.4%; P=.027) and transfusion
(4.4% vs 0.4%; P<.001).
20 18.0%
Ischaemia 11.6%
14.2%
10 D/MI Ischaemia 8.7%

%
8.8% D/MI
6.6%
MI 8.5% MI 6.6%
Death 0.4% Death 0%
0
Bivalirudin (N=267) Eptifibatide (N=530)
Death (D), myocardial infarction (MI), or ischaemia on Holter monitoring through 48 hours.
The composite event of D, MI, or ischaemia on Holter monitoring through 48 hours occurred
in 18% of the bivalirudin arm compared with 14.2% of the pooled eptifibatide arms
(odds ratio [OR], 1.35; 95% confidence interval [CI], 0.91-2.01; P=0.150), whereas
the composite of D or MI occurred in 8.8% and 6.6%, respectively (OR, 1.37; 95%
CI, 0.81-2.31; P=0.246). One patient in the eptifibatide arm died outside of the 48-hour
window (at 3 days after randomisation) secondary to a retroperitoneal bleed.
Abstract and figure adapted from Gibson CM et al. J Am Coll Cardiol. 2006;47(12):2364-2373.
Conclusions
Among moderate- to high-risk patients with ACS undergoing PCI,
greater CFR was observed with bivalirudin versus eptifibatide.
Although eptifibatide improved myocardial perfusion and shortened
the duration of post-PCI ischaemia, it resulted in higher minor bleeding
and transfusion rates. There was no difference between the agents in
ischaemic events and biomarkers for myonecrosis, inflammation, and
thrombin generation.
32
PURSUIT Integrilin
PURSUIT Trial Investigators. Inhibition of platelet glycoprotein IIb/IIIa
with eptifibatide in patients with acute coronary syndromes. N Engl J
Med. 1998;339(7):436-443.
Background
The pathophysiologic basis of acute coronary syndromes (ACS) is the
aggregation of platelets. Eptifibatide, a synthetic cyclic heptapeptide
and a selective high-affinity inhibitor of the platelet glycoprotein IIb/IIIa
receptor, is involved in platelet aggregation.
Objectives
The objective of this study was to assess glycoprotein IIb/IIIa inhibition
with eptifibatide when administered with indirect thrombin inhibition
versus direct thrombin inhibition with bivalirudin monotherapy for
patients with NSTE-ACS.
Methods
The patients who were enrolled in the study had presented with
ischaemic chest pain within the previous 24 hours and had either
electrocardiographic changes indicative of ischaemia (but not
persistent ST-segment elevation) or high serum concentrations of
creatine kinase–myocardial band isoenzymes. They were randomised
in a double-blind manner to receive a bolus and infusion of either
eptifibatide or placebo, in addition to standard therapy for up to 72
hours (or up to 96 hours, if coronary intervention was performed
toward the end of the 72-hour period). A composite of death and
nonfatal myocardial infarction (MI) occurring up to 30 days after the
index event constituted the primary endpoint.
Results
A total of 10,948 patients were enrolled between November 1995 and
January 1997. There was a 1.5% absolute reduction in the incidence
of the primary endpoint in the eptifibatide group compared with the
placebo group (14.2% vs 15.7% in the placebo group; P=.04). This
benefit, which was apparent by 96 hours and was sustained through
30 days, was also consistent in most major subgroups except for
women. (For men: odds ratios [ORs] for death or nonfatal MI, 0.8;
95% confidence interval [CI], [0.7-0.9]. For women: ORs for death or
nonfatal MI, 1.1; 95% CI, 0.9 to 1.3). The eptifibatide group reported
more common incidence of bleeding; however, there was no increase
in the incidence of hemorrhaegic stroke.
20
15.7%
Cumulative Incidence, %
14.2%
10
Placebo
Eptifibatide
P=0.03 by the log-rank test
0
0 5 10 15 20 25 30
Kaplan-Meier curves showing the incidence of death or nonfatal myocardial infarction
at 30 days. This analysis is based on endpoints as assessed by the central clinical-events
committee. The percentages shown are for the incidence at 30 days.
Abstract and figure adapted from PURSUIT Trial Investigators. N Engl J Med.
1998;339(7):436-443.
Conclusions
In patients with ACS who did not have persistent ST-segment
elevation, the incidence of the composite endpoint of death or nonfatal
MI was reduced due to the inhibition of platelet aggregation with
eptifibatide.
33
ADMIRAL ReoPro
Montalescot G, Barragan P, Wittenberg O, et al. Abciximab before
direct angioplasty and stenting in myocardial infarction regarding
acute and long-term follow-up. Platelet glycoprotein IIb/IIIa inhibition
with coronary stenting for acute myocardial infarction. N Engl J Med.
2001;344(25):1895-1903.
Background
A platelet glycoprotein IIb/IIIa inhibitor may provide additional clinical
benefit when administered in conjunction with primary coronary
stenting for the treatment of acute myocardial infarction (AMI).
However, there are limited data on this combination therapy.
Methods
Before they underwent coronary angiography, 300 patients with AMI
were randomised in a double-blind manner to either abciximab plus
stenting (149 patients) or placebo plus stenting (151 patients). Thirty-
day and 6-month clinical outcomes were evaluated post-procedure.
The left ventricular ejection fraction and the angiographic patency of
the infarct-related vessel were evaluated at 24 hours and 6 months.
Results
The composite primary endpoint of death, reinfarction, or urgent
revascularisation of the target vessel at 30 days was seen in 6% of the
patients in the abciximab group versus 14.6% of those in the placebo
group (P=.01); at 6 months, the corresponding figures were 7.4%
and 15.9% (P=.02). The improved clinical outcomes in the abciximab
group were linked to the greater frequency of grade 3 coronary flow
(according to the classification of the Thrombolysis in Myocardial
Infarction trial) in this group compared with the placebo group before
the procedure (16.8% vs 5.4%; P=.01), immediately afterward (95.1%
vs 86.7%; P=.04), and 6 months afterward (94.3% vs 82.8%; P=.04).
The abciximab group had 1 major bleeding event (0.7%), while the
placebo group had none.
30 Days
20
Stent plus placebo
Cumulative Incidence of Primary Endpoint, %
Stent plus abciximab

15
14.6
10
5 6.0
0
0 5 10 15 20 25 30 35
20 6 Months
15
15.9
10
5 7.4
0
0 25 50 75 100 125 150 175 200
Kaplan-Meier curves showing the cumulative incidence
of the primary endpoint at 30 days and at 6 months.
Abstract and figure adapted from Montalescot G et al. N Engl J Med. 2001;344(25):1895-1903.
Conclusions
Early administration of abciximab versus placebo in patients with
AMI improves coronary patency before stenting, stenting procedure
success rate, 6-month coronary patency rate, left ventricular function,
and clinical outcomes.
34
BRAVE-3 ReoPro
Mehilli J, Kastrati A, Schulz S, et al. Abciximab in patients with acute
ST-segment elevation myocardial infarction undergoing primary
percutaneous coronary intervention after clopidogrel loading: a
randomised double-blind trial. Circulation. 2009;119(14):1933-1940.
Background
For patients with acute myocardial infarction (AMI), there has been
an improvement in the efficacy of primary percutaneous coronary
interventions due to the use of the glycoprotein IIb/IIIa receptor
inhibitor. However, it is unclear if the benefits of abciximab persist
after adequate clopidogrel loading in patients with acute ST-segment
elevation myocardial infarction (STEMI).
Methods and Results
Eight hundred patients with acute STEMI within 24 hours from
symptom onset were treated with clopidogrel 600 mg and were
randomised in a double-blind manner to receive either abciximab
(n=401) or placebo (n=399) in the intensive care unit before being sent
to the catheterisation laboratory. Infarct size was the primary endpoint
and was measured by single-photon emission computed tomography
with technetium-99m sestamibi; before hospital discharge it was 15.7%
± 17.2% (mean ± SD) of the left ventricle in the abciximab group and
16.6% ± 18.6% of the left ventricle in the placebo group (P=.47).
Twenty patients in the abciximab group (5.0%) and 15 patients in
the placebo group (3.8%) (relative risk, 1.3; 95% CI, 0.7-2.6; P=.40)
reached the 30-day composite of death, recurrent MI, stroke, or urgent
revascularisation of the infarct-related artery. Seven patients in each
group (1.8%) had major bleeding complications.
50
45
Left Ventricle, %
40
35
P=0.47
30
25
20 16.6 15.7
15
10
5
0
Placebo Abciximab
n=374 n=382
Graphs showing the primary endpoint of infarct size
in both groups (mean ± SD).
Abstract and figure adapted from Mehilli J et al. Circulation. 2009;119(14):1933-1940.
Conclusions
For patients presenting with AMI within 24 hours of symptom onset and
receiving clopidogrel 600 mg, no reduction in infarct size was observed
after the upstream administration of abciximab.
35
CADILLAC ReoPro
Stone GW, Grines CL, Cox DA, et al. Comparison of angioplasty with
stenting, with or without abciximab, in acute myocardial infarction.
N Engl J Med. 2002;346(13):957-966.
Background
Primary percutaneous transluminal coronary angioplasty (PTCA),
when compared with thrombolytic therapy in acute myocardial
infarction (AMI), reduces the rates of death, reinfarction, and stroke.
However, recurrent ischaemia, restenosis, and reocclusion of the
infarct-related artery remain problematic. Coronary stenting and
platelet glycoprotein IIb/IIIa inhibitors in combination with PTCA could
further improve outcomes.
Methods
Using a 2-by-2 factorial design, 2082 patients with AMI were
randomised to undergo PTCA alone (518 patients), PTCA plus
abciximab therapy (528), stenting alone with the MultiLink stent (512),
or stenting plus abciximab therapy (524).
Results
A total of 94.5% to 96.9% of patients had restoration of normal flow
in the target vessel with no variation according to the reperfusion
strategy. The 6-month primary composite endpoint of death,
reinfarction, disabling stroke, and ischaemia-driven revascularisation
of the target vessel was reached in 20% of patients after PTCA,
16.5% of patients after PTCA plus abciximab, 11.5% of patients after
stenting, and 10.2% of patients after stenting plus abciximab (P<.001).
No significant differences in the rates of death, stroke, or reinfarction
were observed among the groups; the differences in the rates of target
vessel revascularisation (ranging from 15.7% after PTCA to 5.2%
after stenting plus abciximab; P<.001) were entirely responsible for
the difference in the incidence of the primary endpoint. Independent of
abciximab use, the rate of angiographically established restenosis was
40.8% after PTCA and 22.2% after stenting (P<.001). The respective
rates of reocclusion of the infarct-related artery were 11.3% and 5.7%
(P=.01).
Kaplan-Meier Estimates of the Clinical Outcomes at 30 Days and 6 Monthsa
Stenting Plus PTCA Plus

Stenting Abciximab PTCA Abciximab
Outcome (N=512) (N=524) (N=518) (N=528) P Value
At 30 days
Death 2.2 2.7 2.5 1.1 0.31
Reinfarction 1.0 0.8 0.8 0.8 0.97
Disabling stroke 0.2 0.2 0.2 0.0 0.79
Revascularisation of ischaemic target vessel 3.2 1.6b 5.6 3.4 0.004
Composite endpoint 5.7 4.4 8.3c 4.8 0.02
At 6 months (cumulative)
Death 3.0 4.2 4.5 2.5 0.23
Reinfarction 1.6 2.2 1.8 2.7 0.64
Disabling stroke 0.4 0.4 0.2 0.2 0.88
Revascularisation of ischaemic target vessel 8.3d 5.2e 15.7 13.8 <0.001
Composite endpoint 11.5f 10.2g 20.0 16.5 <0.001
Target-vessel revascularisation for any reason 8.9g 5.7e 16.9 14.8 <0.001
a
PTCA denotes percutaneous transluminal coronary angioplasty.
b
P<0.001 for the 2-way comparison with PTCA, and P<0.05 for the 2-way comparison with PTCA plus abciximab.
c
P<0.02 for the 2-way comparison with PTCA plus abciximab, and P=0.08 for the 2-way comparison with stenting plus abciximab.
d
P<0.001 for the 2-way comparison with PTCA, and P=0.006 for the 2-way comparison with PTCA plus abciximab.
e
P<0.001 for the 2-way comparison with PTCA and with PTCA plus abciximab.
f
g
Abstract and figure adapted from Stone GW et al. N Engl J Med. 2002;346(13):957-966.
Conclusions
Stent implantation (with or without abciximab therapy) must be
considered the routine reperfusion strategy at experienced centres.
36
CAPTURE ReoPro
CAPTURE Investigators. Randomised placebo-controlled trial of
abciximab before and during coronary intervention in refractory
unstable angina: the CAPTURE Study. Lancet. 1997;349(9063):1429-
1435.
Background
In the pathophysiology of unstable angina (UA), platelet aggregation
is the dominant feature. An increased risk of thrombotic complications
is observed in patients with this disorder who undergo percutaneous
transluminal coronary angioplasty (PTCA). Platelet adhesion and
aggregation is prevented by the blockage of the platelet glycoprotein
IIb/IIIa receptor by abciximab. The CAPTURE study was a
randomised, placebo-controlled, multicentre trial to evaluate whether
improved outcomes occur with abciximab in patients with refractory UA
who are undergoing PTCA.
Methods
Patients with refractory UA, defined as recurrent myocardial ischaemia
under medical treatment including heparin and nitrates, were enrolled
in this study. Recruitment was stopped after predefined stopping rules
were met at a planned interim analysis of data for 1050 patients.
This analysis includes data for 1265 patients (of 1400 scheduled).
After angiography, patients were randomised to receive an infusion of
abciximab or placebo for 18 to 24 hours before PTCA, which continued
until 1 hour afterwards. The primary endpoint was the incidence of
death (any cause), myocardial infarction (MI), or urgent intervention
for recurrent ischaemia within 30 days after PTCA. Analyses were by
intention to treat.
Results
By 30 days, the primary endpoint was reached in 71 (11.3%) of 630
patients in the abciximab group, compared with 101 (15.9%) of 635
patients in the placebo group (P=.012). A reduced rate of MI was
seen in the abciximab group compared with the placebo group before
PTCA (4 patients [0.6%] vs 13 patients [2.1%]; P=.029) and during
PTCA (16 patients [2.6%] vs 34 patients [5.5%]; P=.009). Although
major bleeding was not frequent, it occurred more often with abciximab
than with placebo (24 occurrences [3.8%] vs 12 occurrences [1.9%];
P=.043). At 6 months, 193 patients in each group had occurrences of
death, MI, or repeat intervention.
Combined Endpoint
16
14
12 Placebo
Patients, %
10
8
Abciximab
6
4
2
0
0 5 10 15 20 25 30
Time Since Enrolment, Days
Time course of combined primary endpoint.
Abstract and figure adapted from CAPTURE Investigators. Lancet. 1997;349(9063):1429-1435.
Conclusions
In patients with refractory UA treated with abciximab, there was
a substantial reduction in the rate of thrombotic complications—
specifically, MI—before, during, and after PTCA. There was no
evidence that this regimen influenced the rate of MI after the first few
days, or the need for subsequent reintervention.
37
EPIC ReoPro
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(14):956-961.
Background
It is believed that platelets play a part in the ischaemic complications
of coronary angioplasty, such as abrupt closure of the coronary vessel
during or immediately after the procedure. Accordingly, this study
investigated the effect of a chimeric monoclonal antibody Fab fragment
(c7E3 Fab) on the platelet glycoprotein IIb/IIIa receptor in patients
undergoing angioplasty and at a high risk for ischaemic complications.
The platelet glycoprotein IIb/IIIa receptor is the final common pathway
for platelet aggregation.
Methods
This study was a prospective, randomised, double-blind trial. A total of
2099 patients treated at 56 centres received a bolus and an infusion
of placebo, a bolus of c7E3 Fab and an infusion of placebo, or a
bolus and an infusion of c7E3 Fab. They were scheduled to undergo
coronary angioplasty or atherectomy in high-risk clinical situations
involving severe unstable angina, evolving acute myocardial infarction
(AMI), or high-risk coronary morphologic characteristics. The primary
endpoint of the study included any of the following: death, nonfatal MI,
unplanned surgical revascularisation, unplanned repeat percutaneous
procedure, unplanned implantation of a coronary stent, or insertion of
an intra-aortic balloon pump for refractory ischaemia. The occurrences
of endpoint events were tracked for 30 days after randomisation.
Results
There was a 35% reduction in the rate of the primary endpoint with
the c7E3 Fab bolus and infusion versus placebo (8.3% vs 12.8%;
P=.008), while a 10% reduction was noted with the c7E3 Fab bolus
alone (11.5% vs 12.8%; P=.43). There was a consistent reduction in
the number of events with the c7E3 Fab bolus and infusion across the
endpoints of unplanned revascularisation procedures and nonfatal MI.
More frequent bleeding episodes and transfusions were observed in
the group assigned the c7E3 Fab bolus and infusion than in the other
2 groups.
100
Probability, %
99
98
Bolus and infusion
Bolus
Placebo
97
0 12 24 36 48
Hours After Randomisation
Probability of no urgent repeated percutaneous revascularisation procedures in
the 3 treatment groups (Kaplan-Meier plots).
Abstract and figure adapted from EPIC Investigators. N Engl J Med. 1994;330(14):956-961.
Conclusions
There was a reduction in ischaemic complications of coronary
angioplasty and atherectomy with a monoclonal antibody directed
against the platelet IIb/IIIa glycoprotein receptor; however, there was
an increase in the risk of bleeding.
38
EPILOG ReoPro
EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade
and low-dose heparin during percutaneous coronary revascularisation.
N Engl J Med. 1997;336(24):1689-1696.
Background
In patients undergoing high-risk coronary angioplasty or directional
atherectomy, blockade of the platelet glycoprotein IIb/IIIa receptor with
abciximab (a monoclonal antibody Fab fragment directed against the
receptor) has been shown to reduce ischaemic complications. The
widespread applicability of this treatment is unknown, specifically in
view of the observed risk of haemorrhage.
Methods
This was a prospective double-blind trial in which patients undergoing
urgent or elective percutaneous coronary revascularisation at 69
centres were randomised to receive abciximab with standard-dose
weight-adjusted heparin (initial bolus of 100 U/kg of body weight);
abciximab with low-dose weight-adjusted heparin (initial bolus of 70
U/kg); or placebo with standard-dose weight-adjusted heparin. The
primary efficacy endpoint was death from any cause, myocardial
infarction, or urgent revascularisation within 30 days of randomisation.
Results
With 2792 of the planned 4800 patients enrolled, the trial was
terminated at the first interim analysis. At 30 days, the composite
endpoint rates were 11.7% in the placebo plus standard-dose heparin
group, 5.2% in the abciximab plus low-dose heparin group (hazard
ratio [HR]: 0.43; 95% confidence interval [CI], 0.30-0.60; P<.001), and
5.4% in the abciximab plus standard-dose heparin group (HR: 0.45,
95% CI, 0.32-0.63; P<.001). No significant differences in the risk of
major bleeding were noted among the groups; however, patients who
received abciximab with standard-dose heparin had more frequent
minor bleeding.
Infarction, or Urgent Revascularisation
0.12
Probability of Death, Myocardial
0.08
0.04
Placebo
Abciximab + standard-dose heparin
P<0.001 Abciximab + low-dose heparin
0.00
0 10 20 30
Kaplan-Meier estimate of the probability of the primary efficacy endpoint events
(death, myocardial infarction, or urgent repeated revascularisation) within 30 days
after randomisation, according to treatment assignment.
Abstract and figure adapted from EPILOG Investigators. N Engl J Med. 1997;336(24):1689-
1696.
Conclusions
In patients undergoing percutaneous coronary revascularisation, there
was a marked reduction in the risk of acute ischaemic complications
with no increase in the risk of haemorrhage as a result of the inhibition
of the platelet glycoprotein IIb/IIIa receptor with abciximab together
with low-dose weight-adjusted heparin.
39
EPISTENT ReoPro
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(9122):87-92.
Background
Worldwide, more than 500,000 patients per year undergo coronary
stenting with the use of heparin, aspirin, and ticlopidine for
thromboprophylaxis. This study was a randomised controlled trial
conducted to evaluate the role of platelet glycoprotein IIb/IIIa blockade
for use in elective stenting.
Methods
A total of 2399 patients with ischaemic heart disease and suitable
coronary artery lesions were randomised to stenting plus placebo
(n=809), stenting plus abciximab, a glycoprotein IIb/IIIa inhibitor
(n=794), or balloon angioplasty plus abciximab (n=796) across 63
hospitals in the United States and Canada. The primary endpoint was
a combination of death, myocardial infarction (MI), or need for urgent
revascularisation in the first 30 days. Heparin, aspirin, and standard
pharmacological therapy were administered to all patients.
Results
Eighty-seven (10.8%) of 809 patients in the stent plus placebo group,
42 (5.3%) of 794 patients in the stent plus abciximab group (hazard
ratio [HR]: 0.48, 95% confidence interval [CI], 0.33-0.69; P<.001), and
55 (6.9%) of 796 patients in the balloon plus abciximab group (HR:
0.63, 95% CI, 0.45-0.88; P=.007) experienced the primary endpoint.
Death and large MI were the main outcomes that showed reduced
rates with abciximab—7.8% in the placebo group, 3.0% for the stent
plus abciximab group (P<.001), and 4.7% for the balloon angioplasty
plus abciximab group (P=.01). A total of 2.2% of the patients assigned
to the stent plus placebo group, 1.5% of the patients assigned to the
stent plus abciximab group, and 1.4% of the patients assigned to the
balloon angioplasty plus abciximab group (P=.38) had major bleeding
complications.
Death, Myocardial Infarction, or Urgent Revascularisation
12
10.8%
8
Patients, %
6.9%
5.3%
Stent plus placebo

Balloon angioplasty plus abciximab
Stent plus abciximab
0
0 10 20 30
Cumulative event rate for endpoints for stent plus placebo vs balloon angioplasty
plus abciximab.
Abstract and figure adapted from EPISTENT Investigators. Lancet. 1998;352(9122):87-92.
Conclusions
There is a substantial improvement in the safety of coronary-
stenting procedures due to platelet glycoprotein IIb/IIIa blockade with
abciximab. Balloon angioplasty with abciximab is safer than stenting
without abciximab.
40
FINESSE ReoPro
Ellis SG, Tendera M, de Belder MA, et al. Facilitated PCI in
patients with ST-elevation myocardial infarction. N Engl J Med.
2008;358(21):2205-2217.
Background
The hypothesis of this study was that in patients with acute ST-
segment elevation myocardial infarction (STEMI), percutaneous
coronary intervention (PCI) preceded by early treatment with
abciximab plus half-dose reteplase (combination-facilitated PCI) or
with abciximab alone (abciximab-facilitated PCI) as compared with
abciximab administered immediately before the procedure (primary
PCI [PPCI]) would result in improved outcomes.
Methods
This was an international, double-blind, placebo-controlled study.
Patients with STEMI who presented 6 hours or less after the onset
of symptoms were randomised to receive combination-facilitated
PCI, abciximab-facilitated PCI, or PPCI. Unfractionated heparin or
enoxaparin before PCI and a 12-hour infusion of abciximab after
PCI was administered to all patients. The primary endpoint was the
composite of death from all causes, ventricular fibrillation occurring
more than 48 hours after randomisation, cardiogenic shock, and
congestive heart failure during the first 90 days after randomisation.
Results
A total of 2452 patients were randomised to a treatment group. Early
ST-segment resolution was observed in significantly more patients
with combination-facilitated PCI (43.9%) than with abciximab-facilitated
PCI (33.1%) or PPCI (31.0%) (P=.01 and P=.003, respectively). The
primary endpoint was reached in 9.8% of patients in the combination-
facilitated PCI group, 10.5% of patients in the abciximab-facilitated PCI
group, and 10.7% of patients in the PPCI group (P=.55). Ninety-day
mortality rates were 5.2%, 5.5%, and 4.5%, respectively (P=.49). The
study was terminated prematurely due to poor enrolment.
16
Patients With Primary Composite
12
Endpoint, %
8
Primary PCI
4 Abciximab-facilitated PCI
Combination-facilitated PCI
0
0 15 30 45 60 75 90
Days
Kaplan-Meier estimates of the proportion of patients with the composite endpoint.
The composite endpoint included death from all causes and complications of myocardial
infarction from randomisation through day 90. Data are shown for all patients randomly
assigned to a treatment group. P=0.55 for the comparison of primary percutaneous coronary
intervention (PCI) with reteplase-plus-abciximab-facilitated (combination-facilitated) PCI.
P=0.86 for the comparison of primary PCI with abciximab–facilitated PCI. P=0.68 for the
comparison of abciximab-facilitated PCI with combination-facilitated PCI.
Abstract and figure adapted from Ellis SG et al. N Engl J Med. 2008;358(21):2205-2217.
Conclusions
For patients with STEMI, compared with abciximab given at the time
of PCI, neither facilitation of PCI with reteplase plus abciximab nor
facilitation with abciximab alone significantly improved the clinical
outcomes.
41
GUSTO IV-ACS ReoPro
Ottervanger JP, Armstrong P, Barnathan ES, et al. Long-term results
after the glycoprotein IIb/IIIa inhibitor abciximab in unstable angina:
one-year survival in the GUSTO IV-ACS (Global Use of Strategies To
Open Occluded Coronary Arteries IV—Acute Coronary Syndrome)
Trial. Circulation. 2003;107(3):437-442.
Objectives
The objective of this study was to explore the long-term effects of the
glycoprotein IIb/IIIa inhibitor abciximab in patients with acute coronary
syndrome (ACS) without ST elevation who were not scheduled for
coronary intervention.
Methods and Results

A total of 7800 patients who had ACS without ST elevation,
documented by either elevated cardiac troponin or transient or
persistent ST-segment depression, were enrolled in the study. They
were randomised to abciximab bolus and 24-hour infusion, abciximab
bolus and 48-hour infusion, or matching placebo. The overall mortality
rate was 8.3% (649 patients). One-year mortality rates were 7.8%
in the placebo group, 8.2% in the 24-hour abciximab infusion group,
and 9.0% in the 48-hour abciximab infusion group. Hazard ratios for
abciximab compared with placebo were 1.1 (95% confidence interval
[CI], 0.86-1.29) for the 24-hour infusion of abciximab, and 1.2 (95%
CI, 0.95-1.41) for the 48-hour infusion. A consistent lack of benefit
with abciximab was observed across every subgroup studied. A higher
mortality rate was seen in patients with negative troponin or elevated
C-reactive protein treated with abciximab for 48 hours than with
placebo (8.5% vs 5.8% in those with negative troponins; P=.02;16.3%
vs 12.1% in those with elevated C-reactive protein; P=.04).
100
Survival According to Treatment Allocation, %
P=0.32
95
Placebo
90 24-Hour Abciximab
48-Hour Abciximab
0 3 6 9 12
Months
Proportion of patients who survived up to 1 year after randomisation
to placebo, 24-hour infusion of abciximab, and 48-hour infusion of abciximab.
There was no significant difference between the 3 groups (P=0.32).
Abstract and figure adapted from Ottervanger JP et al. Circulation. 2003;107(3):437-442.
Conclusions
For patients admitted with an ACS with ST depression and/or
elevated troponin who were not scheduled to undergo early coronary
revascularisation, abciximab compared with placebo provided no
survival benefit at 1 year. Abciximab caused excess mortality in
subgroups of patients, particularly those with low cardiac troponin or
elevated C-reactive protein.
42
GUSTO V ReoPro
Topol EJ. Reperfusion therapy for acute myocardial infarction with
fibrinolytic therapy or combination reduced fibrinolytic therapy and
platelet glycoprotein IIb/IIIa inhibition: the GUSTO V randomised trial.
Lancet. 2001;357(9272):1905-1914.
Background
The lack of achievement of early, complete, and sustained reperfusion
in a substantial proportion of patients limits plasminogen activator
therapy for acute myocardial infarction (AMI). Many phase II trials have
supported the potential of combined fibrinolytic therapy and platelet
glycoprotein IIb/IIIa inhibition for improving reperfusion. This study was
a randomised, open-label trial that compared the effect of reteplase
alone versus reteplase plus abciximab for patients with AMI.
Methods
In the first 6 hours of evolving ST-segment elevation myocardial
infarction, 16,588 patients were randomised to standard-dose
reteplase (n=8260) or half-dose reteplase and full-dose abciximab
(n=8328). Thirty-day mortality was the primary endpoint, while various
complications of MI were included in the secondary endpoints.
Analysis was by intention to treat.
Results
The 30-day mortality occurred in 488 (5.9%) patients in the reteplase
group versus 468 patients (5.6%) in the combined reteplase and
abciximab group (odds ratio, 0.95; 95% confidence interval, 0.83-1.08;
P=.43). The combination group reported fewer deaths or nonfatal
reinfarctions than the reteplase group alone, as well as a reduced
need for urgent revascularisation and fewer major nonfatal ischaemic
complications of AMI. In contrast, more non-intracranial bleeding
complications were observed in the combination group. No differences
were observed in the rates of intracranial haemorrhage and nonfatal
disabling stroke.
Complication Odds Ratio and 95% CI Abciximab + Reteplase, P
reteplase, % %
Any complication 28.6 31.7 <0.0001
Reinfarction 2.3 3.5 <0.0001
Recurrent ischaemia 11.3 12.8 0.004
New severe heart failure 4.6 4.8 0.509
Hypotension requiring treatment 9.1 9.4 0.487
Electromechanical dissociation 1.5 1.8 0.122
Ventricular septal defect 0.2 0.3 0.049
Papillary muscle rupture 0.19 0.1 0.1 0.522
Myocardial rupture 0.4 0.6 0.065
Sustained ventricular tachycardia 2.2 2.8 0.020
Atrial fibrillation/flutter 4.2 4.4 0.518
2nd or 3rd degree AVB 2.7 3.3 0.018
Ventricular fibrillation 2.7 3.5 0.008
Asystole 2.1 2.2 0.655
Tamponade 0.4 0.4 0.875
6.92
Pulmonary embolism 0.06 0.04 0.491
Systemic arterial embolism 0.03 0.01 0.05 0.212
Pericardial effusion/ 1.2 1.0 0.234
pericarditis 0.2 1.0 5.0
Abciximab Reteplase
+ Reteplase Better
Better
Complications of myocardial infarction up to day 7.

AVB=atrioventricular block.
Abstract and figure adapted from Topol EJ. Lancet. 2001;357(9272):1905-1914.
Conclusions
The combination of reteplase and abciximab was not superior to
standard reteplase; however, the criteria of noninferiority were fulfilled
by the 0.3% absolute (5% relative) decrease in 30-day mortality.
There was a consistent reduction in the key secondary complications
of MI, including reinfarction with combination therapy; this was partly
counterbalanced by increased non-intracranial bleeding complications.
43
ISAR-REACT ReoPro
Kastrati A, Mehilli J, Schühlen H, et al. A clinical trial of abciximab in
elective percutaneous coronary intervention after pretreatment with
clopidogrel. N Engl J Med. 2004;350(3):232-238.
Background
It is not known whether the glycoprotein IIb/IIIa inhibitor abciximab
is beneficial for patients undergoing elective percutaneous coronary
intervention (PCI) after pretreatment with clopidogrel.
Methods
A total of 2159 patients with coronary artery disease who underwent a
PCI were enrolled in the study. Patients were randomised in a double-
blind manner to receive abciximab (n=1079) or placebo (n=1080). At
least 2 hours before the procedure, all patients were pretreated with
clopidogrel 600 mg. The composite of death, myocardial infarction
(MI), and urgent target vessel revascularisation within 30 days after
randomisation was the primary endpoint of the study.
Results
The primary endpoint rates were 4% (45 patients) in the abciximab
group versus 4% (43 patients) in the placebo group (relative risk,
1.05; 95% confidence interval, 0.69-1.59; P=.82). The bulk of adverse
events were MIs, with rates of 4% (40 patients) in the abciximab group
and 4% (41 patients) in the placebo group (P=.91). Major bleeding
complications occurred in 12 patients (1%) in the abciximab group and
8 patients (1%) in the placebo group (P=.37). Ten patients (1%) in the
abciximab group, but none in placebo group (P=.002), had profound
thrombocytopaenia.
4 Placebo
Abciximab
3
Incidence, %
0
Q-wave Death Any Large Urgent
revascu-
larisation
Myocardial Infarction
The 30-day incidence of adverse events in the abciximab and placebo groups.
There were no significant differences between groups.
Abstract and figure adapted from Kastrati A et al. N Engl J Med. 2004;350(3):232-238.
Conclusions
For patients at low to intermediate risk who undergo elective PCI after
pretreatment with a high loading dose of clopidogrel, no clinically
measurable benefit was observed with abciximab within the first 30
days.
44
ISAR-REACT 2 ReoPro
Kastrati A, Mehilli J, Neumann F-J, et al. Abciximab in patients with
acute coronary syndromes undergoing percutaneous coronary
intervention after clopidogrel pretreatment: the ISAR-REACT 2
randomised trial. JAMA. 2006;295(13):1531-1538.
Objectives
For patients with non–ST-segment elevation acute coronary
syndromes (NSTE-ACS) undergoing percutaneous coronary
intervention (PCI) after pretreatment with clopidogrel 600 mg, the role
of the glycoprotein IIb/IIIa inhibitor abciximab has not been addressed
by specifically designed studies. The objective of this study was to
evaluate whether treatment with abciximab has clinical benefit in
high-risk patients with ACS undergoing PCI after pretreatment with
clopidogrel 600 mg.
Methods and Results
This study was an international, multicentre, randomised, double-
blind, placebo-controlled trial. It enrolled 2022 patients (mean age of
66 years) with NSTE-ACS undergoing PCI and was conducted from
March 2003 through December 2005. Patients were randomised to
receive either abciximab or placebo. Clopidogrel and asprin were
administered to all patients. The primary endpoint was a composite of
death, myocardial infarction, or urgent target vessel revascularisation
occurring within 30 days after randomisation; secondary endpoints
included rates of in-hospital major and minor bleeding. Of 2022
patients enrolled, 1012 were assigned to the abciximab group and
1010 were assigned to the placebo group. There was a 25% reduction
in risk with abciximab, with the incidence of the primary endpoint
being attained in 90 patients (8.9%) assigned to abciximab versus
120 patients (11.9%) assigned to placebo (relative risk [RR], 0.75;
95% confidence interval [CI], 0.58-0.97; P=.03) In patients without an
elevated troponin level, similar incidence of primary endpoints was
seen between the abciximab group (23 of 499 patients [4.6%]) and the
placebo group (22 of 474 patients [4.6%]) (RR, 0.99; 95% CI, 0.56-
1.76; P=.98). However, in patients with an elevated troponin level, a
significantly lower incidence of events was observed in the abciximab
group (67 of 513 patients [13.1%]) compared with the placebo group
(98 of 536 patients [18.3%]), with an RR of 0.71 (95% CI, 0.54-0.95;
P=.02; P=.07 for interaction). The risk of major and minor bleeding, as
well as the need for transfusion, was not significantly different between
the 2 groups.
20
Cumulative Rate of
Primary Endpoint
Placebo Group
10 Abciximab Group
Log-Rank P=0.03
0
0 10 20 30
Kaplan-Meier analysis of cumulative incidence of death, myocardial infarction,
or urgent target vessel revascularisation for both treatment groups.
Abstract and figure adapted from Kastrati A et al. JAMA. 2006;295(13):1531-1538.
Conclusions
The risk of adverse events is reduced with abciximab in patients
with NSTE-ACS undergoing PCI after pretreatment with clopidogrel
600 mg. The benefits of abciximab seem to be restricted to patients
presenting with an elevated troponin level.
45
ISAR-REACT 2 (1-Year Results) ReoPro
Ndrepepa G, Kastrati A, Mehilli J, et al. One-year clinical outcomes
with abciximab vs placebo in patients with non–ST-segment elevation
intervention after pretreatment with clopidogrel: results of the ISAR-
REACT 2 randomised trial. Eur Heart J. 2008;29(4):455-461.
Objectives
The objective of this study was to investigate whether the beneficial
effects of abciximab for patients with non–ST-segment elevation acute
coronary syndromes (NSTE-ACSs) undergoing percutaneous coronary
intervention (PCI) after pretreatment with clopidogrel 600 mg persisted
at 1 year.
Methods and Results
A total of 2022 high-risk patients with NSTE-ACS undergoing
urgent PCI who were randomised to abciximab or placebo after
pretreatment with clopidogrel 600 mg in the Intracoronary Stenting and
Antithrombotic Regimen: Rapid Early Action for Coronary Treatment
2 (ISAR-REACT 2) trial underwent a 1-year follow-up. The primary
outcome of this analysis was the combined incidence of death,
myocardial infarction (MI), or target vessel revascularisation at 1
year, which was reached in 23.3% of patients allocated to abciximab
versus 28% of patients allocated to placebo (relative risk [RR], 0.80;
95% confidence interval [CI], 0.67-0.95; P=.012). A total of 11.6%
of the patients allocated to abciximab versus 15.3% of the patients
allocated to placebo (RR, 0.74; 95% CI, 0.59-0.94, P=.015) attained
the combined incidence of death or MI.
1-Year Clinical Outcome

1-Year Outcome Placebo (n=1010) Abciximab (n=1012) Relative Risk (95% CI) P Value
Death, myocardial infarction, or TVR 281 (28.0) 234 (23.3) 0.80 (0.67-0.95) 0.012
Death or myocardial infarction 154 (15.3) 117 (11.6) 0.74 (0.59-0.94) 0.015
TVR 164 (16.2) 137 (13.2) 0.83 (0.67-1.02) 0.07
Death 49 (4.9) 45 (4.5) 0.91 (0.61-1.37) 0.66
Myocardial infarction 114 (11.3) 88 (8.7) 0.76 (0.58-1.00) 0.05
Data are numbers of patients (%). Percentages are the Kaplan-Meier estimates.
Abstract and figure adapted from Ndrepepa G et al. Eur Heart J. 2008;29(4):455-461.
Conclusions
In high-risk patients with NSTE-ACS undergoing a PCI after
pretreatment with clopidogrel 600 mg, there was a reduced frequency
of occurrence of adverse events with abciximab, and the early benefit
of abciximab was sustained 1 year after administration.
46
ISAR-REACT 2 (Age) ReoPro
Ndrepepa G, Kastrati A, Mehilli J, et al. Age-dependent effect of
abciximab in patients with acute coronary syndromes treated with
percutaneous coronary interventions. Circulation. 2006;114(19):2040-
2046.
Background
An age-based analysis of the efficacy of abciximab for patients with
non–ST-segment elevation acute coronary syndromes (NSTE-ACS)
undergoing percutaneous coronary intervention (PCI) has not been
performed yet.
Objectives
The objective of this study was to explore whether age-dependent
differences exist in the clinical benefit of abciximab for patients with
ACS treated with PCI.
Methods and Results
This study was a retrospective analysis of 2022 patients with ACS
enrolled in the Intracoronary Stenting and Antithrombotic Regimen:
Rapid Early Action for Coronary Treatment (ISAR-REACT 2) study
who were randomised to receive abciximab or placebo during a PCI
procedure. The primary endpoint was the incidence of major adverse
cardiac events (MACE) during the 30 days after PCI. Patients were
divided into 2 groups: patients younger than 70 years of age (n=1220)
and patients older than 70 years of age (n=802), based on the cutoff
age value provided by logistic regression in connection with bootstrap
resampling. The incidence of MACE was 7.7% in the abciximab
group versus 13.3% in the placebo group (relative risk [RR], 0.57;
95% confidence interval [CI], 0.40- 0.80; P=.001) among the younger
patients, whereas the older patients reported similar MACE rates:
10.9% in the abciximab group versus 9.9% in the placebo group (RR,
1.10; 95% CI, 0.72-1.69; P=.65). After adjustment for other variables,
including cardiac troponin, a significant interaction between age and
abciximab (P=.04) with respect to MACE reduction was observed;
abciximab was more effective in younger patients.
30-Day Clinical Outcome

Age >70 Yrs (n=802) Age ≤70 Yrs (n=1220)
Abciximab Placebo Abciximab Placebo
Characteristic (n=377) (n=425) P (n=635) (n=585) P
MACE 41 (10.9) 42 (9.9) 0.65 49 (7.7) 78 (13.3) 0.001
Target vessel revascularisation 5 (1.3) 3 (0.7) 0.59 5 (0.8) 9 (1.5) 0.22
Death or myocardial infarction 39 (10.3) 40 (9.4) 0.65 48 (7.6) 76 (13.0) 0.002
Myocardial infarction 35 (9.3) 36 (8.5) 0.69 47 (7.4) 70 (12.0) 0.007
Death 9 (2.4) 7 (1.6) 0.45 2 (0.3) 9 (1.5) 0.02
Abstract and figure adapted from Ndrepepa G et al. Circulation. 2006;114(19):2040-2046.
Conclusions
For patients with NSTE-ACS undergoing PCI, the efficacy of abciximab
seemed to be age dependent; younger patients experienced more
benefit.
47
ISAR-REACT 2 (Troponins) ReoPro
Iijima R, Ndrepepa G, Mehilli J, et al. Troponin level and efficacy of
abciximab in patients with acute coronary syndromes undergoing
early intervention after clopidogrel pretreatment. Clin Res Cardiol.
2008;97(3):160-168.
Objectives
The objective of this study was to evaluate the affect of troponin level
on the benefit of abciximab for patients with acute coronary syndromes
(ACS) undergoing percutaneous coronary intervention (PCI) after
pretreatment with a high loading dose of clopidogrel.
Methods
The Intracoronary Stenting and Antithrombotic Regimen: Rapid Early
Action for Coronary Treatment (ISAR-REACT 2) trial comprised of
2,022 patients with non─ST elevation ACS undergoing PCI; they were
randomised to abciximab or placebo after pretreatment with a high
loading dose (600 mg) of clopidogrel. Based on troponin levels, the
patients were divided into groups: elevated troponin level (n=1,049)
and no elevated troponin level (n=973). The primary endpoint of the
study was the 30-day composite of death, myocardial infarction (MI),
and urgent reintervention.
Results
The primary endpoint was reached in 13.1% of patients in the
abciximab group versus 18.3% of patients in the placebo group
(relative risk [RR], 0.70; 95% confidence interval [CI], 0.52-0.95;
P=.02) and the combined incidence of death or MI was 12.9% in
the abciximab group versus 17.9% in the placebo group (RR, 0.71;
95% CI, 0.52-0.96; P=.03) in patients with elevated troponin level.
In contrast, in patients with no elevated troponin level, similar rates
of incidence of the primary endpoint were observed in both groups
(4.6%). There was no relation between the risk of bleeding and
troponin level.
Clinical Outcomes
Troponin ≤0.03 µg/L Troponin >0.03 µg/L
Abciximab Placebo Abciximab Placebo
(n=499) (n=474) P (n=513) (n=536) P
Death 3 (0.6) 2 (0.4) 0.70 8 (1.6) 14 (2.6) 0.23
Myocardial infarction 19 (3.8) 18 (3.8) 0.99 63 (12.3) 88 (16.4) 0.056
Urgent reintervention 4 (0.8) 6 (1.3) 0.47 6 (1.2) 6 (1.1) 0.94
Death or myocardial infarction 21 (4.2) 20 (4.2) 0.99 66 (12.9) 96 (17.9) 0.02
Death, myocardial infarction, or urgent reintervention 23 (4.6) 22 (4.6) 0.98 67 (13.1) 98 (18.3) 0.02
Abstract and figure adapted from Iijima R et al. Clin Res Cardiol. 2008;97(3):160-168.
Conclusions
For patients with ACS undergoing PCI after pretreatment with a high
loading dose of clopidogrel, baseline troponin level affects the benefit
of abciximab. The reduced risk of ischaemic events due to abciximab
is seen only in patients with ACS and elevated troponin level.
48
ACUITY Angiomax/Angiox
Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with
acute coronary syndromes. N Engl J Med. 2006;355(21):2203-2216.
Background
An early invasive approach with concomitant antithrombotic therapy
including aspirin, clopidogrel, unfractionated heparin (UFH) or low-
molecular-weight heparin, and glycoprotein IIb/IIIa inhibitors (GPIs)
is recommended by current guidelines for patients with moderate- or
high-risk acute coronary syndromes (ACS). This study investigated
the role of thrombin-specific anticoagulation with bivalirudin in such
patients.
Methods
A total of 13,819 patients with ACS were randomised to 1 of 3
antithrombotic regimens: UFH or enoxaparin plus a GPI, bivalirudin
plus a GPI, or bivalirudin alone. The primary endpoints included
a composite ischaemia endpoint (death, myocardial infarction, or
unplanned revascularisation for ischaemia), major bleeding, and
the net clinical outcome, which was defined as the combination of
composite ischaemia or major bleeding.
Results
Noninferior 30-day rates of the composite ischaemia endpoint (7.7%
and 7.3%, respectively), major bleeding (5.3% and 5.7%, respectively),
and the net clinical outcome endpoint (11.8% and 11.7%, respectively)
were observed with bivalirudin plus a GPI versus heparin plus a GPI.
Bivalirudin alone versus heparin plus a GPI had a noninferior rate
of the composite ischaemia endpoint (7.8% and 7.3%, respectively;
P=.32; relative risk [RR], 1.08; 95% confidence interval [CI], 0.93-1.24)
and significantly lower rates of major bleeding (3.0% vs 5.7%; P<.001;
RR, 0.53; 95% CI, 0.43-0.65) and the net clinical outcome endpoint
(10.1% vs 11.7%; P=.02; RR, 0.86; 95% CI, 0.77-0.97).
Cumulative Composite Ischaemia, %
15.0
12.5
10.0 Bivalirudin alone, 8.0%; P=0.30
7.5
5.0
2.5 Heparin + GP IIb/IIIa inhibitor, 7.4%
Bivalirudin + GP IIb/IIIa inhibitor, 7.9%; P=0.37
0.0
0 10 20 30 40
Conclusions
For patients with moderate- or high-risk ACS who were undergoing
invasive treatment with GPIs, the rates of ischaemia and bleeding
with bivalirudin were similar to those with heparin. Similar rates of
ischaemia and significantly reduced rates of bleeding were observed
with bivalirudin alone.
49
ACUITY (PCI) Angiomax/Angiox
Stone GW, White HD, Ohman EM, et al. Bivalirudin in patients with
intervention: a subgroup analysis from the Acute Catheterisation
and Urgent Intervention Triage strategy (ACUITY) trial. Lancet.
2007;369(9565):907-919.
Objectives
The objective of this study was to evaluate anticoagulation with
bivalirudin during percutaneous coronary intervention (PCI) in
individuals with moderate- and high-risk acute coronary syndromes
(ACS).
Methods
Of the 13,819 individuals in the ACUITY trial who were prospectively
randomised to receive heparin (unfractionated or enoxaparin)
plus glycoprotein IIb/IIIa inhibitors (GPIs), bivalirudin plus GPIs,
or bivalirudin alone, 7789 underwent PCI after angiography. In
this subgroup, the effect of the 3 regimens on the primary 30-day
endpoints of composite ischaemia (death, myocardial infarction, or
unplanned revascularisation for ischaemia), major bleeding, and
net clinical outcomes (composite ischaemia or major bleeding) was
evaluated. Analyses were done by intention to treat. Of the individuals
who underwent PCI, 2561 received heparin plus GPIs, 2609 received
bivalirudin plus GPIs, and 2619 received bivalirudin alone. Twenty-six
(0.3%) individuals dropped out or were lost to follow-up. No significant
differences were observed in the rates of composite ischaemia,
major bleeding, or net clinical outcomes at 30 days between those
individuals who received bivalirudin plus GPIs and those who received
heparin plus GPIs (composite ischaemia: 243 [9%] patients vs 210
[8%] patients; P=.16; major bleeding: 196 [8%] patients vs 174 [7%]
patients; P=.32; net clinical outcomes: 389 [15%] patients vs 341
[13%] patients; P=.1). Similar rates of composite ischaemia were
seen in those who received bivalirudin alone and those who received
heparin plus GPIs (230 [9%] patients vs 210 [8%] patients; P=.45).
Significantly reduced major bleeding was reported in the bivalirudin
alone group versus the heparin plus GPIs group (92 [4%] patients vs
174 [7%] patients; P<.0001; relative risk [RR], 0.52, 95% confidence
interval [CI], 0.40-0.66), resulting in a trend toward better 30-day net
clinical outcomes (303 [12%] patients vs 341 [13%] patients; P=.057;
RR, 0.87; 95% CI, 0.75-1.00).
35
Bivalirudin + IIb/IIIa (n=2609)
30 Bivalirudin alone (n=2619)
25 Heparin* + IIb/IIIa (n=2561)
Patients, %
20
15
Estimate P (log rank)
10 Bivalirudin + IIb/IIIa 9.4% 0.15
Bivalirudin alone 9.0% 0.45 P=0.36
5
Heparin* + IIb/IIIa 8.4% ..
0
0 5 10 15 20 25 30 35

Time-to-event curves for composite ischaemia.
The primary endpoints were measured at 30 days (range 25-30); thus follow-up
is reported to 35 days. P values represent comparisons of the 2 bivalirudin
groups vs heparin plus glycoprotein IIb/IIIa inhibitors.
*Unfractionated heparin or enoxaparin.
Abstract and figure adapted from Stone GW et al. Lancet. 2007;369(9565):907-919.
Conclusions
For patients with moderate- and high-risk ACS treated with GPIs in
whom PCI was done, comparable clinical outcomes were observed
by the substitution of unfractionated heparin or enoxaparin with
bivalirudin. Adverse ischaemic events were suppressed to a similar
extent with bivalirudin anticoagulation alone as with heparin plus GPIs,
along with a significant reduction in the risk of major haemorrhagic
complications.
50
ACUITY (Timing) Angiomax/Angiox
Stone GW, Bertrand ME, Moses JW, et al. Routine upstream initiation
vs deferred selective use of glycoprotein IIb/IIIa inhibitors in acute
coronary syndromes: the ACUITY Timing trial. JAMA. 2007;297(6):591-
602.
Objectives
The objective of this study was to determine the optimal strategy
for the use of glycoprotein IIb/IIIa inhibitors (GPIs) in patients with
moderate- and high-risk ACS undergoing early invasive treatment.
Methods
This study was a prospective, randomised, open-label trial conducted
in 450 academic and community-based institutions in 17 countries
with 30-day clinical follow-up. A total of 9207 patients with moderate-
and high-risk ACS undergoing an invasive treatment strategy were
enrolled in the trial. Patients were randomised to receive either routine
upstream (n=4605) or deferred-selective (n=4602) GPI administration,
respectively. The primary endpoint was evaluation of noninferiority of
deferred GPI use versus upstream administration for the prevention
of composite ischaemic events (death, myocardial infarction, or
unplanned revascularisation for ischaemia) at 30 days using a 1-sided
alpha level of .025. The key secondary endpoints were noninferiority
or superiority of major bleeding and net clinical outcomes (composite
ischaemia or major bleeding).
Results
The upstream group compared with the deferred group reported
more frequent use of GPIs (98.3% vs 55.7%, respectively) and for
a significantly longer period of time (median, 18.3 vs 13.1 hours;
P<.001). At 30 days, 7.9% of patients in the deferred group versus
7.1% of patients in the upstream group had incidence of composite
ischaemia (relative risk, 1.12; 95% confidence interval, 0.97-
1.29; P=.044 for noninferiority; P=.13 for superiority). Upstream
administration of GPIs provides significant benefit in the treatment
of patients undergoing an early invasive treatment strategy. As such,
the criterion for noninferiority was not met. The 30-day rates of major
bleeding were reduced in the deferred group versus the upstream
group (4.9% vs 6.1%, respectively; P<.001 for noninferiority; P=.009
for superiority); similar rates of net clinical outcomes were observed in
the 2 groups, respectively (11.7% vs 11.7%; P<.001 for noninferiority;
P=.93 for superiority).
15
Cumulative Percentage
Deferred Selective
10 Glycoprotein IIb/IIIa Inhibitor
Routine Upstream
5
Glycoprotein IIb/IIIa Inhibitor
Log-Rank P=0.14
0
0 10 20 30 40
Days Since Randomisation
Time-to-event curves of routine upstream and deferred selective
glycoprotein IIb/IIIa inhibitor administration for composite ischaemia.
Abstract and figure adapted from Stone GW et al. JAMA. 2007;297(6):591-602.
Conclusions
Among patients with moderate- and high-risk ACS undergoing
an invasive treatment strategy, there was a numerical increase in
composite ischaemia by deferring the routine upstream use of GPIs
for selective administration in the cardiac catheterisation laboratory
only to patients undergoing percutaneous coronary intervention. This
result was not statistically significant and did not meet the noninferiority
criterion, and was offset by a significant reduction in major bleeding.
51
ACUITY (1-Year Results) Angiomax/Angiox
Stone GW, Ware JH, Bertrand ME, et al. Antithrombotic strategies in
patients with acute coronary syndromes undergoing early invasive
management: one-year results from the ACUITY trial. JAMA.
2007;298(21):2497-2506.
Background
Patients with moderate- and high-risk acute coronary syndromes
(ACS) undergoing early invasive treatment in the ACUITY trial with
bivalirudin monotherapy versus heparin plus glycoprotein IIb/IIIa
inhibitors (GPIs) had noninferior rates of adverse ischaemic events
with a reduction in the rates of major bleeding at 30-day follow-up.
There was a significant reduction in major bleeding by the deferred
upstream use of GPIs for selective administration to patients
undergoing percutaneous coronary intervention (PCI); however, a
small increase in composite ischaemia could not be excluded.
Methods
This study was a prospective, randomised, open-label trial with a
1-year clinical follow-up at 450 academic and community-based
institutions in 17 countries. A total of 13,819 patients with moderate-
and high-risk ACS undergoing invasive treatment were enrolled in the
study between August 23, 2003 and December 5, 2005. Patients were
randomised to receive either heparin plus GPIs (n=4603), bivalirudin
plus GPIs (n=4604), or bivalirudin monotherapy (n=4612). Of these
patients, 4605 received a routine upstream GPI and 4602 were
deferred to selective GPI administration. The main outcome measure
of the study was composite ischaemia (death, myocardial infarction, or
unplanned revascularisation for ischaemia) at 1 year.
Results
One-year composite ischaemia was attained in 15.4% of the patients
treated with heparin plus GPIs and 16.0% of the patients treated
with bivalirudin plus GPIs compared with heparin plus GPIs (hazard
ratio [HR]: 1.05; 95% confidence interval [CI], 0.95-1.16; P=.35), and
16.2% receiving bivalirudin monotherapy (HR: 1.06; 95% CI, 0.95-
1.17; P=.29). One-year mortality was observed in 3.9% of the patients
receiving heparin plus GPIs, 3.9% of the patients receiving bivalirudin
plus GPIs (HR: 0.99; 95% CI, 0.80-1.22; P=.92), and 3.8% of the
patients receiving bivalirudin monotherapy (HR: 0.96; 95% CI, 0.77-
1.18; P=.67). A total of 16.3% of the patients assigned to deferred use
versus 15.2% of the patients assigned to upstream administration
(HR: 1.08; 95% CI, 0.97-1.20; P=.15) had the occurrence of composite
ischaemia. 30 Composite Ischaemia
Composite Ischaemia, %
Bivalirudin monotherapy
Bivalirudin + GP IIb/IIIa inhibitors
20 Heparin + GP IIb/IIIa inhibitors
10
Log-rank P=0.52
0
0 60 120 180 240 300 360
Kaplan-Meier estimates comparing patients randomised to heparin (unfractionated or
enoxaparin) plus GP IIb/IIIa inhibitors, bivalirudin plus GP IIb/IIIa inhibitors, and bivalirudin
monotherapy for composite ischaemia and mortality.
Abstract and figure adapted from Stone GW et al. JAMA. 2007;298(21):2497-2506.
Conclusions
At 1 year, there were no statistical differences in the rates of
composite ischaemia or mortality among patients with moderate- and
high-risk ACS undergoing invasive treatment with the 3 therapies.
No statistically significant difference was observed in the rates of
composite ischaemia between patients receiving routine upstream
administration of GPIs versus deferring their use for patients
undergoing PCI.
52
ACUITY (PCI 1-Year Results) Angiomax/Angiox
White HD, Ohman EM, Lincoff AM, et al. Safety and efficacy of
bivalirudin with and without glycoprotein IIb/IIIa inhibitors in patients
with acute coronary syndromes undergoing percutaneous coronary
intervention 1-year results from the ACUITY (Acute Catheterisation
and Urgent Intervention Triage strategY) trial. J Am Coll Cardiol.
2008;52(10):807-814.
Background
The ACUITY (Acute Catheterisation and Urgent Intervention Triage
strategY) trial demonstrated that in moderate- and high-risk patients
with acute coronary syndrome (ACS) undergoing percutaneous
coronary intervention (PCI), at 30 days, reduced major bleeding and
similar ischaemic outcomes occurred with bivalirudin alone versus
unfractionated heparin (UFH) or enoxaparin plus a glycoprotein IIb/
IIIa inhibitor (GPI). However, the impact of bivalirudin on outcomes in
patients with ACS at 1 year is not known.
Objectives
The objective of this study was to evaluate the impact of bivalirudin on
1-year outcomes in patients with ACS undergoing PCI.
Methods
Of the 13,819 patients enrolled in the ACUITY trial, 7,789 (56.4%)
patients had PCI. One-year composite ischaemia (death, myocardial
infarction, or unplanned revascularisation) and mortality were
evaluated.
Results
Among patients undergoing PCI, 2,561 were randomised to UFH or
enoxaparin plus a GPI, 2,609 to bivalirudin plus a GPI, and 2,619
to bivalirudin monotherapy. At 1 year, similar rates of composite
ischaemia (17.8% vs 19.4% vs 19.2%; P=not significant) and mortality
(3.2% vs 3.3% vs 3.1%; P=not significant) were observed among the
3 groups, respectively.
Clinical Outcomes at 1 Year in Patients Undergoing PCI

Heparin
(UFH or Enoxaparin) Bivalirudin Bivalirudin + GP IIb/IIIa
+ GP IIb/IIIa Inhibitor,% Alone, % Hazard Ratio P Inhibitor, % Hazard Ratios P
(n=2,561) (n=2,619) (95% CI) Valuea (n=2,609) (95% CI) Valueb
Composite ischaemia 456 (17.8) 502 (19.2) 1.09 (0.96-1.23) 0.19 507 (19.4) 1.11 (0.98-1.26) 0.11
Death from any cause 82 (3.2) 80 (3.1) 0.95 (0.70-1.30) 0.76 85 (3.3) 1.02 (0.75-1.38) 0.91
Unplanned revascularisation 292 (11.4) 310 (11.8) 1.04 (0.89-1.22) 0.63 326 (12.5) 1.11 (0.94-1.29) 0.21
for ischaemia
Myocardial infarction 201 (7.8) 244 (9.3) 1.19 (0.99-1.44) 0.06 237 (9.1) 1.17 (0.97-1.41) 0.10
a
Comparison between bivalirudin alone and heparin (UFH or enoxaparin) plus a GP IIb/IIIa inhibitor.
b
Comparison between bivalirudin plus a GP IIb/IIIa inhibitor and heparin (UFH or enoxaparin) plus a GP IIb/IIIa inhibitor.
Abstract and figure adapted from White HD et al. J Am Coll Cardiol. 2008;52(10):807-814.
Conclusions
In moderate- and high-risk patients with ACS undergoing PCI, similar
rates of composite ischaemia and mortality at 1 year were observed
with bivalirudin compared with UFH or enoxaparin plus a GPI.
53
ACUITY (Diabetes) Angiomax/Angiox
Feit F, Manoukian SV, Ebrahimi R, et al. Safety and efficacy of
bivalirudin monotherapy in patients with diabetes mellitus and acute
coronary syndromes: a report from the ACUITY (Acute Catheterisation
and Urgent Intervention Triage Strategy) trial. J Am Coll Cardiol.
2008;51(17):1645-1652.
Background
In the ACUITY trial, 13,819 patients with moderate- or high-risk
acute coronary syndromes (ACS) were randomised to heparin
(unfractionated or enoxaparin) plus glycoprotein IIb/IIIa inhibitor
(GPI), bivalirudin plus GPI, or bivalirudin monotherapy. Bivalirudin
monotherapy resulted in similar protection from ischaemic events and
reduced major bleeding compared with heparin plus GPI. It is unknown
whether these results apply to patients with diabetes.
Objectives
The objective of this study was to investigate the overall and treatment
arm clinical outcomes of patients with diabetes mellitus in the ACUITY
(Acute Catheterisation and Urgent Intervention Triage Strategy) trial.
Methods
The impact of diabetes on 30-day net adverse clinical outcomes
(composite ischaemia [death, myocardial infarction, or unplanned
ischaemic revascularisation] or major bleeding) overall and by
antithrombotic strategy was investigated.
Results
A total of 3,852 randomised patients (27.9%) had diabetes. Higher
30-day rates of net adverse clinical outcomes (12.9% vs 10.6%;
P<.001), composite ischaemia (8.7% vs 7.2%; P=.003), and major
bleeding (5.7% vs 4.2%; P<.001) were observed in diabetic patients
versus nondiabetic patients. Among diabetic patients, compared with
heparin plus GPI, similar rates of net adverse clinical outcomes (14.0%
vs 13.8%; P=.89) were observed with bivalirudin plus GPI, while
treatment with bivalirudin alone resulted in a similar rate of composite
ischaemia (7.9% vs 8.9%; P=.39), reduced major bleeding (3.7% vs
7.1%; P<.001), and reduced net adverse clinical outcomes (10.9% vs
13.8%; P=.02).
Clinical Outcomes at 30 Days by Diabetic Status
Nondiabetic Diabetic
Patients Patients
(n=9,857) (n=3,852) P Value
Net adverse clinical outcomes (primary endpoint) 1,042 (10.6) 496 (12.9) <0.001
Composite ischaemia (primary endpoint) 712 (7.2) 337 (8.7) 0.003
Major bleeding (non-CABG related) (primary endpoint) 418 (4.2) 220 (5.7) <0.001
Death 125 (1.3) 81 (2.1) <0.001
Myocardial infarction 498 (5.1) 202 (5.2) 0.65
Unplanned revascularization for ischaemia 228 (2.3) 111 (2.9) 0.05
Values are expressed as n (%) unless otherwise specified.

CABG=coronary artery bypass graft surgery.
Abstract and figure adapted from Feit F et al. J Am Coll Cardiol. 2008;51(17):1645-1652.
Conclusions
Higher rates of composite ischaemia and major bleeding were
observed in diabetic patients with ACS managed invasively. Bivalirudin
monotherapy compared with heparin plus GPI provides similar
protection from ischaemic events with reduced major bleeding,
resulting in a significant drop in net adverse clinical outcomes.
54
HORIZONS-AMI Angiomax/Angiox
Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin
during primary PCI in acute myocardial infarction. N Engl J Med.
2008;358(21):2218-2230.
Background
Compared with heparin plus glycoprotein IIb/IIIa inhibitors (GPIs),
treatment with the direct thrombin inhibitor bivalirudin caused a
similar suppression of ischaemia with a reduction in hemorrhaegic
complications in patients with stable angina and non–ST-segment
elevation acute coronary syndromes who are undergoing
percutaneous coronary intervention (PCI). It is unknown if bivalirudin in
high-risk patients is efficacious and safe.
Methods
A total of 3602 patients with ST-segment elevation myocardial
infarction (STEMI) who presented within 12 hours after the onset of
symptoms and were undergoing primary PCI were randomised to
receive heparin plus a GPI or bivalirudin alone. Major bleeding and
combined adverse clinical events, defined as the combination of major
bleeding or major adverse cardiovascular events, including death,
reinfarction, target vessel revascularisation for ischaemia, and stroke
(hereinafter referred to as net adverse clinical events) within 30 days
were the 2 primary endpoints.
Results
Treatment with bivalirudin alone versus heparin plus GPIs reduced the
30-day rate of net adverse clinical events (9.2% vs 12.1%; relative risk
[RR], 0.76; 95% confidence interval [CI], 0.63-0.92; P=.005), owing to
a lower rate of major bleeding (4.9% vs 8.3%; RR, 0.60; 95% CI, 0.46-
0.77; P<.001). An increased risk of acute stent thrombosis was seen
within 24 hours in the bivalirudin group, but no significant increase was
observed by 30 days. Treatment with bivalirudin monotherapy versus
treatment with heparin plus GPIs resulted in significantly reduced 30-
day rates of death from cardiac causes (1.8% vs 2.9%; RR, 0.62; 95%
CI, 0.40-0.95; P=.03) and death from all causes (2.1% vs 3.1%; RR,
0.66; 95% CI, 0.44-1.00; P=.047).
Clinical Outcomes at 30 Days
Heparin Plus a
Bivalirudin Glycoprotein IIb/IIIa
Outcome Alone Inhibitor
(N=1800) (N=1802) P Value
Primary PCI population
No. of patients 1678 1662
Net adverse clinical events, No. (%) 154 (9.2) 203 (12.2) 0.005
Major adverse cardiovascular events, No. (%) 90 (5.4) 90 (5.4) 0.95
Major bleeding non-CABG-related, No. (%) 85 (5.1) 142 (8.5) <0.001
Conclusions
For patients with STEMI who are undergoing primary PCI, significantly
lower 30-day rates of major bleeding and net adverse clinical events
were observed with bivalirudin alone versus heparin plus GPIs.
55
ISAR-REACT 3 Angiomax/Angiox
Kastrati A, Neumann FJ, Mehilli J, et al. Bivalirudin versus
unfractionated heparin during percutaneous coronary intervention.
N Engl J Med. 2008;359(7):688-696.
Background
For patients with stable or unstable angina (UA) who undergo
percutaneous coronary intervention (PCI) after pretreatment
with clopidogrel, it is not known whether bivalirudin is superior to
unfractionated heparin (UFH).
Methods
A total of 4570 patients with stable angina or UA (with normal levels
of troponin T and creatine kinase–myocardial band) who were
undergoing PCI after pretreatment with clopidogrel 600 mg at least 2
hours before the procedure were enrolled. There were 2289 patients
randomised in a double-blind fashion to receive bivalirudin, and 2281
patients randomised to receive UFH. The primary endpoint was the
composite of death, myocardial infarction (MI), urgent target vessel
revascularisation (uTVR) due to myocardial ischaemia within 30 days
after randomisation, or major bleeding during the index hospitalisation
(with a net clinical benefit defined as a reduction in the incidence of
the endpoint). The composite of death, MI, or uTVR comprised the
secondary endpoint.
Results
The primary endpoint incidence was 8.3% (190 patients) in the
bivalirudin group versus 8.7% (199 patients) in the UFH group (relative
risk [RR], 0.94; 95% confidence interval [CI], 0.77-1.15; P=.57). One
hundred thirty-four patients (5.9%) in the bivalirudin group and 115
patients (5.0%) in the UFH group (RR, 1.16; 95% CI, 0.91-1.49; P=.23)
attained the secondary endpoint. The major bleeding rates were 3.1%
(70 patients) in the bivalirudin group and 4.6% (104 patients) in the
UFH group (RR, 0.66; 95% CI, 0.49-0.90; P=.008).
10
9
8
Cumulative Incidence, %
7
Relative risk, 0.94 (95% CI, 0.77-1.15)
6
P=0.57
5
4
3
2
Unfractionated heparin
1 Bivalirudin
0
0 10 20 30
Days Since Randomisation
Thirty-day cumulative incidence of the primary endpoint and the
secondary endpoint in the bivalirudin group and the
unfractionated heparin group.
Abstract and figure adapted from Kastrati A et al. N Engl J Med. 2008;359(7):688-696.
Conclusions
For patients with stable angina and UA who underwent PCI after
clopidogrel pretreatment, bivalirudin compared with UFH did not
provide a net clinical benefit (ie, it did not lower the incidence of the
composite endpoint of death, MI, uTVR, or major bleeding), but caused
a significant reduction in the incidence of major bleeding.
56
Meta-analysis (Diabetes) Meta-analyses
Roffi M, Chew DP, Mukherjee D, et al. Platelet glycoprotein IIb/IIIa
inhibitors reduce mortality in diabetic patients with non–ST-segment
elevation acute coronary syndromes. Circulation. 2001;104(23):2767-
2771.
Background
Diabetes mellitus is a major risk factor for adverse outcomes after
acute coronary syndromes (ACS). This study was conducted to
investigate whether diabetic patients with ACS derive particular benefit
from platelet glycoprotein IIb/IIIa receptor inhibition, as this disease
may be associated with increased platelet aggregation.
Methods and Results

This study was a meta-analysis of the diabetic populations enrolled
in 6 large-scale platelet glycoprotein IIb/IIIa inhibitor (GPI) ACS trials:
PRISM, PRISM-PLUS, PARAGON A, PARAGON B, PURSUIT, and
GUSTO IV. Among 6458 diabetic patients, a significant mortality
reduction from 6.2% to 4.6% (odds ratio [OR], 0.74; 95% confidence
interval [CI], 0.59-0.92; P=.007) occurred at 30 days due to platelet
glycoprotein IIb/IIIa inhibition. Conversely, no survival benefit was
seen in 23,072 nondiabetic patients (3.0% vs 3.0%). There was a
statistically significant interaction between platelet glycoprotein IIb/IIIa
inhibition and diabetic status (P=.036). Among 1279 diabetic patients
undergoing percutaneous coronary intervention (PCI) during index
hospitalisation, there was a mortality reduction at 30 days from 4.0%
to 1.2% (OR, 0.30; 95% CI, 0.14-0.69; P=.002) with the use of these
agents.
Trial N Placebo, IIb/IIIa, P Value

% %
PURSUIT 2163 6.1 5.1 0.33
PRISM 687 4.2 1.8 0.07
PRISM-PLUS 362 6.7 3.6 0.17
GUSTO IV 1677 7.8 5.0 0.022
PARAGON A 412 6.2 4.6 0.51
PARAGON B 1157 4.8 4.9 0.93
Pooled 6458 6.2 4.6 0.007
0 0.5 1 1.5 2
IIb/IIIa Better Placebo Better
Breslow-Day P=0.50
Odds Ratio and 95% CI
OR with 95% CIs and corresponding P values for treatment effect on 30-day mortality among
diabetic patients with ACS. Values to the left of 1.0 indicate a survival benefit of platelet GP IIb/IIIa
inhibition.
Abstract and figure adapted from Roffi M et al. Circulation. 2001;104(23):2767-2771.
Conclusions
This meta-analysis, including the entire large-scale trial experience
of intravenous platelet GPIs for the medical management of non–ST-
segment elevation ACS, demonstrated that there was a significant
reduction in mortality at 30 days in diabetic patients using these
agents. The survival benefit seemed to be of greater magnitude in
patients undergoing PCI, though it was not based on a randomised
evaluation. Therefore, the use of platelet GPIs should be strongly
considered in diabetic patients with ACS.
57
Meta-analysis (High-dose tirofiban) Meta-analyses
Dawson CB, Mukherjee D, Valgimigli M, et al. Meta-analysis of high-
dose single-bolus tirofiban versus abciximab in patients undergoing
percutaneous coronary interventions. Circulation. 2006;114(suppl
18):II_647.
Background
Increased incidence of adverse cardiac events at 30 days have been
observed in prior studies with tirofiban (10 μg/kg bolus and 0.15 μg/
kg/min infusion) during percutaneous coronary intervention (PCI)
compared with abciximab. This was a comparative study of the effects
of a high-dose bolus of tirofiban (25 μg/kg) and an infusion with the
conventional abciximab regimen on clinical outcomes at 30 days in
patients undergoing PCI.
Methods
This study was a meta-analysis that used data from 5 trials (n=1,392)
comparing high-dose tirofiban with abciximab (TENACITY, Bolognese
et al, Danzi et al, Gunasekara et al, Valgimigli et al) and analysed
30-day outcomes. The primary endpoint was the composite of death,
myocardial infarction (MI), and target vessel revascularisation (TVR).
The incidence of thrombocytopaenia and major and minor bleeding
were also evaluated. The analysis used a random effects meta-
analysis model.
Results
Six hundred eighty-nine patients were treated with tirofiban and 703
patients received abciximab. No significant differences were observed
between the 2 groups, though there was a trend toward higher
incidence of prior PCI in the tirofiban group. The composite of death,
MI, and TVR at 30 days was reached in 6.1% of patients treated with
tirofiban and 7.3% of patients treated with abciximab (P=.46). There
were also no significant differences in the individual endpoints of
death, MI, and TVR between the 2 groups. Major and minor bleeding
and thrombocytopaenia were not significantly different between the
2 groups.
Endpoint P Value
Composite 0.458
Death 0.401
MI 0.827
TVR 0.500
0 0.5 1.0 2.0 3.0 4.0
Abciximab Better Tirofiban Better
Odds Ratio and 95% CI

Odds ratios with 95% CIs and corresponding P values for treatment effect on endpoints.
Abstract and figure adapted from Dawson CB et al. Circulation. 2006;114(suppl 18):II_647.
Conclusions
For patients undergoing PCI, high-dose single-bolus tirofiban may be
as efficacious as abciximab, with a comparable safety profile. Further
testing is warranted, given the limited statistical power and short
follow-up with the current analysis.
58
Meta-analysis (Tirofiban) Meta-analyses
Valgimigli M, Biondi-Zoccai G, Tebaldi M, et al. Tirofiban as adjunctive
therapy for acute coronary syndromes and percutaneous coronary
intervention: a meta-analysis of randomised trials. Eur Heart J. 2009.
[Epub ahead of print]
Background
The objective of this study was to perform a thorough and updated
systematic review of randomised clinical trials that compared tirofiban
versus placebo or abciximab.
Methods and Results
Randomised trials comparing tirofiban versus placebo or any active
control were explored. Odds ratios (ORs) were calculated from
individual studies and pooled with random effect methods. Thirty-one
studies that had a total of 20,006 patients (12,874 comparing tirofiban
versus heparin plus placebo or bivalirudin alone, and 7132 versus
abciximab) were found. At 30 days, there was a significant reduction in
mortality (OR, 0.68; 95% confidence interval [CI], 0.54-0.86; P=.001)
and death or myocardial infarction (MI) (OR, 0.69; 95% CI, 0.58-
0.81; P<.001) with tirofiban as compared with placebo. There was
an increased risk of minor bleedings [OR, 1.42; 95% CI, 1.13-1.79;
P=.002) or thrombocytopaenia, but the benefit of the treatment was
sustained at follow-up. Compared with abciximab, at 30 days, similar
mortality was noted [OR, 0.90; 95% CI, 0.53-1.54; P=.70), but in the
overall group there was an increase in the composite of death or MI
(OR, 1.18; CI 95%, 0.96-1.45; P=.11) with tirofiban. This trend was not
sustained at medium-term follow-up, or while evaluating studies testing
a regimen of tirofiban 25 μg/kg bolus.
Tirofiban Control Odds Ratio Odds Ratio
Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI
2.2.3 Tirofiban 25 µg/kg bolus dose
Danzi 1 50 2 50 0.7% 0.49 [0.04, 5.58]
Ernst 1 29 0 30 0.4% 3.21[0.13, 82.07]
EVEREST 0 30 1 30 0.4% 0.32 [0.01, 8.24]
FATA 9 351 6 341 3.9% 1.47 [0.52, 4.17]
MULTISTRATEGY 14 372 14 372 7.4% 1.00 [0.47, 2.13]
STRATEGY 3 87 6 88 2.1% 0.49 [0.12, 2.02]
TENACITY 11 189 16 194 6.6% 0.69 [0.31, 1.52]
Subtotal (95% CI) 1108 1105 21.4% 0.87 [0.56, 1.35]
Total events 39 45
Heterogeneity:Tau2 = 0.00; Chi2 = 3.27, df = 6 (P=0.77); I2=0%
Test for overall effect: Z = 0.62 (P=0.54)
2.2.2 Tirofiban 10 µg/kg bolus dose
Ernst 0 30 0 30 Not estimable
Neumann 0 20 0 20 Not estimable
TARGET 173 2398 138 2421 78.6% 1.29 [1.02, 162]
Subtotal (95% CI) 2448 2471 78.6% 1.29 [1.02, 162]
Total events 173 138
Heterogeneity: Not applicable
Test for overall effect Z= 2.13 (P=0.03)
Total (95% CI) 3556 3576 100% 1.18 [0.96, 1.45]

Total events 212 183
Heterogeneity:Tau2 = 0.00; Chi2 = 5.63, df = 7 (P=0.58); I2=0%
Test for overall effect Z= 1.61 (P=0.11) 0.002 0.1 10 500
Favours tirofiban Favours control
Forest plot of comparison: tirofiban vs abciximab, outcome: 30-day death or myocardial

infarction. CI, confidence interval: Weight, statistical weight (an indirect estimate of study precision
and impact on overall pooled estimates of the single study result).
Abstract and figure adapted from Valgimigli M et al. Eur Heart J. 2009. [Epub ahead of print]
Conclusions
Compared with placebo, the administration of tirofiban caused a
reduction in mortality, the composite of death or MI, and increases
in minor bleedings. Compared with abciximab, in studies based on a
regimen of tirofiban 10 μg/kg bolus, rather than a regimen of tirofiban
25 μg/kg bolus, an early ischaemic hazard not in favor of tirofiban was
observed.
59
ESC NSTEMI Guidelines
Bassand JP, Hamm CW, Ardissino D, et al. Guidelines for the diagnosis
and treatment of non–ST-segment elevation acute coronary syndromes.
Eur Heart J. 2007;28(13):1598-1660.
Recommendations for glycoprotein IIb/IIIa inhibitors (GPIs):

• In addition to oral antiplatelet agents, either eptifibatide or tirofiban
are recommended for initial early treatment of patients at
intermediate to high risk, particularly patients with elevated
troponins, ST-depression, or diabetes.
• The risk of ischaemic and bleeding events should be
considered while choosing the combinations of antiplatelet agents
and anticoagulants.
• The same drug should be administered during and after
percutaneous coronary intervention (PCI) to patients who received
initial treatment with eptifibatide or tirofiban prior to angiography.
• Abciximab is recommended immediately following angiography in
high-risk patients not pretreated with GPIs who are proceeding to
PCI. Eptifibatide or tirofiban use in this setting is less well
established.
• GPIs must be used in combination with an anticoagulant.
• An alternative to the use of GPIs plus unfractionated heparin/low-
molecular-weight heparin may be the use of bivalirudin.
• Abciximab has the most secure evidence when anatomy is known
and PCI is planned to be performed within 24 hours with GPIs.
Adapted from Bassand JP et al. Eur Heart J. 2007;28(13):1598-1660.
60
ESC STEMI Guidelines
Van de Werf F, Bax J, Betriu A, et al. Management of acute myocardial
infarction in patients presenting with persistent ST-segment elevation:
the Task Force on the Management of ST-Segment Elevation Acute
Myocardial Infarction of the European Society of Cardiology. Eur Heart J.
2008;29(23):2909-2945.
Reperfusion Therapy (Primary PCI)

Abciximab: Class IIa, level of evidence A
Tirofiban: Class IIb, level of evidence B
Eptifibatide: Class IIb, level of evidence C
Glycoprotein IIb/IIIa Antagonists

The final pathway of platelet aggregation is blocked by platelet
glycoprotein IIb/IIIa inhibitors. Abciximab, rather than the other 2
members of the family, tirofiban and eptifibatide, has been the focus
of most of the studies on the role of glycoprotein IIb/IIIa antagonists
in ST-segment elevation myocardial infarction (STEMI). The value of
periprocedural administration of intravenous abciximab in addition to
aspirin and heparin has been evaluated by several randomised trials in
this setting. At 30 days, a 32% reduction in mortality with abciximab and
no effect on the risk of haemorrhagic stroke and major bleeding was seen
in a systematic review of these trials. There was no significant impact of
abciximab on the patency of infarct-related vessels, and administering
it upstream of a planned percutaneous coronary intervention (PCI)
procedure was not advantageous compared with its administration in
the catheterisation lab. Abciximab is administered intravenously as a
0.25 mg/kg bolus, 0.125 mg/kg/min infusion (maximum 10 mg/min for 12
hours). However, it remains to be elucidated whether patients with STEMI
who receive an optimal clopidogrel treatment prior to PCI receive an
additional benefit due to abciximab. In the On-TIME 2 trial (N=984), there
was an improvement in ST-segment resolution, but there was a reduction
in patency of the infarct vessel and also a significant reduction in net
clinical benefit when compared with placebo.
Adapted from Van de Warf F et al. Eur Heart J. 2008;29(23):2909-2945.
61
ACC/AHA STEMI Guidelines
Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for
the management of patients with ST-elevation myocardial infarction.
Circulation. 2004;110(9):e82-e293.
Glycoprotein IIb/IIIa Inhibitors

Class IIa
It is reasonable to start treatment with abciximab as early as possible
before primary percutaneous coronary intervention (PPCI) (with or
without stenting) for patients with ST-segment elevation myocardial
infarction (STEMI). (Level of evidence: B.)
Class IIb
Treatment with tirofiban or eptifibatide may be considered before PPCI
(with or without stenting) for patients with STEMI. (Level of evidence: C.)
The Writing Committee believes that it is reasonable to start treatment

with abciximab as early as possible in patients undergoing PPCI (with
or without stenting) but a Class IIa recommendation was assigned
due to the size and limitations of the available dataset. The data are
limited on tirofiban and eptifibatide compared with abciximab in PPCI.
However, due to the common mode of action of the agents, a modest
amount of angiographic data, and general clinical experience to date,
treatment with tirofiban or eptifibatide may be considered as antiplatelet
therapy to support PPCI for STEMI with or without stenting (Class IIb
recommendation).
Platelet function returns toward normal within 4 hours of stopping

treatment in patients treated with the small-molecule glycoprotein IIb/IIIa
receptor antagonists tirofiban and eptifibatide. In patients treated with
abciximab, platelet aggregation does not return toward normal for greater
than 48 hours. Platelet transfusions for patients who were recently
treated with abciximab, reduced heparin dosing during cardiopulmonary
bypass, and possible use of antifibrinolytic agents such as aprotinin or
tranexamic acid constitute management strategies other than delaying
surgery. In patients who are scheduled for elective coronary artery
bypass graft surgery, clopidogrel should be withheld for at least 5 days—
and preferably for 7 days—before surgery, because clopidogrel, when
added to aspirin, increases the risk of bleeding during major surgery.
Adapted from Antman EM et al. Circulation. 2004;110(9):e82-e293.
62
Important Product Information Appendix
GENERIC NAME: TIROFIBAN—INJECTABLE
BRAND NAME(S): Aggrastat®
Uses. Tirofiban is a type of blood thinner used (usually in combination with
heparin) to help prevent blood clotting that occurs during certain heart conditions
(eg, acute coronary syndrome) or medical procedures (eg, percutaneous
coronary intervention [PCI]). Tirofiban works by preventing platelets in the blood
from sticking to each other. When platelets stick to each other, this can cause
blood clots that may lead to medical complications.
How to Use. Follow all instructions for proper mixing or dilution (if necessary)
and refer to the tirofiban dosing chart for the recommended intravenous (IV)
dosing. If you have questions regarding the use of this medication, consult your
pharmacist. Give this medication by vein as an initial dose (bolus dose) followed
by an IV infusion as directed by your doctor. The dosage is based on your
weight, medical condition, and response to therapy. Before using, check this
product visually for particles or discoloration. If either is present, do not use the
liquid. Learn how to store and discard needles and medical supplies safely.
Consult your pharmacist.
Side Effects. Injection site reactions (eg, minor bleeding, redness, or discomfort)
may occur. If any of these effects persist or worsen, notify your doctor promptly.
Tell your doctor immediately if any of these serious side effects occur: easy/
persistent bruising or bleeding, pink- or red-colored urine, black stool, coffee-
ground vomit, one-sided weakness, vision problems, confusion, or slurred
speech. Tell your doctor immediately if any of these unlikely but serious side
effects occur: swelling, tingling, weakness in the arms or legs, numbness,
difficulty urinating, unusually slow heartbeat, pain (especially in the pelvis or
legs), dizziness, or fever. If you notice other effects not listed above, contact your
doctor or pharmacist.
Precautions. This medication is not recommended for use if you have any of the
following medical conditions: recent or current bleeding, recent spinal (epidural)
puncture/anesthesia, history of stroke (within 30 days or any history of
hemorrhagic stroke), history of aneurysms or brain tumors, recent surgery or
injury (within 30 days), severe high blood pressure, or certain heart or blood
vessel problems (eg, acute pericarditis, aortic dissection, intracranial
hemorrhage). Tell your doctor your medical history, especially of: kidney disease,
low platelet counts (thrombocytopenia), eye problems (retinal bleeding), or any
allergies. Caution is advised when using this drug in the elderly because they
may be more sensitive to the effects of the drug. Tell your doctor if you are
pregnant before using this medication. It is not known whether this drug passes
into breast milk. Consult your doctor before breast-feeding.
Drug Interactions. Tell your doctor of all prescription and nonprescription
medications you may use, especially other “blood thinning” medications (eg,
aspirin, clopidogrel, dipyridamole, ticlopidine, heparin, warfarin, NSAIDs such as
ibuprofen, or thrombolytics such as alteplase). Tirofiban has been used
effectively in combination with other “blood thinners” such as aspirin, clopidogrel,
ticlopidine, and anticoagulants such as heparin. Be sure to check with your
doctor or pharmacist regarding which medicines you need to take after leaving
the hospital. This drug is not recommended for use with other drugs similar to
tirofiban (ie, other GP IIb/IIIa inhibitors such as abciximab or eptifibatide). Ask
your doctor or pharmacist for more details. Do not start or stop any medicine
without doctor or pharmacist approval.
63
GENERIC NAME: BIVALIRUDIN—INJECTABLE
BRAND NAME(S): Angiomax®, Angiox®
Uses. Bivalirudin is a blood thinner used in patients with certain heart problems
(unstable angina) during a type of heart procedure (eg, percutaneous transluminal
coronary angioplasty [PTCA]). This medication helps prevent blood clots from
forming during and after this type of procedure and is usually used along with
aspirin.
How to Use. Follow all instructions for proper mixing and dilution with the correct
intravenous (IV) fluids. If you have any questions regarding the use of this
medication, consult your pharmacist. Give this medication by vein exactly as
prescribed by the doctor. The dosage is based on the patient’s weight, medical
condition, and response to therapy. This medication should not be mixed with
other injectable medications or used for longer than 24 hours. Consult your
pharmacist. Before using, check this product visually for particles or discoloration.
If either is present, do not use the liquid. Learn how to store and discard needles
and medical supplies safely.
Side Effects. Nausea, vomiting, heartburn, pain/redness/swelling at the injection
site, headache, or trouble sleeping may occur. If any of these effects persist or
worsen, contact your doctor or pharmacist. Tell the doctor immediately if any of
these serious side effects occur: unusual bleeding or bruising, blurred vision,
dizziness, lightheadedness, pain (especially back pain, stomach/abdominal
pain, or pelvic pain), mental/mood changes, or persistent sore throat or fever.
Tell the doctor immediately if any of these unlikely but serious side effects occur:
unusually slow heartbeat, change in amount of urine, or unusual tiredness or
weakness. Tell the doctor immediately if any of these highly unlikely but very
serious side effects occur: one-sided weakness, loss of coordination, slurred
speech, confusion, or trouble breathing. If you notice any other effects not listed
above, contact your doctor or pharmacist.
Precautions. Tell the doctor your complete medical history, especially of kidney
problems or other blood or bleeding problems (eg, active bleeds, anemia,
coagulopathy, or thrombocytopenia). Tell the doctor if you are pregnant before
using this medication. It is not known whether this drug passes into breast milk.
Consult your doctor before breast-feeding.
Drug Interactions. Tell your doctor of all prescription and nonprescription
medications used, especially other blood thinners (heparins, warfarin,
thrombolytics, or platelet inhibitors). Do not start or stop any medicine without
doctor or pharmacist approval.
64
GENERIC NAME: EPTIFIBATIDE—INJECTABLE
BRAND NAME(S): Integrilin®
Uses. Eptifibatide is used to help prevent blood clotting that occurs during
certain heart conditions (eg, acute coronary syndrome) or medical procedures
(eg, percutaneous coronary intervention [PCI]). It works by preventing platelets
in the blood from sticking to each other. When platelets stick to each other, this
can cause blood clots that may lead to medical complications.
How to Use. Follow all instructions for proper mixing and refer to the eptifibatide
dosing chart for the recommended intravenous (IV) dosing. If you have questions
regarding the use of this medication, consult your pharmacist. Give this
medication as an initial dose (bolus dose) into a vein (IV push) followed by an IV
infusion as directed by your doctor. The dosage is based on your weight, medical
condition, and response to therapy. Before using, check this product visually for
particles or discoloration. If either is present, do not use the liquid. Learn how to
store and discard needles and medical supplies safely. Consult your
pharmacist.
Side Effects. Injection site reactions (eg, minor bleeding, redness, or discomfort)
may occur. If any of these effects persist or worsen, notify your doctor promptly.
Tell your doctor immediately if any of these serious side effects occur: easy
bruising or bleeding, pink or red-colored urine, black stool, coffee-ground vomit,
one-sided weakness, vision problems, confusion, or slurred speech. If you
notice other effects not listed above, contact your doctor or pharmacist.
Precautions. This medication is not recommended for use if you have any of the
following medical conditions: active bleeding problems, poorly controlled high
blood pressure, certain types of stroke (stroke within 30 days or any history of
hemorrhagic stroke), major surgery in the past 6 weeks, or severe kidney
disease (requiring dialysis). Tell your doctor your medical history, especially of:
kidney problems, low platelet counts, bleeding problems (eg, clotting difficulty or
any stomach, eye, brain, or lung bleeding), high blood pressure (hypertension),
or any allergies. Caution is advised when using this drug in the elderly because
they may be more sensitive to the effects of the drug. Use caution and/or limit
other injections you may receive while being treated with this drug. Receiving
other injections (IV or intramuscular [IM]) may increase your risk for bleeding.
Tell your doctor if you are pregnant before receiving this medication. It is not
known whether this drug passes into breast milk. Consult your doctor before
breast-feeding.
Drug Interactions. This drug is not recommended for use with other drugs
similar to eptifibatide (ie, other GP IIb/IIIa inhibitors such as abciximab). Ask your
doctor or pharmacist for more details. Tell your doctor or pharmacist all
prescription and nonprescription medications you may use, especially other
“blood thinning” medications (eg, aspirin, clopidogrel, ticlopidine, dipyridamole,
heparin, warfarin, NSAIDs such as ibuprofen, or thrombolytics such as alteplase)
or furosemide injection. Eptifibatide has been used effectively in combination
with other “blood thinners” such as aspirin, clopidogrel, ticlopidine, and
anticoagulants such as heparin. Be sure to check with your doctor or pharmacist
regarding which medicines you need to take after leaving the hospital. Do not
start or stop any medicine without doctor or pharmacist approval.
65
GENERIC NAME: ABCIXIMAB—INJECTION
BRAND NAME(S): ReoPro®
Uses. This medication keeps blood cells (platelets) from sticking together. It is
used during certain heart artery procedures (eg, angioplasty).
How to Use. This medication is given by injection usually 10 to 60 minutes prior
to the procedure followed by a continuous infusion into a vein for up to 12 hours.
Your dose will be determined by your condition and response. Do not increase
the dose, use it more often, or continue using this drug longer than prescribed.
Do not shake the container.
Side Effects. Nausea, vomiting, dizziness, or irritation at the injection site may
occur. If any of these effects persist or become bothersome, inform your doctor.
Notify your doctor if you experience: bruising or bleeding, skin rash, breathing
trouble, rapid or abnormal heartbeat, chest pain, or swelling of the feet or ankles.
If you notice other effects not listed above, contact your doctor or pharmacist.
Precautions. Should not be used if there is any bleeding (eg, gastrointestinal
bleeding) or history of stroke. Should be used carefully if at all in patients
weighing less than 75 kg or older than 65 years of age or who have a history of
gastrointestinal disease. Tell your doctor if you have other illnesses, recent
surgeries or trauma, or any allergies. This medication should be used only if
clearly needed during pregnancy. Discuss the risks and benefits with your doctor.
It is not known if this medication appears in breast milk. Consult your doctor
before breast-feeding.
Drug Interactions. Should not be used with dextran or thrombolytics. Tell your
doctor of any over-the-counter or prescription medications you use, including:
blood thinners taken within 7 days, aspirin, NSAIDs (eg, ibuprofen), or ticlopidine.
Do not start or stop any medicine without doctor or pharmacist approval.
66
Notes
Notes
Notes
Developed through a collaboration with
theheart.org and Selva.
Supported by an educational grant from Iroko

Pharmaceuticals.

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A Pocket Guide to the Studies

This pocket guide contains the abstracts of nearly 50 of the major

Finally, key product information for Aggrastat, Integrilin, ReoPro, and

Integrilin® (eptifibatide) Year* Page

ReoPro® (abciximab) Year* Page

Meta-analyses Year* Page

Appendix: Important Product Information Page

Abstract and figure adapted from Taglieri N et al. Am J Cardiol. 2009;103(6):785-790.

IPA, 10 min (%) 95.88 ± 5.85* 91.22 ± 7.52*

Abstract and figure adapted from Mardikar HM et al. Am Heart J. 2007;154(2):344.e1-344.e5.

Abstract and figure adapted from Januzzi JL Jr et al. Circulation. 2002;105(20):2361-2366.

Abstract and figure adapted from Januzzi JL Jr et al. Am J Cardiol. 2003;91(4):457-461.

Composite 32.0 39.9 (0.53, 1.06)

30 days Composite 20.1 29.0 (0.44, 1.03)

Composite 14.8 21.8 (0.41, 1.10)

Composite 7.7 8.3 (0.45, 1.97)

0.1 1.0 10.0

Abstract and figure adapted from Théroux P et al. Circulation. 2000;102(20):2466-2472.

Abstract and figure adapted from Januzzi JL et al. Am J Cardiol. 2000;86(7):713-717.

Abstract and figure adapted from RESTORE Investigators. Circulation. 1997;96(5):1445-1453.

cTnl ≥0.1 ng/mL, No. 555 532

cTnl <0.1 ng/mL, No. 362 372

Abstract and figure adapted from Morrow DA et al. JAMA. 2001;286(19):2405-2412.

0.5 1.0 1.5 2.0 2.5 3.0

CRP=C-reactive protein. DM=diabetes mellitus.

Methods and Results

RR, 0.58; 95% CI, 0.39-0.88;

<2-h group 18-h group

No diabetes 87/268 (32.5) 79/263 (30.0)

No ACS 51/143 (35.7) 45/159 (28.3)

All 92/306 (30.1) 88/311 (28.3)

Methods and Results

Methods and Results

10.0 9.3 P=NS

Primary endpoint: Composite of death, MI, uR, or TBO at 96 hours.

Abstract and figure adapted from ESPRIT Investigators. Lancet. 2000;356(9247):2037-2044.

Methods and Results

Abstract and figure adapted from Labinaz M et al. Am J Cardiol. 2002;90(6):585-590.

Death or MI at 30 Days and 12 Months Among the 2 Risk Groups

Death or MI, 95% CI

Partial 22.2 24.5 NS

Complete 50.2 47.5 NS

10 D/MI Ischaemia 8.7%

Stent plus abciximab

Kaplan-Meier Estimates of the Clinical Outcomes at 30 Days and 6 Monthsa

Stenting Plus PTCA Plus

Abstract and figure adapted from CAPTURE Investigators. Lancet. 1997;349(9063):1429-1435.

Stent plus placebo

Abstract and figure adapted from EPISTENT Investigators. Lancet. 1998;352(9122):87-92.

Methods and Results

Abstract and figure adapted from Ottervanger JP et al. Circulation. 2003;107(3):437-442.

Complications of myocardial infarction up to day 7.

Abstract and figure adapted from Topol EJ. Lancet. 2001;357(9272):1905-1914.

1-Year Clinical Outcome

30-Day Clinical Outcome

Abstract and figure adapted from Ndrepepa G et al. Circulation. 2006;114(19):2040-2046.

10.0 Bivalirudin alone, 8.0%; P=0.30

Days From Randomisation

Abstract and figure adapted from Stone GW et al. Lancet. 2007;369(9565):907-919.

Abstract and figure adapted from Stone GW et al. JAMA. 2007;297(6):591-602.

Abstract and figure adapted from Stone GW et al. JAMA. 2007;298(21):2497-2506.

Clinical Outcomes at 1 Year in Patients Undergoing PCI