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140 Part II / GPIIb/IIIa Blockade During Coronary Intervention
patients had one or more stents placed. Almost all subjects (97.7%) received a thienopy-
ridine, mainly clopidogrel.
Early study drug discontinuation occurred at approximately the same rate in both treat-
ment groups. Study drug was discontinued before 12 h in 9.3% (192) and before 16 h in
11.7% (242) of the patients. A total of 35 patients in the eptifibatide group and 43 patients
in the placebo group crossed over to open-label eptifibatide therapy.
There was a 37% reduction in the primary composite clinical endpoint of death, myo-
cardial infarction, urgent target vessel revascularization, or crossover bailout therapy for
thrombotic complications at 48 h. These events occurred in 108 of the 1024 placebo-
treated patients and in 69 of the 1040 eptifibatide-treated patients (p = 0.0015). Other
event rates for individual components and combinations of components of the endpoint
are shown in Fig. 9. All components and combinations of components of the primary end-
point had the same directionality and approximate relative risk reduction as the primary
composite endpoint.
Subgroup analysis, depicted in Fig. 10, demonstrated benefit irrespective of baseline
characteristics including age, weight, sex, diabetes, and disease presentation. Interestingly,
the degree of heparin anticoagulation, as measured by the ACT, did not predict events
in any of the treatment groups. In the placebo group, the frequency of the primary com-
posite endpoint was closely similar among patients when they were divided into tertiles
of maximum ACT (10.0%, 95% CI 6.9–13.2, in the lowest tertile; 11.5%, 95% CI 8.1–
14.8, in the middle tertile; and 10.3%, 95% CI 6.8–13.7, in the highest tertile). The benefit
of treatment with eptifibatide was also similar across the tertiles of ACT, with the lowest
overall event rate of the primary composite endpoint occurring in patients receiving epti-
fibatide who were in the lowest tertile. This suggests that, in contradistinction to conven-
tional wisdom, increasing degrees of anticoagulation with heparin do not further reduce
adverse clinical event rates in coronary stent PCI.
Table 5
Treatment Indices
Eptifibatide Placebo Total
Characteristic (n = 1040) (n = 1024) (n = 2064)
Median infusion duration (h) 18.3 (18.0–20.1) 18.4 (18.0–20.2) 18.4 (18.0–20.2)
(25–75 quartiles)
PCI done 1025 (99) 1015 (99) 2040 (99)
Number of stents placed
Total 986 (95) 997 (97) 1983 (96)
1 676 (65) 650 (64) 1326 (64)
2 234 (23) 242 (24) 476 (23)
3 54 (5) 90 (9) 144 (7)
≥4 22 (2) 15 (2) 37 (2)
Femoral arteriotomy closure device 189 (18) 167 (16) 356 (17)
Median max ACT (s) 273 (234–316) 263 (230–302) 268 (232–309)
(25–75 quartiles)
Thienopyridine use 1009 (97) 1006 (98) 2015 (98)
Abbreviations: PCI, percutaneous coronary intervention; Max ACT, maximum procedural activated
clotting time.
a
Data are numbers, with percent in parentheses, except for rows 1 and 9.
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Chapter 6 / Eptifibatide in Coronary Interventions 141
Fig. 9. Risk ratios (95% CI) for major endpoint components at 48 h—the ESPRIT trial. RRR =
relative risk ratio; UTVR = urgent target vessel revascularization; MI = myocardial infarction; large
MI = CK-MB more than five times upper limit of normal. (From ref. 27, with permission from
Elsevier Science.)
Fig. 10. Subgroup analysis of the primary endpoint including risk ratios (95% CI)—the ESPRIT
trial. ACT = activated clotting time; CAD = coronary artery disease; ACS = acute coronary syndrome;
RRR = relative risk ratio. The weight tertiles for men were <81 kg, 81–95 kg, and >95 kg, and for women
<68 kg, 68–82 kg, and >82 kg. (From ref. 27, with permission from Elsevier Science.)
The initial benefit found at 48 h was sustained to 30 d (Fig. 11) and at 1 yr (Fig. 12), as
shown by the Kaplan-Meier curves. There was a 35% relative risk reduction in the second-
ary composite endpoint of death, myocardial infarction, and urgent target vessel revas-
cularization at 30 d (10.5% vs 6.8%, p = 0.0034).The majority of events occurred in the
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142 Part II / GPIIb/IIIa Blockade During Coronary Intervention
Fig. 11. Cumulative incidence of composite endpoints at 30 d with eptifibatide vs placebo treatment—
the ESPRIT trial. (A) Composite endpoint of death, myocardial infarction, and urgent TVR. (B) Compos-
ite endpoint of death and myocardial infarction. TVR = target vessel revascularization; RRR = relative
risk ratio. (From ref. 27, with permission from Elsevier Science.)
first 48 h. Benefits were sustained over time. The absolute difference between the com-
posite of death, myocardial infarction, and all target vessel revascularization was actu-
ally larger at 1 yr than at 30 d (3.7% absolute risk reduction at 30 d, 4.6% absolute risk
reduction at 1 yr) Although there was a trend favoring mortality reduction, most of the
benefit was owing to a reduced rate of myocardial infarction. After 1 yr of follow-up, 20
deaths (2%) occurred in the placebo group compared with 14 deaths (1.4%) with eptifiba-
tide [hazard ratio (HR) 0.69; 95% CI, 0.35–1.36; p = 0.28). Over the same period, the
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Chapter 6 / Eptifibatide in Coronary Interventions 143
combined endpoint of death and myocardial infarction was reduced from 12.4 to 8.0 with
the use of eptifibatide (HR, 0.63; 95% CI, 0.48–0.83; p = 0.001; Fig. 12). There was no
evidence of an increase in event rate (or rebound) at the time of discontinuation of treatment.
Rates of severe and moderate bleeding as assessed by the site investigator did not differ
between groups. However, when measured by the quantitative TIMI bleeding criteria, an
increase in bleeding rates with eptifibatide treatment was found. When TIMI bleeding
was analyzed by tertiles of the ACT, rates were not increased in the lowest tertile: 0.6%
Fig. 12. Cumulative incidence of composite endpoints at 1 yr with eptifibatide vs placebo treatment
—the ESPRIT trial. (A) Composite endpoint of death and myocardial infarction. Hazard ratio, 0.63;
95% confidence interval, 0.48–0.83; p = 0.001. (B) Composite endpoint of death, myocardial infarc-
tion and urgent TVR. Hazard ratio, 0.76; 95% confidence interval, 0.63–0.93; p = 0.007. (From ref. 28.)
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144 Part II / GPIIb/IIIa Blockade During Coronary Intervention
vs 0.7% for placebo and eptifibatide, respectively. Rates of bleeding increased as the
ACT rose, with bleeding being enhanced by treatment with eptifibatide. There were two
cases of acute profound thrombocytopenia in the eptifibatide treatment group (a decrease
in the platelet count to <20 × 10
9
/L within 24 h of start of treatment). No platelet trans-
fusion was necessary as the platelet count rapidly resolved (within hours) after drug
discontinuation. No clinical sequelae were reported. Finally, red blood cell transfusion
was uncommon (Table 6).
In summary, the ESPRIT trial answered most of the unresolved questions from IMPACT-
II. First, whereas IMPACT-II studied patients undergoing balloon angioplasty, the ESPRIT
trial proved the benefit of eptifibatide as an adjunct to elective stent implantation in pro-
ducing significant and clinically relevant reductions in ischemic complications of this pro-
cedure. These benefits were achieved despite exclusion of the highest risk patients, the
group expected to experience the greatest improvements. Moreover, these results were
obtained in the context of high-pressure stent deployment strategies coupled with thieno-
pyridine therapy. Treatment effects were not only robust but were maintained to 1 year
and were consistent among all patient subgroups.
Second, the clinical efficacy seen in ESPRIT further solidified the coupling of the degree
of platelet GPIIb/IIIa receptor inhibition with clinical efficacy. Pharmacodynamic studies
had shown that the eptifibatide dose tested in ESPRIT achieved and maintained blockade
of >90% of available GPIIb/IIIa receptors in >90% of patients, corresponding to >90%
inhibition of ex vivo platelet aggregation after stimulation by 20 µM ADP in blood suspended
in PPACK as the anticoagulant. This was a substantially greater degree of inhibition of
platelet aggregation than the 50–60% inhibition achieved in IMPACT-II, and the treatment
effect was on a par with that seen in the PCI trials of abciximab. For example, in the Evalu-
ation of IIb/IIIa Platelet Inhibition for Stenting (EPISTENT) trial, the subgroup of patients
Table 6
Stroke and Bleeding Complications
a
Eptifibatide Placebo Total
Characteristic (n = 1040) (n = 1024) (n = 2064)
Intracranial bleeding 2 (0.2) 1 (0.1) 3 (0.1)
Nonhemorrhagic stroke 1 (0.1) 0 1 (<0.1)
Severe bleeding 7 (0.7) 5 (0.5) 12 (0.6)
Moderate bleeding 14 (1) 11 (1) 25 (1)
Major bleeding (TIMI)
Overall* 13 (1) 4 (0.4) 17 (1)
ACT < 244 (n = 661) 2/312 (0.6) 2/349 (0.6) 4/661 (0.6)
ACT 244–292 (n = 678) 6/330 (1.8) 1/348 (0.3) 7/678 (1.0)
ACT > 292 (n = 676) 5/374 (1.3) 1/302 (0.3) 6/676 (0.9)
Minor bleeding (TIMI) 29 (2.8) 18 (1.7) 47 (2.3)
Platelet count < 20,000 2 (0.2) 0 2 (0.1)
RBC transfusion
b
15 (1) 10 (1) 25 (1)
Abbreviations: RBC, red blood cell; ACT, activated clotting time; TIMI, bleeding classified by TIMI grade
as determined by site investigator.
a
Data are numbers, with percent in parentheses.
b
Includes CABG-related transfusions of red blood cells.
*p = 0.027.
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Chapter 6 / Eptifibatide in Coronary Interventions 145
pretreated with ticlopidine experienced an absolute reduction of the composite endpoint
of death, myocardial infarction, and urgent revascularization at 30 d of 3.7% (from 8.9
to 5.2%) with the use of abxicimab compared with placebo (29). This compares favorably
with the 3.7% absolute reduction (from 10.5 to 6.8%) for the same endpoint in ESPRIT.
Third, analysis of the bleeding complications and clinical outcomes according to the
degree of heparin anticoagulation confirmed the findings first observed in the abxicimab
trials that lower doses of heparin (targeting an ACT of 200–250 s) are probably optimal
in PCI when adjunctive GPIIb/IIIa blockade is used. In ESPRIT, patients receiving eptifi-
batide who were in the lowest tertile of heparin anticoagulation had both the lowest rate
of the primary composite endpoint and the lowest rate of bleeding complications. Similarly,
rates of severe and moderate bleeding per the quantitative TIMI bleeding criteria also did
not differ from the rates found in patients randomized to placebo in the lowest tertile.
Finally, the low rate of occurrence of thrombocytopenia (0.2%), although still trouble-
some, compares favorably with the incidence of 0.7% reported with abxicimab (30).
In conclusion, in a population of patients undergoing elective stent implantation, treat-
ment with the 180/2.0/180 double-bolus regimen of eptifibatide lowers the risk of death,
myocardial infarction, and target vessel revascularization. The clinical efficacy is consis-
tent and robust across components of the endpoint and across patient subgroups, is durable
and long-lasting, and is typical of that seen in other trials of platelet glycoprotein inhibi-
tion. When combined with lower degrees of anticoagulation with heparin, these benefits
are achieved without increasing the risk of bleeding. In light of these results, all patients
(without contraindication for GPIIb/IIIa inhibitors) should be considered for treatment
when undergoing percutaneous coronary intervention.
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blockade with percutaneous coronary intervention. JAMA 1997;
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6. The EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low dose heparin during
percutaneous coronary revascularisation. N Engl J Med 1997;336:1689–1696.
7. Lincoff AM, Tcheng JE, Califf RM, et al. Standard versus low dose weight adjusted heparin in patients
treated with the platelet glycoprotein IIb/IIIa receptor antibody fragment abciximab (c7E3 Fab) during
percutaneous coronary revascularisation. The PROLOG investigators. Am J Cardiol 1997;79:286–291.
8. The CAPTURE Investigators. Randomized placebo controlled trial of abciximab before and during coro-
nary intervention in refractory unstable angina: the CAPTURE study. Lancet 1997;349:1429–1435.
9. Lefkovits J, Plow EF, Topol EJ. Platelet glycoprotein IIb/IIIa receptors in cardiovascular medicine.
N Engl J Med 1995;332:1553–1559.
10. Phillips DR, Charo IF, Parise LV, Fitzgerald LA. The platelet membrane glycoprotein IIb/IIIa complex.
Blood 1988;71:831–843.
11. Pytela R, Pierschbacher MD, Ginsberg MH, Plow EF, Ruoslahti E. Platelet membrane glycoprotein IIb/
IIIa: a member of a family of Arg-Gly-Asp-specific adhesion receptors. Science 1986;231:1559–1562.
12. Mustard JF, Kinlough-Rathbone RL, Packham MA. Comparison of fibrinogen association with normal
and thrombasthenic platelets on exposure to ADP or chymotrypsin. Blood 1979;54:987–993.
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13. Dennis MS, Henzel WJ, Pitti RM, et al. Platelet glycoprotein IIb/IIIa protein antagonists from snake
venoms: evidence for a family of platelet aggregation inhibitors. (ArgGlyAsp/fibrinogen receptor/
trigramin/echistatin/kistrin). Proc Natl Acad Sci USA 1989;87:2471–2475.
14. Scarborough RM, Naughton MA, Teng W. Design of potent and specific integrin antagonists with high
specificity for glycoprotein IIb/IIIa. J Biol Chem 1993;268:1066–1073.
15. Charo IF, Scarborough RM, Du Mee CP, et al. Therapeutics I: pharmacodynamics of the glycoprotein
IIb/IIIa antagonist integrelin: phase 1 clinical studies in normal healthy volunteers. Circulation 1992;86
(Suppl I):I–260.
16. Scarborough RM, Rose JW, Hsu MA. Barbourin. A GPIIb/IIIa-specific integrin antagonist from the
venom of Sistrurus m barbouri. J Biol Chem 1991;266:9359–9362.
17. Tcheng JE, Harrington RA, Kottke-Marchant K, et al. Multicenter, randomized, double-blind, placebo-
controlled trial of the platelet integrin glycoprotein IIb/IIIa blocker Integrelin in elective coronary
intervention. Circulation 1995;76:2151–2157.
18. Harrington RA, Klieman NS, Kottke-Marchant K, et al. Immediate and reversible platelet inhibition
after intravenous administration of a peptide glycoprotein IIb/IIIa inhibitor during percutaneous coro-
nary intervention. Am J Cardiol 1995;76:1222–1227.
19. The IMPACT II Investigators. Randomised placebo-controlled trial of effect of eptifibatide on compli-
cations of percutaneous coronary intervention: IMPACT II. Lancet 1997;349:1422–1428.
20. Lincoff AM, Tcheng JE, Ellis SG, et al., for the IMPACT II Investigators. Randomized trial of platelet
glycoprotein IIb/IIIa inhibition with Integrelin for prevention of restenosis following coronary interven-
tion: the IMPACT II angiographic substudy. Circ Suppl 1995;92:I–2905.
21. Phillips DR, Teng W, Arfsten A, et al. Effect of calcium on GP IIb/IIIa interactions with Integrelin-
enhanced GP IIb/IIIa binding and inhibition of platelet aggregation by reductions in the concentration
of ionized calcium in plasma anticoagulated with citrate. Circulation 1997;96:1488–1494.
22. Tcheng JE. Glycoprotein IIb/IIIa inhibitors: putting the EPIC, IMPACT II, RESTORE, and EPILOG
trials into perspective. Am J Cardiol 1996;78(Suppl 3A):35–40.
23. The PURSUIT Trial Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients
with acute coronary syndromes. N Engl J Med 1998;339:436–443.
24. Tcheng JE, Talley JD, O’Shea JC, et al. Clinical pharmacology of higher dose eptifibatide in percuta-
neous coronary intervention (the PRIDE study). Am J Cardiol 2001;88:1097–1102.
25. Gilchrist IC, O’Shea JC, Kosoglou T, et al. Pharmacodynamics and pharmacokinetics of higher-dose,
double-bolus eptifibatide in percutaneous coronary intervention. Circulation 2001;104:406–411.
26. O’Shea JC, Hafley GE, Greenberg S, et al. ESPRIT Investigators (Enhanced Suppression of the Platelet
IIb/IIIa Receptor with Integrilin Therapy trial). Platelet glycoprotein IIb/IIIa integrin blockade with
eptifibatide in coronary stent intervention: the ESPRIT trial: a randomized controlled trial. JAMA 2001;
285:2468–2473.
27. The ESPRIT Investigators. Enhanced suppression of the platelet iib/iiia receptor with integrilin ther-
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2037–2044.
28. O’Shea JC, Buller CE, Cantor WJ, et al., for the ESPRIT Investigators. Long-term efficacy of platelet
glycoprotein IIb/IIIa Integrin blockade with eptifibatide in coronary stent intervention. JAMA 2002;
287:618–621.
29. Steinhubl SR, Ellis SG, Wolski K, Lincoff AM, Topol EJ. Ticlopidine pretreatment before coronary
stenting is associated with sustained decrease in adverse cardiac events: data from the evaluation of
platelet IIb/IIIa inhibitor for stenting (EPISTENT) trial. Circulation 2001;103:1403–1409.
30. Berkowitz SD, Harrington RA, Rund MM, Tcheng JE. Acute profound thrombocytopenia after c7E3
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Chapter 7 / Tirofiban: The RESTORE and TARGET Trials 147
147
From: Contemporary Cardiology: Platelet Glycoprotein IIb/IIIa
Inhibitors in Cardiovascular Disease, 2nd Edition
Edited by: A. M. Lincoff © Humana Press Inc., Totowa, NJ
7 Tirofiban
in Interventional Cardiology
The RESTORE and TARGET Trials
CONTENTS
INTRODUCTION
TIROFIBAN IN PERCUTANEOUS CORONARY INTERVENTION
PCI IN PATIENTS PRETREATED WITH TIROFIBAN
CONCLUSIONS
REFERENCES
Nicholas Valettas, MASC, MD
and Howard C. Herrmann, MD
INTRODUCTION
The discovery of the pivotal role played by the Arg-Gly-Asp (RGD) tripeptide sequence
in the binding of fibrinogen to the glycoprotein IIb/IIIa (GPIIb/IIIa) receptor (1), coupled
with the realization that the naturally occurring snake venom disintegrins also exerted
their potent antiplatelet effect via the same RGD domain (2,3), led to the development
of a series of nonpeptide RGD mimetics with increased specificity for the GPIIb/IIIa inte-
grin (4,5). Subsequent nuclear magnetic resonance studies of one disintegrin, eichistatin,
revealed that the key RGD unit resided in a loop segment of the protein with a distinct
spatial arrangement (6). A specific search for a similarly structured peptidomimetic led
to the discovery of a tyrosine analog inhibitor of GPIIb/IIIa (7). Terminal modification
of this compound produced MK-383 (L-700,462; tirofiban), a GPIIb/IIIa inhibitor with
substantially increased potency, as evidenced by a >2000-fold decrease in the median
inhibitory concentration (IC
50
) (8,9). Tirofiban (Aggrastat
®
, Merck & Co., West Point, PA)
is indicated for use in patients with acute coronary syndromes including those under-
going percutaneous coronary intervention (PCI). This chapter reviews the clinical use of
tirofiban in interventional cardiology with emphasis on its use as primary therapy in PCI
and as pretreatment in patients with an acute coronary syndrome prior to PCI. An integral
part of this discussion will focus on the key trials, RESTORE and TARGET, that have
helped define tirofiban’s role in interventional practice.
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148 Part II / GPIIb/IIIa Blockade During Coronary Intervention
Pharmacology
Tirofiban HCl (Fig. 1) is a low-molecular-weight (495.08 Daltons) nonpeptide tyro-
sine derivative that is supplied either as a premixed solution (50 µg/mL) for injection or
as a concentrated solution for intravenous infusion after dilution. It selectively binds to
the GPIIb/IIIa integrin with greater affinity when the receptor is in the activated state than
in the resting state (Fig. 2), with dissociation constants of 1.6 and 15 nM, respectively
(10). The hypothetical advantages of this differential affinity, including the possibility
of fewer adverse effects, remain to be determined. Unlike abciximab (11,12), tirofiban
does not bind to the vitronectin receptor nor to the leukocyte integrin Mac-1 (13). Both
these integrins are felt to play putative roles in neointimal hyperplasia and restenosis fol-
lowing coronary angioplasty, vitronectin by stimulating smooth muscle cell proliferation
in injured tissue (14), and Mac-1 by recruiting monocytes to the site of vascular injury (15).
Although the vitronectin receptor is upregulated shortly after coronary angioplasty (16)
and antagonism of this integrin by an RGD-peptide inhibitor reduced neointimal prolifer-
ation in an animal model of vascular injury (17), subsequent animal (18) and human (19,
20) studies have failed to confirm any advantage to blockade of this receptor in clinical
practice.
The half-life of tirofiban in healthy subjects is approx 2 h, with 65% of the drug cleared
from plasma by renal excretion and about 25% excreted unchanged in bile. Patients with
a creatinine clearance of <30 mL/min (including patients requiring dialysis) exhibit a >50%
decrease in plasma clearance, necessitating a corresponding adjustment in drug dosage.
Plasma clearance is also reduced in individuals >65 yr of age by an estimated 20–25% com-
pared with clearance in those <65 yr (21). However, no gender differences in plasma
clearance are known to exist (22). Tirofiban binds weakly to plasma proteins, with 35%
of an administered dose remaining free in human plasma. Furthermore, hepatic metabo-
lism of the parent compound is limited such that even in patients with moderate hepatic
insufficiency, plasma clearance of the drug is not significantly different from its clearance
in healthy subjects (23).
Pharmacodynamics
The antiplatelet activity of tirofiban in humans was initially studied in a two-part,
double-blind, placebo-controlled, dose-escalation study in healthy male subjects using
1-h and 4-h intravenous infusions (24). Tirofiban inhibited platelet aggregation induced
by collagen (2 µg/mL) and ADP (3.4 µM) in a dose-dependent manner, with IC
50
values
of 66 ± 8 nM and 39 ± 4 nM, respectively. The percent inhibition of platelet aggregation
as a function of the concentration of tirofiban (Fig. 3) demonstrated a sigmoid relationship
between these two variables, with a steep slope and saturation of its antiplatelet effect
occurring within a narrow concentration range. These kinetics are consistent with compe-
Fig. 1. Structural formula of tirofiban hydrochloride monohydrate.
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Chapter 7 / Tirofiban: The RESTORE and TARGET Trials 149
titive inhibition of the GPIIb/IIIa receptor (25). Complete inhibition of both collagen-
and ADP-induced platelet aggregation was evident by 30 min following the initiation of
an infusion of tirofiban at a rate of 0.40 µg/kg/min. The bleeding time was also prolonged
by a mean 4.6-fold and returned to normal 3 h after the end of the 1-h infusion.
The pharmacodynamic activity of tirofiban was further defined in a multicenter, dose-
ranging study in high-risk patients undergoing PCI (26). Patients who were randomized
to the active treatment arm received one of three dosing regimens initiated the moment the
guidewire crossed the lesion: 5, 10, and 10 µg/kg bolus followed by continuous infusions
of 0.05, 0.10, and 0.15 µg/kg/min, respectively. The pharmacodynamic effect of tirofiban
on ex vivo platelet aggregation in response to 5 µM ADP was then evaluated both before
and at several time points during and after drug administration. Rapid inhibition of plate-
let aggregation (IPA) was seen with the 10 µg/kg bolus dose, with >90% IPA achieved by
5 min (Fig. 4). IPA was maintained at >90% at 2 h and at the end of the infusion (16–24 h)
Fig. 2. The competitive displacement of L-736,622 by tirofiban from the activated form (●) and the
resting form (■) of purified GPIIb/III yields dissociation constants of 1.6 and 15 nM, respectively.
(Adapted from ref. 10, with permission.)
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