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130 Part II / GPIIb/IIIa Blockade During Coronary Intervention
A consistent, similar degree of benefit was imparted to all patients regardless of risk pro-
file. Efficacy was realized regardless of baseline demographic characteristics, medical
history, procedures performed, or angiographic features. Representative data are included
in Table 2.
Time to Events
As might be expected of a short-acting parenteral agent, separation and differentiation
of the treatment event curves from placebo occurred early, within the first 24 h (the period
of drug infusion; Fig. 2). The differences resulted from a reduction in thrombosis, as
manifest by a reduction in angiographically apparent true abrupt closure (Table 1). The
plots included in Fig. 3, the Kaplan-Meier event curves to 6 mo, illustrate three points.
First, the two dosing approaches studied in IMPACT II are indistinguishable in clinical
effect; second, the absolute difference achieved during treatment remains constant and
durable without degradation over time; and third, the majority of the benefit of eptifibatide
treatment was the result of reducing the incidence of myocardial infarction or death. In
particular, Fig. 3B points out that eptifibatide treatment had no effect on the need for
subsequent (clinically driven) revascularization. With regard to angiographic restenosis,
in the 900-patient IMPACT II Angiographic Substudy (in which all patients were required
to return for 6-mo follow-up angiography), no differences in rates of angiographic resten-
osis among the treatment groups were observed (20). Finally, all the plots illustrate that
Table 2
30-Day Composite Clinical Efficacy Results by Baseline Characteristics
a
Eptifibatide Eptifibatide
135/0.5 135/0.75
Characteristic (n = 1300) (n = 1286)
Age
≤65 yr 0.687 (0.493, 0.958) 0.816 (0.596, 1.117)
>65 yr 0.875 (0.586, 1.306) 0.897 (0.593, 1.356)
Gender
Male 0.706 (0.523, 0.954) 0.834 (0.626, 1.111)
Female 0.919 (0.565, 1.495) 0.870 (0.524, 1.447)
Tertiles
Lowest weight (≤77 kg) 0.847 (0.557, 1.288) 0.951 (0.629, 1.439)
Middle weight (77–90 kg) 0.781 (0.507, 1.202) 0.846 (0.549, 1.304)
Highest weight (>90 kg) 0.630 (0.388, 1.025) 0.729 (0.462, 1.153)
Diabetes 0.827 (0.472, 1.450) 0.725 (0.406, 1.295)
No diabetes 0.743 (0.558, 0.989) 0.872 (0.661, 1.151)
Previous intervention 0.979 (0.593, 1.618) 1.108 (0.685, 1.791)
Previous CABG 0.685 (0.373, 1.259) 0.969 (0.553, 1.697)
High-risk stratum 1.005 (0.680, 1.484) 0.885 (0.593, 1.320)
Elective stratum 0.620 (0.442, 0.871) 0.817 (0.593, 1.125)
Balloon angioplasty 0.752 (0.577, 0.980) 0.851 (0.658, 1.100)
Rotablator 0.551 (0.275, 1.104) 0.577 (0.288, 1.158)
Stent implantation 0.377 (0.181, 0.783) 0.473 (0.233, 0.959)
a
Treated as randomized analyses. Data are point estimates with 95% confidence intervals for the odds ratios.
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Chapter 6 / Eptifibatide in Coronary Interventions 131
Fig. 2. Kaplan-Meier plot of probability of end-point events to 72 h—the IM PACT II trial. Compo-
nents of the composite clinical efficacy endpoint were death, myocardial infarction, or urgent revas-
cularization. Most events occurred within 6 h of coronary intervention. Both eptifibatide regimens
reduced events to essentially the same degree. (From ref. 19.)
coronary intervention itself induces adverse clinical events. Of endpoint events to 30 d,
>75% of events occurred within the first 24 h of the procedure.
Components of the Composite Endpoint
The event rates for the individual components of the primary efficacy endpoint were
reduced with eptifibatide treatment, which was consistent with the overall treatment effect
seen in IMPACT II (Table 3). Most of the treatment effect was in reducing the incidence
of periprocedural myocardial infarction, with lesser absolute contributions from the other
elements tracked. Stents were required for abrupt closure in 18 (1.4%) patients in the pla-
cebo group compared with 7 (0.5%) in each of the eptifibatide treatment groups. This
finding paralleled the greater overall use of stent implantation in the placebo group at the
initial coronary intervention (5.0% vs 2.7% in the 135/0.5 group, p = 0.002). Other statis-
tics concerning the individual components of the composite endpoint are listed in Table 3.
Adverse Events
There was no increase in the frequency of major bleeding, blood transfusion, or other
morbidity associated with eptifibatide administration. Rates of major bleeding were 4.8%
vs 5.1% vs 5.2% for the placebo, 135/0.5, and 135/0.75 groups, respectively. Transfusion
rates were likewise comparable. The majority (approx 60%) of all bleeding events were
attributable to the vascular access site. Four patients sustained an intracranial hemorrhage,
one each in the placebo and 135/0.5 groups and two in the 135/0.75 treatment group. Rates
of thrombocytopenia were low overall and indistinguishable among groups, with no patients
developing acute profound thrombocytopenia. Finally, no patients developed anti-epti-
fibatide antibodies.
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132 Part II / GPIIb/IIIa Blockade During Coronary Intervention
Fig. 3. Kaplan-Meier plots of probability of endpoint events to 6 mo—the IMPACT II trial. (A) Plot
of death or myocardial infarction. (B) Plot of all revascularization (percutaneous coronary interven-
tion or coronary artery bypass surgery). (A) Illustrates that the benefit achieved early is maintained fo r
the entire observation period; absolute differences established early remained constant. Almost all the
benefit is owing to a reduction in rates of myocardial infarction; no differences in death were realized
(data not shown). (B) Indicates that eptifibatide treatment did not influence the subsequent need for
revascularization. (From ref. 19.)
IMPACT II: Issues, Questions, and Directions
The IMPACT II study added to the body of evidence focusing on the central role of the
platelet in mediating the ischemic complications of coronary intervention. Despite what
was accomplished, however, key questions remained after the IMPACT II trial. One
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Chapter 6 / Eptifibatide in Coronary Interventions 133
Table 3
Primary Composite Efficacy Outcomes and Components: Patients Receiving Any Study Drug (Treated as Randomized Analyses)
Eptifibatide Eptifibatide
Placebo 135/0.5 135/0.75
(n = 1285) (n = 1300) (n = 1286)
30-Day composite endpoint, n (%; 95% CI) 149 (11.6; 9.8, 13.3) 118 (9.1; 7.5–10.6) 128 (10.0; 8.3–11.6)
Significance vs placebo — p = 0.035 p = 0.180
Odds ratio vs placebo (95% CI for OR) — 0.76 (0.59–0.98) 0.84 (0.66–1.08)
Endpoint components, n (%; 95% CI)
Death 14 (1.1; 0.5–1.7) 6 (0.5; 0.1–0.8) 11 (0.9; 0.4–1.4)
Myocardial infarction 106 (8.2; 6.7–9.8) 86 (6.6; 5.3–8.0) 90 (7.0; 5.6–8.4)
CK-MB ≥ 3× upper normal limit 72 (5.6; 4.3–6.9) 54 (4.2; 3.1–5.2) 46 (3.6; 2.6–4.6)
CK-MB ≥ 5× upper normal limit 51 (4.0; 2.9–5.0) 38 (2.9; 2.0–3.8) 28 (2.2; 1.4–3.0)
Q waves 20 (1.6; 0.9–2.2) 12 (0.9; 0.4–1.4) 15 (1.2; 0.6–1.8)
Q waves or CK-MB ≥ 5× upper normal limit 59 (4.6; 3.4–5.7) 47 (3.6; 2.6–4.6) 39 (3.0; 2.1–4.0)
Death or CK-MB ≥ 3× upper normal limit 82 (6.4; 5.0–7.7) 57 (4.4; 3.3–5.5) 54 (4.2; 3.1–5.3)
Significance vs placebo — p = 0.024 p = 0.013
Odds ratio vs placebo (95% CI for OR) 0.67 (0.48, 0.95) 0.64 (0.45, 0.92)
Urgent or emergency bypass surgery 36 (2.8; 1.9–3.7) 19 (1.5; 0.8–2.1) 26 (2.0; 1.3–2.8)
Urgent or emergency repeat percutaneous revascularization 37 (2.9; 2.0–3.8) 35 (2.7; 1.8–3.6) 36 (2.8; 1.9–3.7)
Stent for abrupt closure 18 (1.4; 0.8–2.0) 7 (0.5; 0.1–0.9) 7 (0.5; 0.1–0.9)
Abbreviations: CK, creatine kinase; CI, confidence interval; OR, odds ratio.
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134 Part II / GPIIb/IIIa Blockade During Coronary Intervention
issue was the inverse dose-response results at 30 d between the lower dose (135/0.5) and
higher dose (135/0.75) regimens in IMPACT II. Curiously, the 30-d (primary endpoint)
mark coincided with the greatest separation of effect between the two dosing approaches;
as noted above, the 6-mo event curves for the two dosing approaches became virtually
identical. These findings appear to be attributable to a number of factors. First, the effi-
cacy of eptifibatide in IMPACT II was largely secondary to the (identical) 135 µg/kg bolus
used in both arms, not the continuous infusion. Second, neither of the infusion regimens
adequately inhibited platelet function and were more similar than different in biologic
activity. Finally, the role of statistical chance cannot be discounted; in fact, the differences
between the primary endpoint rates at 30 d are statistically negligible.
Perhaps the critical dilemma was that the treatment effect was less than expected,
particularly in the context of the results achieved in the EPIC trial with the monoclonal
antibody fragment abciximab (4). Several investigations conducted subsequent to the con-
clusion of the IMPACT II trial lent support to the notion that higher doses of eptifibatide
might provide better clinical efficacy. In a key observation by Phillips and colleagues (21),
it was elucidated that the pharmacodynamic effects of eptifibatide were overestimated
in the Phase II dose-finding studies. This overestimation was secondary to the use of the
anticoagulant sodium citrate to suspend the blood samples; since citrate chelates calcium,
and since calcium normally occupies the ligand binding site within GPIIb/IIIa, ex vivo
ADP-induced platelet aggregation was artificially enhanced vis à vis the in vivo clinical
effect. The best current estimate is that the doses used in IMPACT II achieved only 30–50%
of maximal platelet GPIIb/IIIa integrin blockade (22).
Two additional studies have been conducted that have direct relevance to the issue of
eptifibatide dosing and the potential for more robust clinical efficacy. The first was the
10,948-patient PURSUIT trial of eptifibatide vs placebo as an adjunct to the management
of patients presenting with an acute coronary syndrome (23). In PURSUIT, the dosing of
eptifibatide was a bolus of 180 µg/kg followed by an infusion at 2.0 µg/kg-min. Among
the 1228 patients in PURSUIT who underwent coronary intervention during study drug
infusion, the relative reduction in the composite endpoint of death or myocardial infarc-
tion at 30 d was 30% with eptifibatide treatment (16.8% vs 11.8%, p = 0.01). This suggested
that a higher dose regimen (than that used in IMPACT II) would provide a greater relative
risk reduction in end-point events.
In the Platelet Aggregation and Receptor Occupancy with Integrilin—a Dynamic Eval-
uation (PRIDE) study, the pharmacodynamic effects of three single-bolus and two double-
bolus dosing regimens of eptifibatide during coronary intervention were investigated (24).
Also incorporated into the PRIDE trial was a lower dose strategy for heparin anticoagu-
lation, using a 70 U/kg heparin bolus to achieve an ACT of 200–300 s. Inhibition of platelet
aggregation was determined with blood suspended in a calcium chelator (sodium citrate)
and in PPACK (D-Phe-Pro-Arg-CH
2
Cl, an anticoagulant that does not chelate calcium)
using 20 µM adenosine diphosphate to stimulate platelet aggregation. Representative
data from the 135/0.75 and 180/2.0 infusion regimens are depicted in Fig. 4 and show that
ex vivo determinations of inhibition of platelet aggregation are dependent on the antico-
agulant used to suspend the blood sample. With measurements of platelet aggregation
performed on specimens suspended in PPACK, only the 180/2.0 regimen attained >80%
platelet inhibition through most of the treatment. Data derived from the PRIDE trial also
demonstrated that a concentration of 1650 ng/mL of eptifibatide was necessary to attain
80% of platelet GPIIb/IIIa receptor occupancy (Fig. 5). However, this concentration was
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Chapter 6 / Eptifibatide in Coronary Interventions 135
Fig. 4. Inhibition of platelet aggregation by eptifibatide—the PRIDE trial. Two dosing regimens from
the PRIDE trial are shown, the 135 µg/kg bolus plus 0.75 µg/kg/min infusion and the 180 µg/kg bolus
plus 2.0 µg/kg/min infusion. Blood samples were suspended in either sodium citrate anticoagulant
or PPACK anticoagulant. Assays of blood in citrate reported higher degrees of platelet inhibition
than blood in PPACK at the same concentration of eptifibatide. The higher dose (180/2.0) regimen sup-
pressed platelet aggregation below 20% of baseline, whereas the lower dose (135/0.75) regimen did not.
Data are normalized to 100% aggregation at baseline. PPACK = D-Phe-Pro-Arg-CH
2
Cl. (From ref. 24.)
Fig. 5. Relationship of eptifibatide plasma concentration to platelet GPIIb/IIIa receptor occupancy
relationship—the PRIDE trial. Ninety-five percent confidence interval (CI) curves are also included.
Eighty percent occupancy was achieved when the steady-state concentration exceeded the threshold
concentration of 1650 ng/mL (95% CI 1406–1967 ng/mL), as shown. (From ref. 24.)
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136 Part II / GPIIb/IIIa Blockade During Coronary Intervention
Fig. 6. Plasma concentration of eptifibatide over 24 h using the 180/2.0 dosing regimen—the PRIDE
trial. The 1650 ng/mL threshold concentration level is highlighted. (From ref. 24.)
only reached with the 180/2.0 regimen after 8 h of infusion, once a steady state was achieved
(Fig. 6). This led to the hypothesis that a larger bolus (or, alternatively, a second bolus within
10 min of the first) would be necessary to obtain maximal efficacy with the 180/2.0 regi-
men. Finally, further pharmacodynamic modeling determined that to attain and maintain
>80% receptor occupancy (and >80% inhibition of platelet aggregation) throughout the
duration of treatment, a 180/2.0/180 double-bolus regimen would be required (Fig. 7) (25).
Finally, several other issues remained unresolved after IMPACT-II. First, the PROLOG
(7) and EPILOG (6) trials of abciximab, studies conducted in approximately the same
time frame as IMPACT II, reported lower rates of major bleeding with reduced heparin
dosing and early sheath removal. Whether the safety profile of eptifibatide could be sim-
ilarly improved was unknown. More importantly, IMPACT-II did not study the efficacy
of eptifibatide in improving outcomes with elective intracoronary stent implantation.
Even though extrapolation of the results of the abciximab trials suggested that GPIIb/IIIa
inhibition in general would be efficacious in coronary stenting, further studies were still
needed after IMPACT-II to evaluate the specific efficacy of eptifibatide.
ESPRIT
The Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy
(ESPRIT) trial was designed as a pivotal, Phase III trial of eptifibatide in patients under-
going stent implantation during percutaneous coronary intervention (26–28). The crucial
issue was to evaluate a new, novel dosing regimen of eptifibatide developed to attain and
maintain >80% platelet GPIIb/IIIa integrin blockade throughout the duration of treat-
ment. The study evaluated the efficacy of treatment in nonurgent PCI in patients receiv-
ing second- and third-generation stents using high-pressure stent deployment techniques
and concomitant thienopyridine therapy.
ESPRIT was a multicenter, parallel-group, randomized, double-blind, placebo-controlled
(with open-label crossover) clinical trial that enrolled 2064 patients in 92 centers in the
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Chapter 6 / Eptifibatide in Coronary Interventions 137
United States and Canada. Patient enrollment into ESPRIT took place from June 1999 into
February 2000. Figure 8 shows the flow of patients through the trial. Patients with known
coronary artery disease scheduled to undergo PCI with stent implantation in a native cor-
onary artery (and who, per the judgment of the operator, did not require pretreatment with
a GPIIb/IIIa inhibitor) were considered for inclusion. Patients excluded from the study
included those who had sustained a myocardial infarction within 24 h before randomiza-
tion and patients with continuing chest pain requiring urgent PCI. Other exclusion cri-
teria included PCI within the previous 3 mo, previous stent placement at the target lesion,
a target lesion within a saphenous vein graft, treatment with a GPIIb/IIIa inhibitor or a thie-
nopyridine in the previous 30 d, stroke or transient ischemic attack within 30 d, history
of hemorrhagic stroke, bleeding diathesis or abnormal bleeding within 30 d of randomi-
zation, major surgery in the preceding 6 wk, uncontrolled hypertension (>200/100 mmHg),
thrombocytopenia (platelet count < 100 × 10
9
/L), or serum creatinine level > 350 µmol/L
(4.0 mg/dL).
Patient were randomized to received either a 180 µg/kg double bolus of eptifibatide
administered 10 min apart coupled with a continuous infusion (started immediately after
the first bolus) of 2 µg/kg/min for 18–24 h (1 µg/kg/min for patients with serum creatinine
>177 µmol/L), or placebo. Concomitant medications included heparin to maintain an ACT
between 200 and 300 s, aspirin, and either clopidogrel or ticlopidine (with use of a loading
dose).
Fig. 7. Pharmacokinetic modeling of double-bolus eptifibatide—the PRIDE trial. Shown are the pre-
dicted effects of a 180 µg/kg bolus and 2.0 µg/kg/min infusion alone and after a second 180 µg/kg bolus
at 5-, 10-, 15-, or 30-min intervals after the initial bolus. (From ref. 25.)
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138 Part II / GPIIb/IIIa Blockade During Coronary Intervention
The protocol permitted the use of open-label “bailout” GPIIb/IIIa inhibitor therapy in
emergency situations (abrupt closure, no reflow, or coronary thrombosis). Bailout GPIIb/
IIIa inhibitor use did not result in unblinding of study drug assignment.
The primary endpoint was a composite of death, myocardial infarction, urgent target
vessel revascularization and bailout GPIIb/IIIa inhibitor therapy given for a thrombotic
complication within 48 h after randomization. The key secondary efficacy endpoint was
the composite of death, myocardial infarction, and urgent target vessel revascularization
within 30 d after randomization. Endpoint myocardial infarction was defined by crea-
tive kinase (CK)-MB elevation ≥3 times upper limit of normal on two assays in the first
24 h after PCI or a clinical event judged to be compatible with myocardial infarction by
the Clinical Events Committee and supported by predetermined electrocardiographic
findings and/or cardiac marker elevations. Safety endpoints were bleeding, blood trans-
fusion, and stroke within 48 h or hospital discharge. Bleeding was assessed as major or
minor according to the Thrombolysis in Myocardial Infarction (TIMI) criteria.
The sample size was based on a predicted 33% reduction of an expected 11% adverse
clinical event rate at 30 d in the placebo arm. With 86% power and an α of 0.05 (two-tailed),
the projected sample size for the study was 2400 patients. Because the anticipated recruit-
Fig. 8. Flow of patients through 12-mo follow-up—the ESPRIT trial. (From ref. 28.)
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Chapter 6 / Eptifibatide in Coronary Interventions 139
ment period was less than 6 mo, no interim analyses were preplanned. However, since
the actual recruitment period extended beyond 8 mo, the Data and Safety Monitoring
Board independently chose to assess both safety and efficacy. For this analysis, the Data
Safety and Monitoring Board prespecified a p value < 0.005 for the rate of death or myo-
cardial infarction at 48 h as criteria warranting termination of the trial. Analyses were by
intention to treat. At the interim analysis (conducted with 2007 patients randomized), the
Data and Safety Monitoring Board recommended the premature termination of enroll-
ment for efficacy. At the interim analysis, complete data were available of 1758 patients
to 48 h and 1384 patients to 30 d. A 43% relative risk reduction in irreversible endpoints
of death or myocardial infarction at 48 h (95% CI 19–61; p = 0.0017) was the primary
determinant of recommendation for termination. Other prerequisite conditions of the
board included consistency of reduction in death or myocardial infarction at 30 d, consis-
tency across other components of the endpoint at 48 h and 30 d, absence of safety con-
cerns, and results of other clinical trials of GPIIb/IIIa inhibition in PCI.
The baseline demographic and angiographic characteristics among the 2064 patients
enrolled in the study were evenly distributed between treatment groups (Table 4). Patients
classified as having an acute coronary syndrome within 48 h or an acute ST-segment ele-
vation myocardial infarction within 7 days before the intervention represented 18% of
the study population. Table 5 outlines specific treatment characteristics of the two study
groups. A PCI procedure was actually performed in 98.8% of patients, and >96% of the
Table 4
Baseline Characteristics
a
Eptifibatide Placebo Total
Characteristic (n = 1040) (n = 1024) (n = 2064)
Median age (yr)
(25–75 quartiles) 62 (54–71) 62 (54–71) 62 (54–71)
Median weight (kg)
(25–75 quartiles) 84.0 (73.9–95.3) 84.7 (75.0–97.0) 84.4 (74.0–96.0)
Women 280 (27) 282 (28) 562 (27)
USA/Canada 772 (74)/268 (26) 759 (74)/265 (26) 1531(74)/533 (26)
Previous MI 331 (32) 321 (31) 652 (32)
Previous PCI 237 (23) 246 (24) 483 (23)
Previous CABG 106 (10) 105 (10) 211 (10)
Diabetes 208 (20) 211 (21) 419 (20)
Hypertension 608 (59) 605 (59) 1213 (59)
Hypercholesterolemia 600 (58) 599 (59) 1199 (58)
Smoker 250 (24) 228 (23) 478 (23)
Stable angina 407 (39) 387 (38) 794 (39)
UA/NQMI (2–180 d) 331 (32) 333 (33) 664 (32)
UA/NQMI within 2 d 139 (13) 140 (14) 279 (14)
ST elevation MI within 7 d 44 (4) 49 (5) 93 (5)
Positive functional test only 96 (9) 91 (9) 187 (9)
Other anginal equivalent 23 (2) 24 (2) 47 (2)
Abbreviations: MI, myocardial infarction; PCI, percutaneous coronary intervention; CABG, coronary
artery bypass grafting; UA, unstable angina; NQMI, non-Q-wave myocardial infarction.
a
Data are numbers, with percents in parentheses, except for the first two rows.
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