gp iib-iiia inhibitors

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GP IIb/IIIa InhibitorsA Pocket Guide to the StudiesInvolving GP IIb/IIIa Inhibitors in

Acute Coronary Syndrome andCardiovascular Disease

2010


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Glycoprotein IIb/IIIa inhibitors (GPIs) play an important role in the

current treatment of acute coronary syndrome (ACS) and have played

a signicant role in increasing patient survival.

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

studies involving the 3 currently marketed GPIsAggrastat (tiroban),

Integrilin (eptibatide), 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 andwithout GPIs in the treatment of patients with ACS.

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

Angiomax/Angiox is included in the Appendix.

INTRODUCTION

1


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Table of ContentsGPI Studies

ADVANCEEVEREST

FATAFATA [LVF]MR PCIMULTISTRATEGYOn-TIME 2On-TIME 2 [1 year]PRISM-PLUSPRISM-PLUS [Renal]PRISM-PLUS [Age]PRISM-PLUS [Diabetes]PRISM-PLUS [Troponins]RESTORETACTICS-TIMI 18TACTICS-TIMI 18 [Troponins]TACTICS-TIMI 18 [Diabetes]TARGETTENACITY3T/2R

20042006

200820092007200820082009199820022003200020001997200120012007200120052009

Aggrastat (tiroban) Year* Page

ACUITYACUITY [PCI]ACUITY [Timing]ACUITY [1 year]ACUITY [1-year PCI]ACUITY [Diabetes]HORIZONS-AMIISAR-REACT 3

20062007200720072008200820082008

Angiomax/Angiox (bivalirudin) Year* Page

Antithrombin Studies

Meta-analysis [Diabetes]Meta-analysis [High-dose tiroban]Meta-analysis [Tiroban]

200120062009

Meta-analyses Year* Page

Appendix: Important Product Information PageAggrastatAngiomax/ AngioxIntegrilinReoPro

ESC NSTEMIESC STEMIACC/AHA STEMI

Guidelines Page

34

5678910111213141516171819202122

ASSISTBRIEF-PCICLEAR PLATELETSCLEAR PLATELETS-2EARLY ACSESPRITESPRIT [Diabetes]ESPRIT [High risk]EVA-AMIPROTECTTIMI-30PURSUIT

20082009200520092009200020022006200720061998

Integrilin (eptibatide) Year* Page

2324252627282930313233

ADMIRALBRAVE-3CADILLACCAPTUREEPICEPILOGEPISTENTFINESSEGUSTO IV-ACSGUSTO VISAR-REACTISAR-REACT 2ISAR-REACT 2 [1 year]ISAR-REACT 2 [Age]ISAR-REACT 2 [Troponins]

200120092002199719941997199820082003200120042006200820062008

ReoPro (abciximab) Year* Page

343536373839404142434445464748

4950515253545556

575859

606162

63646566

200720082004

*Year of primary publication or major meeting presentation.

2


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Please see Important Product Information in the Appendix.

ADVANCE Aggrastat

Valgimigli M, Percoco G, Barbieri D, et al. The additive value of

tiroban 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.

High-dose bolus (HDB) tiroban use in the catheterisation laboratory is

controversial. Specically, in patients with acute coronary syndromes

undergoing percutaneous coronary intervention (PCI), no evidence

exists to show that tiroban administered in the catheterisation

laboratory is superior to heparin alone. This nding may reect

suboptimal platelet inhibition when tiroban is employed with the

RESTORE (Randomised Efcacy Study of Tiroban for Outcomes andRestenosis) regimen.

Background

The aim of this study was to investigate whether HDB tiroban was

safe and effective for high-risk patients undergoing PCI.

oBjectives

3

HDB Tirofiban

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).

0 100 200 300 400

Days

P=0.01

Placebo

SurvivalPro

bability

0.0

0.2

0.4

0.6

0.8

1.0

HDB tiroban is safe and causes a signicant reduction of ischaemic/

thrombotic complications during high-risk PCI.

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 tiroban (25 g/kg/3

min and an infusion of 0.15 g/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/IIIainhibitors (GPIs).

Methods

The cumulative primary endpoint rates were 35% and 20% in the

placebo group and HDB tiroban group, respectively (hazard ratio:

0.51; 95% condence interval, 0.29-0.88; P=.01). This difference

mainly reects reduced MI and bailout use of GPIs. However, there

was no signicant effect on TVR or death. Similar safety proles were

noted for tiroban and placebo.

results

Abstract and gure adapted from Valgimigli M et al. J Am Coll Cardiol. 2004;44(1):14-19.

conclusions


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FATA Aggrastat

Marzocchi A, Manari A, Piovaccari G, et al. Randomised comparison

between tiroban and abciximab to promote complete ST-resolution in

primary angioplasty: results of the facilitated angioplasty with tiroban

or abciximab (FATA) in ST-elevation myocardial infarction trial. Eur

Heart J. 2008;29(24):2972-2980.

The FATA trial demonstrated that HDB tiroban was not equivalent toabciximab as an adjunctive therapy for PPCI.

conclusions

This study evaluated whether high-dose bolus (HDB) tiroban was

equivalent to the standard dose of abciximab for patients undergoing

primary percutaneous coronary intervention (PPCI), as measured by

ST-segment resolution (STR).

oBjectives

The FATA trial (Facilitated Angioplasty With Tiroban 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 tiroban

(n=351). The primary endpoint was the rate of complete (at least

70%) STR 90 minutes after the rst balloon ination. Major bleedings,death, reinfarction, and new revascularisations at 30 days were also

evaluated.

Methods

Baseline characteristics of the 2 groups were well balanced, with onlyminor differences observed between the study groups; specically,the incidence of previous MI rates (tiroban 6% vs abciximab 2.6%;

P=.03). The procedure was successful in 96.7% of the patients inthe abciximab group and in 96.6% of the patients in the tirobangroup (P=.94). Of the patients treated with tiroban, 67.05% reachedthe primary endpoint of complete STR at 90 minutes comparedwith 70.45% of the patients in the abciximab group ( 3.4%, 95%condence interval, 10.35 to 3.56), which lies beyond the predened

10% equivalence boundaries. Both groups had similar rates ofsecondary endpoints

results

Abstract and gure adapted from Marzocchi A et al. Eur Heart J. 2008;29(24):2972-2980.

5

Absent

Partial

Complete

ST-resolution

Tirofiban Abciximab

Ra

teofST-Segment

Resolution,%

0

20

40

60

80

100

67.05 70.45

14.459.85

Rates of complete (70%), partial (30%-70%), and absent (


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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.

In patients undergoing elective high-risk PCI, a higher degree of

platelet inhibition was noted with high-dose tiroban at 10 minutes

and at 6 to 8 hours in this head-to-head study comparing high-dosetiroban with double-bolus eptibatide. Clopidogrel addition did not

acutely prolong the IPA from intravenous GPIs, but did do so at 24

hours.

conclusions

The goal of this study was to compare different combinations ofglycoprotein IIb/IIIa inhibitors (GPIs) and clopidogrel to facilitate the

evaluation of several antiplatelet regimens in elective high-risk patients

undergoing PCI.

oBjectives

This was a randomised open-label study at 3 heart centres in India.

One hundred twenty patients were enrolled between July 2006 andSeptember 2006 and were randomised to 1 of the 4 groups: group A,

tiroban; group B, eptibatide; group C, tiroban plus clopidogrel

600-mg loading dose; and group D, eptibatide 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.

Methods

High-dose tiroban versus eptibatide 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


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MULTISTRATEGY Aggrastat

Valgimigli M, Campo G, Percoco G, et al. Comparison of angioplasty

with infusion of tiroban 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.

For patients with STEMI undergoing PCI, tiroban 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 signicantly reduced risk

of MACE compared with uncoated stents within 8 months after

intervention.

conclusions

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 bundlebranch block. HDB tiroban 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 prespecied noninferiority margin of 9%

difference (relative risk [RR], 0.89). For stent comparison, the rate of

MACE, dened as the composite of death from any cause, reinfarction,

and clinically driven target-vessel revascularisation within 8 monthswas 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 tiroban infusion (RR, 1.020;

97.5% condence interval, 0.958-1.086; P


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On-TIME 2 Aggrastat

Vant Hof AW, Ten Berg J, Heestermans T, et al. Prehospital initiation of

tiroban 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.

Prehospital initiation of HDB tiroban 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.

conclusions

This study investigated whether the early administration of the

glycoprotein IIb/IIIablocker tiroban at rst medical contact in theambulance or referral centre can improve the results of primary

coronary angioplasty (PCI).

oBjectives

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 werecandidates to undergo PCI were randomised to either high-bolus dose

(HDB) tiroban (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.

Methods

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 signicantly lower for patients pretreated

with HDB tiroban than for those who received placebo. The major

bleeding rate was not signicantly different between the HDB tiroban

group and the placebo group (19% [SD 4%] vs 14% [SD 3%],

respectively; P=.36).

results

Abstract and gure adapted from Vant Hof AW et al. Lancet. 2008;372(9638):537-546.

The most effective magnitude and timing of antiplatelet therapy is

important for patients with acute ST-elevation myocardial infarction

(STEMI).

Background

9

Pa

tients,%

0

5

10

15

20

25

30

35

45P=0.035

38.1%

Tirofiban

n=172/451

45.1%

Placebo

n=205/455

40

50

Residual ST Deviation >3 mm 1 Hour

After Angiography/PCI


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On-TIME 2 (1-Year Outcomes) Aggrastat

Hamm C. on behalf of the On-TIME 2 investigators. Prehospital

Tiroban in ST-Elevation Myocardial Infarction: One Year Outcome

of ON-TIME-2. Presented at: American College of Cardiologys 58th

Annual Scientic Session; March 29-31, 2009; Orlando, FL.

Early administration of tiroban 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% ofthe study population), there was a signicant reduction in mortality. The

highest efcacy of tiroban 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.

conclusions

Nine hundred eighty-four patients with ST-segment elevation

myocardial infarction (STEMI) who were candidates to undergopercutaneous coronary intervention (PCI) were randomised to either

high-dose bolus tiroban or placebo in the ambulance or other

prehospital setting. An additional 414 patients received either tiroban

or no tiroban 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 afterPCI. 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 tiroban had signicantly better

ST-segment resolution 1 hour after undergoing PPCI (the primary

endpoint) compared with the group of patients who did not receive

tiroban. There was a reduction in the secondary composite clinical

endpoint at 30 days in patients treated with tiroban. The strongtrend toward mortality benet at 30 days was sustained at 1 year in

the tiroban group (double blind, 3.4% with tiroban versus 5.3%

with placebo; relative risk [RR] 0.78; 95% condence interval [CI],

0.53-1.14; P=.157; open label: 4.4% with tiroban 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 signicant reduction in

mortality with tiroban versus placebo (P=.007). The greatest efcacyof tiroban 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.

Methodsand results

Abstract and gure adapted from Hamm C. Presention at: American College of Cardiologys

58th Annual Scientic Session; March 29-31, 2009; Orlando, FL.

The On-TIME 2 trial was a double-blind, randomised, placebo-

controlled trial in 24 centres in the Netherlands, Germany, and

Belgium.

Background

10

1-Year Survival: Patients With Primary PCI

Tirofiban

Placebo85

90

95

100

Event-FreeSurvival,%

Days After Randomisation0 90 180 270 360

P=0.009

double blind, n=826


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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 tiroban in unstable angina and nonQ-wave myocardial

infarction. N Engl J Med. 1998;338(21):1488-1497.

The platelet glycoprotein IIb/IIIa receptor inhibitor tiroban

administered in combination with heparin and aspirin versus treatment

with only heparin and aspirin reduced the incidence of ischaemic

events in patients with ACS.

conclusions

The aim of this study was to investigate tiroban, a specic inhibitor ofthe platelet glycoprotein IIb/IIIa receptor, in the treatment of unstable

angina and nonQ-wave myocardial infarction (MI).

oBjectives

A total of 1915 patients were randomised in a double-blind manner

to receive tiroban, heparin, or tiroban plus heparin. Aspirin was

administered to patients if its use was not contraindicated. The studydrugs 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.

Methods

Excess mortality at 7 days in the group receiving tiroban alone (4.6%

vs 1.1% for the patients treated with heparin alone) resulted in thestudy being halted prematurely for this group. At 7 days, reduced

frequency of the composite primary endpoint was observed in patients

who received tiroban plus heparin versus those who received heparin

alone (12.9% vs 17.9%; risk ratio, 0.68; 95% condence interval,

0.53-0.88; P=.004). Reduced composite endpoint rates were noted in

the tiroban 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 orMI rate was 4.9% in the tiroban plus heparin group versus 8.3% in

the heparin only group (P=.006). The comparable gures 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. Benecial 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).

results

Abstract and gure adapted from PRISM-PLUS Study Investigators. N Engl J Med.

1998;338(21):1488-1497.

Although antithrombotic therapy improves the prognosis of patients

with acute coronary syndromes (ACS), the syndromes still remain a

therapeutic challenge.

Background

11

Kaplan-Meier curves showing the cumulative incidence of events among patients

randomly assigned to receive tirofiban plus heparin or heparin alone.

Days After Randomisation

Heparin

Tirofiban plus heparin

P=0.02

0 6030 90 120 150105 135 16515 45 75 180

0.10

0.00

ProbabilityofDeath,Myocardial

Infarction,orRefractoryIschaemia

0.30

0.40

0.20


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PRISM-PLUS (Renal) Aggrastat

Januzzi JL Jr, Snapinn SM, DiBattiste PM, et al. Benets and safety

of tiroban among acute coronary syndrome patients with mild to

moderate renal insufciency: 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.

Patients with mild to moderate impairment in renal function in

the PRISM-PLUS trial were treated safely and effectively with a

combination of tiroban and heparin to reduce their risk for adverse

ischaemic cardiovascular events.

conclusions

Participants enrolled in the PRISM-PLUS trial were stratied by

creatinine clearance (CrCl). Based on treatment assignment to

tiroban/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 astrong association between decreasing renal function and adverse

outcomes, which increased the risk for ischaemic complications at

all examined time points (P


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PRISM-PLUS (Age) Aggrastat

Januzzi JL Jr, Sabatine MS, Wan Y, et al. Interactions between age,

outcome of acute coronary syndromes, and tiroban therapy.Am J

Cardiol. 2003;91(4):457-461.

The benets of tiroban treatment were preserved across the age

groups studied, with an acceptable age-related risk for bleeding.

conclusions

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.

oBjectives

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 benecial effects of treatment with tiroban

on ischaemic endpoints were investigated. Assessment of the effect

of age and treatment assignment was based on bleeding risk,

which followed the same classication 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.

Methods

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% condence 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 tiroban resulted

in signicant 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


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PRISM-PLUS (Diabetes) Aggrastat

Throux 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.

The present study reveals that adding tiroban to heparin and aspirin

may be benecial to diabetic patients presenting with UA and NSTEMI

in the prevention of ischaemic complications, particularly MI or death.

conclusions

The objective of this study was to investigate the benet of platelet

glycoprotein IIb/IIIa receptormediated inhibition of platelet aggregation

by tiroban in diabetic patients in the Platelet Receptor Inhibition in

Ischaemic Syndrome Management in Patients Limited by Unstable

Signs and Symptoms (PRISM-PLUS) study.

oBjectives

Of the 1570 PRISM-PLUS patients treated with either tiroban plus

heparin (n=773) or heparin alone (n=797), approximately 23% in each

treatment group were diabetic. In the diabetic subgroup, treatment with

tiroban 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 signicant)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 tiroban therapy and diabetic

status were signicant.

Methodsand results

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

A substantial increase in the incidence of infarction or death is

observed in diabetic patients who initially present with unstable angina

(UA) or nonST-elevation myocardial infarction (NSTEMI) compared

with patients without diabetes.

Background

14

48 hours

7 days

30 days

180 days

Composite

MI/death

Composite

MI/death*

Composite

MI/death*

Composite

MI/death

H, %T+H, % CI

8.37.7

3.10.0

21.814.8

29.020.1

15.54.7

39.932.0

19.211.2

9.31.2

10.01.00.1

(0.45, 1.97)

(0.41, 1.10)

(0.03, 0.52)

(0.44, 1.03)

(0.13, 0.62)

(0.53, 1.06)

(0.31, 0.95)

ND

Risk Ratio (95% CI)Diabetic PatientsNon-Diabetic Patients

*Statistically significant (P


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PRISM-PLUS (Troponins) Aggrastat

Januzzi JL, Hahn SS, Chae CU, et al. Effects of tiroban plus heparin

versus heparin alone on troponin I levels in patients with acute

coronary syndromes.Am J Cardiol. 2000;86(7):713-717.

Patients with ACS treated with tiroban and heparin versus heparin

alone displayed lower serum TnI levels, implying reduced myocardialinjury.

conclusions

The goal of this study was to investigate the effects of the GPI tirobanon 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.

oBjectives

Serial blood samples of patients receiving the combination therapy

of tiroban/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 signicantly 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,

signicantly reduced mean TnI levels over the initial 24-hour period

were noted in the combination therapy group (3.2 5.0 vs 8.5 14.8ng/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 signicant compared with heparin monotherapy (peak, P=.029;

mean, P=.035). Signicantly 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 tiroban and heparin

compared with heparin monotherapy.

Methodsand results

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

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 undened.

Background

15

P=NS

CH

Baseline

P=0.017

CH

Peak

TroponinI,n

g/mL

0

5

10

15

20

25

45

P=0.016

Mean

H C

Baseline, peak, and mean Tnl levels in subjects treated with combination

therapy of tirofiban/heparin (C) versus heparin monotherapy (H).


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RESTORE Aggrastat

RESTORE Investigators. Effects of platelet glycoprotein IIb/IIIa

blockade with tiroban on adverse cardiac events in patients with

unstable angina or acute myocardial infarction undergoing coronary

angioplasty. Circulation. 1997;96(5):1445-1453.

Tiroban 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 signicant.

conclusions

The RESTORE trial (Randomised Efcacy Study of Tiroban forOutcomes and REstenosis) was a randomised, double-blind, placebo-

controlled trial of tiroban in patients undergoing coronary interventions

(balloon angioplasty or directional atherectomy) within 72 hours of

presentation with an acute coronary syndrome (ACS), dened 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 recurrentischaemia, 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 tiroban 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 tiroban 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 tiroban 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% forthe tiroban group, a relative reduction of 24% (P=.052). No signicant

differences in major bleeding, including transfusion, were seen

between the 2 groups (3.7% in the placebo group and 5.3% in the

tiroban group; P=.096). The incidence of Thrombolysis In Myocardial

Infarction major bleeding was 2.1% in the placebo group versus 2.4%

in the tiroban group (P=.662). Similar rates of thrombocytopaenia

were observed for the placebo and tiroban groups (0.9% for the

placebo group vs 1.1% for the tiroban group; P=.709).

Methodsand results

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

Following coronary angioplasty, 4% to 12.8% of patients experience

adverse cardiovascular events associated with thrombotic occlusion.

Tiroban, a GP IIb/IIIa inhibitor, inhibits ex vivo platelet aggregation in

response to a variety of agonists.

Background

16

ProportionWithCompositeEndpoint

0.00

0.03

0.06

0.09

0.12

Day

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

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.

P=0.005

(Day 2)

P=0.022

(Day 7)

P=0.160

(Day 30)

Tirofiban

Placebo


18/71


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

tiroban. N Engl J Med. 2001;344(25):1879-1887.

In patients with UA and MI without ST-segment elevation who were

treated with the GPI tiroban, an early invasive strategy resulted in a

signicant 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 issupported by these data.

conclusions

A total of 2220 patients with UA and MI without ST-segment elevationwere 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 ndings. Aspirin, heparin,

and the glycoprotein IIb/IIIa inhibitor (GPI) tiroban 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.

Methods

At 6 months, the primary endpoint rates were 15.9% in the earlyinvasive strategy group and 19.4% in the conservative strategy

group (odds ratio [OR], 0.78; 95% condence 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


19/71


TACTICS-TIMI 18 (Troponins) Aggrastat

Morrow DA, Cannon CP, Rifai N, et al. Ability of minor elevations of

troponins I and T to predict benet 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.

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 benet from an early invasive strategy.

conclusions

The aim of this study was to prospectively evaluate whether an early

invasive strategy was more benecial than a conservative strategy for

patients with acute coronary syndrome (ACS) with elevated baseline

troponin levels.

oBjectives

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.

Methods

There was a signicant decrease in the primary endpoint with the

invasive versus conservative strategy (15.3% vs 25.0%; odds ratio

[OR], 0.54; 95% condence interval [CI], 0.40-0.73), in patients with a

cTnI level of 0.1 ng/mL or higher (n=1087). No detectable benet was

observed with early invasive treatment (16.0% vs 12.4%; OR, 1.4;

95% CI, 0.89-2.05; P


20/71


TACTICS-TIMI 18 (Diabetes ) Aggrastat

Ray KK, Cannon CP, Morrow DA, et al. Synergistic relationship

between hyperglycaemia and inammation 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.

Diabetes was associated with increased inammation and higherglucose levels in patients with ACS; patients with both hyperglycaemia

and inammation had worse outcomes. To reduce cardiovascular

risk among diabetic patients, improved control of inammation and

hyperglycaemia should be analysed in future ACS trials.

conclusions

The objective of this study was to explore the relationship between

diabetes and inammation and the possibly synergistic relationship

between hyperglycaemia and inammation on clinical outcomes in

nonST-elevation acute coronary syndromes (NSTE-ACS).

oBjectives

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 inammatory 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, and190.6 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,

stratication 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 ndingswere 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 proteinand clinical outcomes was statistically signicant (P=.01) following

multivariable adjustment. TACTICS-TIMI 18 displayed a similar pattern.

Methodsand results

Abstract and gure adapted from Ray KK et al. Eur Heart J. 2007;28(7):806-813.

19

CRP

Non-DMLow CRP (Reference)

DMLow CRP

Non-DMHigh CRP

P=0.76HR=1.10CI, 0.58-2.08

P=0.28HR=1.53CI, 0.71-3.28

P=0.02HR=2.17CI, 1.12-4.18

DMHigh CRP

HR of Death or MI

0.5 1.0 2.0 3.01.5 2.5

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.


21/71


TARGET Aggrastat

Topol EJ, Moliterno DJ, Herrmann HC, et al. Comparison of two

platelet glycoprotein IIb/IIIa inhibitors, tiroban and abciximab, for

the prevention of ischaemic events with percutaneous coronary

revascularisation. N Engl J Med. 2001;344(25):1888-1894.

The trial was intended to evaluate the noninferiority of tiroban versus

abciximab. However, the results demonstrate that tiroban offered

reduced protection from major ischaemic events compared with

abciximab.

conclusions

The objective of this study was to evaluate whether there aredifferences in safety or efcacy between 2 such inhibitors, tiroban and

abciximab.

oBjectives

This trial used a double-blind, double-dummy design at 149 hospitals

in 18 countries to randomise patients to receive either tiroban 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 tiroban compared with abciximab.

Methods

The occurrence of the primary endpoint was more frequent among the

2398 patients in the tiroban group than among the 2411 patients inthe abciximab group (7.6% vs 6.0%; hazard ratio [HR]: 1.26; 1-sided

95% condence interval [CI], 1.51, demonstrating lack of equivalence;

2-sided 95% CI, 1.01-1.57, demonstrating the superiority of abciximab

over tiroban; 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 signicant

difference was observed in the incidence of MI between the tiroban

group and the abciximab group (6.9% and 5.4%, respectively; P=.04).

The relative benet 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 signicant

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 tiroban.

results

Abstract and gure adapted from Topol EJ et al. N Engl J Med. 2001;344(25):1888-1894.

Platelet glycoprotein IIb/IIIa inhibitors have caused a signicant

reduction in the incidence of death or nonfatal myocardial

infarction (MI) at 30 days in the setting of percutaneous coronary

revascularisation.

Background

20

Tirofiban (N=2398)

Abciximab (N=2411)P=0.038

Days

Patients,%

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).

0 10 20 30

8

0

6

4

2

7

5

3

1


22/71


TENACITY Aggrastat

Moliterno DJ, Topol E, Califf R, et al. Tiroban Evaluation ofNovel

Dosing vs Abciximab with Clopidogrel and Inhibition ofThrombin

Study. Presented at: Transcatheter Cardiovascular Therapeutics (TCT)

annual meeting; October 16-21, 2005; Washington, DC.

The TENACITY study successfully enrolled a cohort at higher risk fordeath, MI, and uTVR (7.8% event rate). A very small percentage of

patients (3.2%) required tiroban infusion beyond 12 hours. The low

rate of death, MI, uTVR, and major bleeding with the tiroban plus

bivalirudin combination is provocative and warrants further study.

conclusions

Patients were randomised to either tiroban 25 g/kg bolus and

0.15 g/kg/min 12-hour infusion or abciximab 0.25 mg/kg bolusand 0.125 g/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 vesselrevascularisation (uTVR). The study was stopped early solely for

nancial reasons after 189 patients receiving tiroban and 194 patients

receiving abciximab had completed randomisation and treatment.

For the primary endpoint, the 30-day event rates were 6.9% for

tiroban and 8.8% for abciximab (odds ratio, 0.77; 95% condence

interval, 0.37-1.64). MajorTIMI bleeding was 0.5% for both tiroban

and abciximab; minor bleeding was 1.1% and 1.5% for tiroban andabciximab, respectively. For the combined endpoint of death, MI,

uTVR, and major bleeding, event rates were lower for the tiroban

plus bivalirudin combination (5.6%) than for the tiroban plus heparin

(10.1%), abciximab plus bivalirudin (10.5%), and abciximab plus

heparin (9.1%) combinations.

Methodsand results

Abstract and gure developed from Moliterno DJ et al. Presentation at: Transcatheter

Cardiovascular Therapeutics (TCT) annual meeting; October 16-21, 2005; Washington, DC.

TENACITY is a multicentre, double-blind, randomised comparison of

tiroban 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 efcacy of a single high-dose bolus regimen of

tiroban 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

efcacy of bivalirudin versus heparin among patients receiving tiroban

or abciximab.

Background

21

10%

8%

6%

4%

2%

0

30-Day Clinical Outcome

Abciximab (n=194) Tirofiban (n=189)

OR=0.77

(0.37, 1.64)OR=0.74

(0.33, 1.66)

OR=0.20

(0.01, 4.28)

OR=0.69

(0.31, 1.53)

OR=3.13

(0.32, 30.36)

8.8

6.9

5.9

7.78.2

5.9

1.0 0

1.60.5

Death/MI Urgent TVRDeathComposite MI


23/71


3T/2R Aggrastat

Valgimigli M, Campo G, de Cesare N, et al. Intensifying platelet

inhibition with tiroban in poor responders to aspirin, clopidogrel, or

both agents undergoing elective coronary intervention: results from

the double-blind, prospective, randomised Tailoring Treatment with

Tiroban in Patients Showing Resistance to Aspirin and/or Resistanceto Clopidogrel study. Circulation. 2009;119(25):3215-3222.

Intensied platelet inhibition with tiroban 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.

conclusions

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 unstablecoronary 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 tiroban

(n=132) or placebo (n=131). The primary endpoint was dened 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 tiroban group versus

35.1% of the patients (n=46) in the placebo group (relative risk, 0.58;

95% condence interval, 0.39-0.88; P=.009). The tiroban 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 lowlikely explained

by a substantial use of the transradial approachand similar between

the 2 groups.

Methodsand results

Abstract and gure adapted from Valgimigli M et al. Circulation. 2009;119(25):3215-3222.

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 reects suboptimal

platelet inhibition that may therefore benet from more potent

antiplatelet agents such as tiroban.

Background

22

PlaceboTirofiban

RR, 0.58; 95% CI, 0.39-0.88;P=0.009

PatientsWithTro

poninI/T>3xElevation,%

0

10

20

30

40

Rates of periprocedural MI according to the primary

endpoint definition. RR indicates relative risk.


24/71


ASSIST Integrilin

Le May MR on behalf of ASSIST trial investigators. A Safety and

Efcacy Study of Integrilin Facilitated PCI versus Primary PCI in

ST Elevation Myocardial Infarction. Presented at: Transcatheter

Cardiovascular Therapeutics 20th Annual Scientic Symposium;

October 12-17, 2008; Washington DC.

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

eptibatide yields similar results to abciximab. Evaluation of clinical

outcomes by a direct comparison of eptibatide to a control group has

not yet been examined. Also, there are a limited number of studiesutilising a high loading dose of clopidogrel in PPCI.

In patients with acute STEMI pretreated with high-dose clopidogrel,

PCI with eptibatide (versus PCI with heparin alone) initiated before

catheterisation did not provide clinical benet and resulted in increased

bleeding.

Background

conclusions

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 eptibatide; 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.

Methods

No differences were observed in the clinical and proceduralcharacteristics, including door-to-balloon time and procedural success

between the 2 groups. Eptibatide plus heparin compared with heparin

alone provided no benet 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 benet of eptibatide 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 MyocardialInfarction major or minor bleeding in the eptibatide plus heparin group

versus the heparin alone group (22.4% vs 14.6%; P=.04).

results

23

Abstract and gure adapted from Le May MR on behalf of ASSIST trial investigators.

Presentation at: Transcatheter Cardiovascular Therapeutics 20th Annual Scientic

Symposium; October 12-17, 2008; Washington DC.

Heparin plus eptifibatide

Heparin

PatientsWithPrimary

Endpoint,%

Days

Log-rankP=0.70

0

2

4

6

8

0 6 12 18 24 30

6.5%

5.5%

Kaplan-Meier estimates, 30 days.


25/71


BRIEF-PCI Integrilin

Fung AY, Saw J, Starovoytov A, et al. Abbreviated infusion of

eptibatide after successful coronary intervention The BRIEF-PCI

(Brief Infusion of Eptibatide Following Percutaneous Coronary

Intervention) randomised trial. J Am Coll Cardiol. 2009;53(10):837-845.

The recommended regimen for eptibatide 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.

This study revealed that eptibatide infusion can be safely shortenedto 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.

Background

conclusions

The objective of this study was to evaluate whether the earlydiscontinuation of eptibatide infusion in nonemergent PCI was

associated with a higher frequency of periprocedural ischaemic

myonecrosis.

oBjectives

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

eptibatide 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 dened as

troponin-I elevation greater than 0.26 g/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 toReduced Clinical Events) trial criteria were the secondary endpoints.

Methods

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% condence interval, 7.8%; P


26/71


CLEAR PLATELETS Integrilin

Gurbel PA, Bliden KP, Zaman KA, et al. Clopidogrel loading with

eptibatide to arrest the reactivity of platelets: results of the Clopidogrel

Loading With Eptibatide to Arrest the Reactivity of Platelets (CLEAR

PLATELETS) study. Circulation. 2005;111(9):1153-1159.

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 eptibatide

in comparison with these regimens is unclear.

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 conrm these results.

Background

conclusions

One hundred twenty patients undergoing elective stenting were

enrolled in a 2-by-2 factorial study of clopidogrel 300 mg with or

without eptibatide, or clopidogrel 600 mg with or without eptibatide.

(Clopidogrel Loading With Eptibatide to Arrest the Reactivity of

Platelets [CLEAR PLATELETS] study.) Immediately after stenting,

patients were administered clopidogrel. Platelet reactivity was

evaluated using aggregometry and ow cytometry. A 2-fold or higherincrease in platelet inhibition was observed with the addition of

eptibatide to clopidogrel 600 mg alone at 3, 8, and 18 to 24 hours

after stenting based on the measurement by 5 mol/L adenosine

diphosphateinduced aggregation (P


27/71


CLEAR PLATELETS-2 Integrilin

Gurbel PA, Bliden KP, Saucedo JF, et al. Bivalirudin and clopidogrel

with and without eptibatide for elective stenting: effects on

platelet function, thrombelastographic indexes, and their relation

to periprocedural infarction results of the CLEAR PLATELETS-2

(Clopidogrel with Eptibatide to Arrest the Reactivity of Platelets) study.J Am Coll Cardiol. 2009;53(8):648-657.

Bivalirudin is commonly administered alone to clopidogrel-nave

patients and to patients on clopidogrel maintenance therapy (MT)

undergoing elective stenting. It is not known how the addition of

eptibatide to bivalirudin affects platelet reactivity (PR) and thrombin-

induced platelet-brin 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 eptibatide

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 theoccurrence of periprocedural infarction.

The addition of eptibatide to bivalirudin in elective stenting reduced

PR to multiple agonists and the tensile strength of the TIP-FCSbothof 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.

Background

conclusions

Patients (n=200) stratied to clopidogrel treatment status were

randomised to receive bivalirudin (n=102) or bivalirudin plus

eptibatide (n=98). Immediately after stenting, 128 clopidogrel-nave

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

eptibatide resulted in markedly reduced PR at all times (5- and 20-

M adenosine diphosphateinduced, and 15- and 25-M thrombin

receptor activator peptideinduced aggregation; P


28/71


EARLY ACS Integrilin

Giugliano RP, White JA, Bode C, et al. Early versus delayed,

provisional eptibatide in acute coronary syndromes.N Engl J Med.

2009;360(21):2176-2190.

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.

For patients who had ACS without ST-segment elevation, eptibatideadministration 12 hours or more before angiography was not superior

to the provisional administration of eptibatide after angiography.

Increased risk of nonlife-threatening bleeding and need for

transfusion were noted with the early use of eptibatide.

Background

conclusions

EARLY ACS was a comparative study of early, routine administration

of eptibatide versus delayed, provisional administration in 9492patients who were assigned to an invasive strategy for the treatment

of ACS without ST-segment elevation. Patients were randomised to

receive either early eptibatide (2 boluses, each containing 180 g/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 eptibatide after angiography (delayed

eptibatide). The primary efcacy 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 rst 30 days constituted the key secondary

endpoint. Bleeding and the need for transfusion within the rst 120

hours after randomisation were the key safety endpoints.

Methods

Of the patients in the early eptibatide group, 9.3% attained the

primary endpoint. Ten percent of the patients in the delayed-

eptibatide group attained the primary endpoint (odds ratio [OR], 0.92;

95% condence interval [CI], 0.80-1.06; P=.23) At 30 days, 11.2% of

the patients in the early eptibatide group, as compared with 12.3% of

the patients in the delayed-eptibatide group (OR, 0.89; 95% CI, 0.79

to 1.01; P=.08) had incidence of death or MI. Signicantly higher rates

of bleeding and red-cell transfusion were noted in patients in the early-

eptibatide group. The rates of severe bleeding and nonhemorrhaegic

serious adverse events were not signicantly different between the

2 groups.

results

27

Abstract and gure adapted from Giugliano RP et al. N Engl J Med. 2009;360(21):2176-2190.

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.

Primary and Secondary Endpoints

Delayed-Eptifibatide Group

(n=4722)

Early-Eptifibatide Group

(n=4684)

Primary

Endpointat 96 Hours

Secondary

Endpointat 30 Days

Death/MI

at 96 Hours

Patients,%

14.0

12.0

10.0

8.0

6.0

4.0

2.0

0.0

P=NS10.0P=NS

8.3

12.3 P=NS

11.2

9.3

7.5


29/71


ESPIRIT Integrilin

ESPRIT Investigators. Novel dosing regimen of eptibatide in planned

coronary stent implantation (ESPRIT): a randomised, placebo-

controlled trial. Lancet. 2000;356(9247):2037-2044.

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 eptibatide.

There was a substantial reduction of ischaemic complications in

coronary stent intervention with routine GPI pretreatment with

eptibatide, which was found to be better than reserving treatment to

the bailout situation.

Background

conclusions

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 eptibatide (given as two

180 g/kg boluses 10 minutes apart) and a continuous infusion of

2 g/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.

Methods

The trial was terminated early for efcacy. There was a reduction in

the rate of the primary endpoint from 10.5% with placebo (108 of 1024patients; 95% condence interval [CI], 8.7%-12.4%) to 6.6% with

eptibatide (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

eptibatide (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

eptibatide 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).

results

28

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

Eptifibatide

Days From Randomisation

CumulativeEventRate,

%

RR=0.65%

P=0.0030

100 20 25155 30

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.

8

12

0

4

Placebo

10.5%

6.8%

100


30/71


ESPIRIT (Diabetes) Integrilin

Labinaz M, Madan M, OShea 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.

Glycoprotein IIb/IIIa receptor blockade with eptibatide lowers the

incidence of ischaemic complications in patients undergoing non-

urgent coronary stent implantation. The interaction of eptibatide 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.

Treatment with eptibatide 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 eptibatide between

patients with and without diabetes.

Background

conclusions

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) comparedwith nondiabetic patients (24.5% vs 18.4%; P=.008). Treatment with

eptibatide had a similar effect on the 1-year composite endpoint of

death, MI, or TVR in diabetic patients (hazard ratio [HR]: 0.71; 95%

condence 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

eptibatide (HR: 0.37; 95% CI, 0.10-1.41); this latter rate was similar tothe mortality rate of 1.4% observed in nondiabetic patients treated with

eptibatide. However, treatment with eptibatide in diabetic patients

had no signicant effect on TVR (HR: 0.90; 95% CI, 0.57-1.41).

Methodsand results

29

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

Clinical Outcomes of Diabetic Patients and Nondiabetic Patients Assigned to Epifibatide or Placebo

DiabeticsNondiabetics

Eptifibatide, %Eptifibatide, % Placebo, %Placebo, %PValuea(n=232)(n=234)(n=807)(n=788)Time/Clinical Event

48 hours

30 days

6 months

1 year

aThe Pvalue is for the interaction of treatment with diabetes.

Death 0 01 (0.1)2 (0.3) 0.998

Death/MI/urgent TVR 13 (5.6)22 (9.4)58 (7.2)84 (10.7) 0.755Death/MI 13 (5.6)21 (9.0)53 (6.6)82 (10.4) 0.990Death 1 (0.4)2 (0.9)3 (0.4)4 (0.5) 0.795

Death/MI/TVR 42 (18.6)53 (23.2)104 (13.1)133 (17.1) 0.866Death/MI 16 (6.9)29 (12.5)61 (7.6)87 (11.1) 0.568

Death 2 (0.9)6 (2.6)6 (0.7)8 (1.0) 0.420TVR 31 (13.8)29 (13.0)57 (7.3)67 (8.7) 0.405

Death/MI/TVR 47 (20.8)64 (28.2)131 (16.6)157 (20.2) 0.639Death/MI 18 (7.8)31 (13.4)65 (8.1)94 (12.0) 0.679Death 3 (1.3)8 (3.5)11 (1.4)12 (1.5) 0.270

TVR 36 (16.1)40 (18.1)81 (10.4)89 (11.6) 0.954

Death/MI 9 (3.9)18 (7.7)48 (6.0)75 (9.5) 0.639Death/MI/urgent TVR 9 (3.9)18 (7.7)53 (6.6)76 (9.6) 0.503Death/MI/urgent TVR/thrombotic bailout 11 (4.7)20 (8.6)58 (7.2)87 (11.0) 0.710


31/71


ESPRIT (High Risk) Integrilin

Puma JA, Banko LT, Pieper KS, et al. Clinical characteristics predict

benets from eptibatide 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.

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 eptibatide or

placebo in the Enhanced Suppression of the Platelet IIb/IIIa Receptor

With Integrilin Therapy (ESPRIT) trial.

Treatment with eptibatide improved outcomes for all patients.

However, a subgroup of patients who may derive the greatest benet

from its use during coronary stent placement can be dened by

preprocedural clinical characteristics.

Background

conclusions

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 benet from

treatment.

oBjectives

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 dened as high-risk characteristics, whereas,

age less than 75 years, absence of diabetes, and any other reason for

admission were dened as low-risk characteristics.

Methods

The high-risk group had 1,018 patients (50.8% eptibatide, 49.2%

placebo), while the low-risk group had 1,045 patients (50.0%

eptibatide, 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 groupcompared with the low-risk group. A total of 15.89% of the patients

receiving placebo and 7.99% of the patients receiving eptibatide in

the high-risk group, as well as 9.02% of the patients receiving placebo

and 8.11% of the patients receiving eptibatide in the low-risk group

attained the 1-year composite endpoint of death or MI.

results

30

Abstract and gure adapted from Puma JA et al. J Am Coll Cardiol. 2006;47(4):715-718.

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

Death or MI, 95% CI

30 Days12 Months

High risk (eptifibatide) 6.19% (4.11-8.27)7.99% (5.64-10.34)

High risk (placebo) 12.38% (9.49-15.26)15.89% (12.67-19.10)

Low risk (eptifibatide) 6.51% (4.40-8.63)8.11% (5.76-10.46)

Low risk (placebo) 8.03% (5.70-10.36)9.02% (6.56-11.48)


32/71


EVA-AMI Integrilin

Zeymer U on behalf of the EVA-AMI Investigators. Eptibatide versus

Abciximab in primary PCI for acute ST elevation myocardial infarction.

EVA-AMI Trial. Presented at: 2007 Scientic Sessions of the American

Heart Association; November 3-7 2007; Orlando, FL.

Eptibatide 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 eptibatide

compared with abciximab as adjunctive treatment for patients

undergoing PPCI.

Eptibatide double bolus was equally effective as abciximab asadjunctive treatment to PPCI with respect to myocardial reperfusion.

There were no differences in preliminary clinical events between

the 2 agents. Therefore, eptibatide seems to be an alternative to

abciximab for patients with STEMI undergoing PPCI.

Background

conclusions

EVA-AMI was an international, multicentre, randomised, open,

parallel-group, comparative study of eptibatide 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 PPCIwere enrolled in the study. The patients were randomised to receive

either eptibatidegiven as 2 bolusesand 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. Eptibatide

was noninferior for the primary endpoint (59.6% in the abciximabgroup vs 63.1% in the eptibatide group; P=not signicant). In fact,

the proportion of patients with no ST resolution after 60 minutes was

statistically lower in the eptibatide arm (5.4% in abciximab group vs

14.7% in eptibatide group; P=.021). There were no differences in

in-hospital events between the abciximab group and the eptibatide

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.

Methodsand results

31

Abstract and gure adapted from Zeymer U on behalf of the EVA-AMI Investigators. Presented

at: 2007 Scientic Sessions of the American Heart Association; November 3-7 2007;

Orlando, FL.

Sum ST-Resolution 60 Minutes After

PCI Intention-to-Treat Analysis

Eptifibatide, % Abciximab, % PValue

Single leadcomplete

No

Partial

Complete

(n=200)(n=225)

47.5

24.5

28.0

41.046.2

NS

NS

NS

NS

50.2

22.2

27.6


33/71


PROTECTTIMI-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 inammation

among antiplatelet and antithrombotic agents: the PROTECTTIMI-30

trial. J Am Coll Cardiol. 2006;47(12):2364-2373.

There is no certainty about the optimal combination of an antiplatelet

and antithrombin regimen to maximise efcacy and minimise

bleeding among patients with nonST-segment elevation acute

coronary syndrome (NSTE-ACS) undergoing percutaneous coronary

intervention (PCI).

Among moderate- to high-risk patients with ACS undergoing PCI,

greater CFR was observed with bivalirudin versus eptibatide.

Although eptibatide 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, inammation, and

thrombin generation.

Background

conclusions

The objective of this study was to assess glycoprotein IIb/IIIa inhibition

with eptibatide when administered with indirect thrombin inhibition

versus direct thrombin inhibition with bivalirudin monotherapy for

patients with NSTE-ACS.

oBjectives

Eight hundred fty-seven patients with NSTE-ACS were randomised to

receive eptibatide plus reduced-dose unfractionated heparin (n=298),eptibatide plus reduced-dose enoxaparin (n=275), or bivalirudin

monotherapy (n=284).

Methods

Among angiographically evaluable patients (n=754), signicantly

greater post-PCI coronary ow reserve ([CFR] the primary endpoint)

was noted with bivalirudin (1.43 vs 1.33 for pooled eptibatide arms;

P=.036). Eptibatide treatment versus bivalirudin resulted in morefrequent normal rates of Thrombolysis In Myocardial Infarction (TIMI)

myocardial perfusion grade (57.9% vs 50.9%; P=.048). Signicantly

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 eptibatide compared with bivalirudin

(0.7%, n=4 vs 0%; P=not signicant), 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


34/71


PURSUIT Integrilin

PURSUIT Trial Investigators. Inhibition of platelet glycoprotein IIb/IIIa

with eptibatide in patients with acute coronary syndromes. N Engl J

Med. 1998;339(7):436-443.

The pathophysiologic basis of acute coronary syndromes (ACS) is theaggregation of platelets. Eptibatide, a synthetic cyclic heptapeptide

and a selective high-afnity inhibitor of the platelet glycoprotein IIb/IIIa

receptor, is involved in platelet aggregation.

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

eptibatide.

Background

conclusions

The objective of this study was to assess glycoprotein IIb/IIIa inhibition

with eptibatide when administered with indirect thrombin inhibition

versus direct thrombin inhibition with bivalirudin monotherapy forpatients with NSTE-ACS.

oBjectives

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 kinasemyocardial band isoenzymes. They were randomisedin a double-blind manner to receive a bolus and infusion of either

eptibatide 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.

Methods

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 eptibatide group compared with the

placebo group (14.2% vs 15.7% in the placebo group; P=.04). This

benet, 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% condence interval [CI], [0.7-0.9]. For women: ORs for death or

nonfatal MI, 1.1; 95% CI, 0.9 to 1.3). The eptibatide group reported

more common incidence of bleeding; however, there was no increase

in the incidence of hemorrhaegic stroke.

results

33

Abstract and gure adapted from PURSUIT Trial Investigators. N Engl J Med.

1998;339(7):436-443.

EptifibatideCumulativeIncidence,%

15.7%

14.2%

Placebo

P=0.03 by the log-rank test

20

20 30

10

105 15 25

0

0

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.



35/71


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.

A platelet glycoprotein IIb/IIIa inhibitor may provide additional clinical

benet 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.

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.

Background

conclusions

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.

Methods

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 gures 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 ow

(according to the classication of the Thrombolysis in MyocardialInfarction 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.

results

34

Abstract and gure adapted from Montalescot G et al. N Engl J Med. 2001;344(25):1895-1903.


C

umulativeIncidenceof

PrimaryEndpoint,%

0 10 15 20 25 35305

0 50 15075 100 200125 17525

Stent plus placeboStent plus abciximab

30 Days

6 Months

Kaplan-Meier curves showing the cumulative incidence

of the primary endpoint at 30 days and at 6 months.

0

10

15

20

5

0

10

15

20

5

14.6

6.0

15.9

7.4


36/71


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 clopi

gp iib-iiia inhibitors

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