O'Shea JC, Buller CE, Cantor WJ, Chandler AB, Cohen EA, Cohen DJ, Gilchrist IC, Kleiman NS, Labinaz M, Madan M, Hafley GE, Califf RM, Kitt MM, Strony J, Tcheng JE, for the ESPRIT Investigators . Long-term Efficacy of Platelet Glycoprotein IIb/IIIa Integrin Blockade With Eptifibatide in Coronary Stent Intervention. JAMA. 2002;287(5):618-621. doi:10.1001/jama.287.5.618
Author Affiliations: Duke Clinical Research Institute, Durham, NC (Drs O'Shea, Califf, and Tcheng, and Ms Hafley); Vancouver General Hospital, Vancouver, British Columbia (Dr Buller); St Michael's Hospital, Toronto, Ontario (Dr Cantor); University Hospital, Augusta, Ga (Dr Chandler); Sunnybrook & Women's College Health Science Centre, Toronto, Ontario (Drs E. Cohen and Madan); Beth Israel Deaconess Medical Center, Boston, Mass (Dr D. Cohen); Pennsylvania State University, Hershey (Dr Gilchrist); Baylor College of Medicine, Houston, Tex (Dr Kleiman); University of Ottawa Heart Institute, Ottawa, Ontario (Dr Labinaz); COR Therapeutics, Inc, South San Francisco, Calif (Dr Kitt); and Schering-Plough Research Institute, Kenilworth, NJ (Dr Strony).
Context In the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin
Therapy (ESPRIT) trial, treatment with eptifibatide, a platelet glycoprotein
IIb/IIIa integrin blocker, was found to reduce the ischemic complications
of nonurgent coronary stent implantation at 48 hours and 30 days.
Objective To determine whether eptifibatide treatment continues to provide durable,
long-term benefit after coronary stent intervention.
Design and Setting The ESPRIT trial was a randomized, double-blind, placebo-controlled,
parallel-group, crossover-permitted trial conducted from June 1999 through
February 2000 at 92 tertiary care centers in the United States and Canada.
Participants A total of 2064 patients scheduled to undergo nonurgent percutaneous
coronary intervention with stent implantation.
Intervention Patients were randomly assigned to receive placebo (n = 1024) or eptifibatide
(two 180-µg/kg boluses, 10 minutes apart, with a continuous infusion
of 2.0 µg/kg per minute; n = 1040), started immediately before stent
implantation and continued for 18 to 24 hours. Patients also received aspirin,
heparin, and a thienopyridine.
Main Outcome Measures Composite rates of death or myocardial infarction (MI) and death, infarction,
or target vessel revascularization during the 12 months after enrollment.
Results Complete follow-up data were available for 988 patients given eptifibatide
(95.0%) and 976 patients given placebo (95.3%). By 12 months, the composite
of death or MI had occurred in 8.0% of eptifibatide-treated patients and in
12.4% of placebo-treated patients (hazard ratio [HR], 0.63; 95% confidence
interval [CI], 0.48-0.83; P = .001). The composite
rate of death, MI, or target vessel revascularization was 17.5% in eptifibatide-treated
patients vs 22.1% in placebo-treated patients (HR, 0.76; 95% CI, 0.63-0.93; P = .007).
Conclusions Long-term outcomes of nonurgent coronary stent implantation appear to
be improved through blockade of the platelet glycoprotein IIb/IIIa integrin
Over the past decade, evidence has documented the efficacy of intravenous
platelet glycoprotein (Gp) IIb/IIIa integrin blockade as an adjunct to percutaneous
coronary intervention (PCI).1,2
Blockade of the Gp IIb/IIIa receptor reduces ischemic complications of PCI
across all indications for PCI, among the various devices used for PCI, throughout
a broad range of heparin anticoagulation strategies, and across several different
The Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin
Therapy (ESPRIT) trial evaluated the efficacy of the rapidly reversible Gp
IIb/IIIa integrin blocker eptifibatide for coronary stent implantation.9 Routine preemptive treatment with eptifibatide conferred
significant clinical benefits over a strategy of reserving therapy until complications
developed; there was a 37% relative risk reduction in the primary composite
end point of death, myocardial infarction (MI), need for urgent target vessel
revascularization, or crossover to Gp IIb/IIIa inhibitor therapy for thrombosis
within 48 hours compared with placebo (6.6% vs 10.5%, P = .002).10 This brief report extends
those observations to 1 year.
The design, methods, and primary results of the ESPRIT trial have been
described in detail.9,10 To summarize,
from June 1999 through February 2000, at 92 tertiary care centers in the United
States and Canada, 2064 patients scheduled to undergo nonurgent PCI with stent
implantation were randomized to receive either placebo or eptifibatide treatment
(Integrilin, COR Therapeutics, Inc, South San Francisco, Calif, and Schering-Plough
Research Institute, Kenilworth, NJ) started immediately before PCI. The primary
inclusion criterion was the intent to treat a native coronary artery stenosis
with stent implantation without the planned use of a platelet Gp IIb/IIIa
inhibitor. The primary exclusion criteria were acute MI within 24 hours before
randomization and ongoing chest pain precipitating urgent referral for PCI.
Eptifibatide was given as two 180-µg/kg boluses 10 minutes apart, and
as a continuous infusion of 2.0 µg/kg per minute started with the first
bolus and continued for 18 to 24 hours. Treatment was initiated immediately
before the PCI procedure was performed. All patients were to receive concomitant
aspirin, and a weight-adjusted heparin regimen was recommended (initial bolus
of 60 U/kg) with a target activated clotting time between 200 and 300 seconds.
Treatment with ticlopidine or clopidogrel was allowed on the day of the procedure
but not before; the choice of loading dose was left to the treating physician.
The PCI was performed according to local standards, and any approved stent
could be implanted. The local research ethics or institutional review board
for each center approved the protocol, and all patients or a representative
provided written informed consent for participation in the trial and for 1-year
Outcomes at 12 months, including death, MI, and target vessel revascularization,
were prospectively defined secondary end points of the trial. Masking of the
study-drug allocation was maintained through 1 year of follow-up. All analyses
were performed according to the intention-to-treat principle (all randomized
patients, as randomized) using SAS version 6.12 (SAS Institute, Inc, Cary,
NC). Survival analysis methods were used for the 1-year analyses. Pairwise
comparisons between the 2 treatment groups were made with use of the log-rank
test, with event rates calculated by the Kaplan-Meier method. Treatment effects
by subgroups are displayed as hazard ratios (HRs) with 95% confidence intervals
(CIs); these were calculated using a Cox proportional hazards model.
Follow-up of all end point clinical events, obtained by telephone contact
or clinic visit at or beyond 12 months after randomization, was available
for 988 of 1040 (95.0%) patients assigned to receive eptifibatide and 976
of 1024 (95.3%) patients assigned to receive placebo; mortality status was
available for 1017 (97.8%) and 1007 (98.3%) patients, respectively (Figure 1). Baseline demographic and angiographic
characteristics were balanced and did not differ between treatment groups.
At 12 months, the key secondary composite end point of death or MI had
occurred in 12.4% of placebo-treated patients but in only 8.0% of eptifibatide-treated
patients (HR, 0.63; 95% CI, 0.48-0.83; P = .001; Figure 2A). A beneficial treatment effect
was seen in this end point across patient subgroups defined by age, weight,
sex, presence or absence of diabetes, and clinical condition (Figure 3). There were no significant interactions between subgroups
With regard to other end points, the triple composite of death, MI,
or target vessel revascularization at 12 months was reduced from 22.1% in
the placebo-treated patients to 17.5% with eptifibatide treatment (HR, 0.76;
95% CI, 0.63-0.93; P = .007; Figure 2B). Death was a rare event; 20 (2%) placebo-treated and
14 (1.4%) eptifibatide-treated patients died over the 12 months of the study
(HR, 0.69; 95% CI, 0.35-1.36; P = .28).
Overall rates for target vessel revascularization were greater in diabetic
patients (HR, 1.59; 95% CI, 1.21-2.08; P<.001).
This end point tended to be reduced with eptifibatide treatment in both the
diabetic (HR, 0.90; 95% CI, 0.57-1.41; P = .65) and
nondiabetic (HR, 0.89; 95% CI, 0.66-1.20; P = .43)
The long-term results of ESPRIT show that the 48-hour and 30-day benefits
of eptifibatide in reducing the ischemic complications of PCI with stent implantation
are sustained to at least 1 year. Numerically, there was a slight but measurable
continued separation of the endpoint curves between 30 days and 1 year. These
results affirm the clinical utility of eptifibatide treatment during PCI by
showing a long-term, robust, and clinically meaningful benefit.
The mechanism by which a short (<24 hours) infusion of a potent Gp
IIb/IIIa antagonist given at the time of PCI continues to protect against
adverse cardiovascular events to 1 year after that procedure is unclear. The
consistent results observed now between the trials of abciximab, particularly
EPISTENT (Evaluation of Platelet IIb/IIIa Inhibitor for Stenting)11 and the more recent TARGET (Do Tirofiban and ReoPro
Give similar Efficacy Trial),12 suggests that
this is a class effect of platelet Gp IIb/IIIa inhibitors. Because the duration
of direct drug action extends to only 2 days at best, mechanisms of long-term
benefit, such as the indirect inhibition of CD40 ligand by these agents,13 may be relevant.
In ESPRIT, at 12 months, consistent treatment effects were seen between
patients with and without diabetes. Overall, the diabetic patients had higher
rates of target vessel revascularization, consistent with other reports.14,15 The suggestion derived from the EPISTENT
trial, that platelet Gp IIb/IIIa inhibition with abciximab could significantly
affect restenosis in patients with diabetes, does not appear to be borne out
in preliminary analysis from the TARGET trial.16
In TARGET, the rate of target vessel revascularization was higher in patients
with diabetes receiving abciximab than in those treated with the small-molecule
antagonist tirofiban, although these initial data await presentation in a
full-length, peer-reviewed format.16
In summary, these data add to the evidence that long-term outcomes of
PCI can be improved through inhibition of the platelet Gp IIb/IIIa integrin
and support the routine use of Gp IIb/IIIa inhibitor therapy for patients
undergoing PCI. Additional efficacy continues to accrue long after the completion
of the PCI procedure. The strategy of intense inhibition begun just before
PCI and maintained by infusion, especially in the early hours immediately
after PCI, appears be superior to a "watchful waiting" or "bailout" strategy
in which treatment is withheld until an actual complication arises.