Context The Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin
Therapy (ESPRIT) trial showed the efficacy of adjunctive, double-bolus eptifibatide
therapy in reducing ischemic complications of nonurgent coronary stent implantation
at 48 hours and at 30 days.
Objective To determine whether the beneficial effects of eptifibatide persist
at 6 months after treatment.
Design Follow-up study of a randomized, double-blind, placebo-controlled, crossover-permitted
trial conducted from June 1999 through February 2000.
Setting Ninety-two 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 or eptifibatide (two
180-µg/kg boluses 10 minutes apart and continuous infusion of 2.0 µg/kg
per minute), started immediately before stent implantation and continued for
18 to 24 hours. Complete follow-up data were available for 988 (95.0%) of
1040 patients given eptifibatide and 977 (95.4%) of 1024 patients given placebo.
Main Outcome Measures Composite rates of death or myocardial infarction (MI); death, MI, or
target vessel revascularization; and their individual components 6 months
after enrollment, compared between the 2 groups.
Results By 6 months, the composite end point of death or MI had occurred in
7.5% of eptifibatide-treated patients and in 11.5% of placebo-treated patients
(hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.47-0.84; P = .002). The composite of death, MI, or target vessel revascularization
was 14.2% in eptifibatide-treated patients vs 18.3% in placebo-treated patients
(HR, 0.75; 95% CI, 0.60-0.93; P = .008). Most of
this benefit accrued early (<48 hours after initiation of therapy) and
was maintained through 6 months. Six-month mortality in the eptifibatide group
was 0.8% vs 1.4% in the placebo group (HR, 0.56; 95% CI, 0.24-1.34; P = .19) and target vessel revascularization occurred in
8.6% of the eptifibatide group vs 9.4% of the placebo group (HR, 0.91; 95%
CI, 0.68-1.22; P = .51).
Conclusion Adjunctive eptifibatide therapy during coronary stent implantation provides
benefit through 6-month follow-up.
Coronary thrombosis is central to the pathogenesis of atherosclerosis,
acute myocardial infarction (AMI), acute coronary syndromes, and ischemic
complications of percutaneous coronary intervention (PCI).1
Aside from the obvious and dramatic effects of abrupt thrombosis of an epicardial
vessel, the effects of thrombosis on microcirculation (such as microembolization
and vasospasm) also portend poor outcomes in coronary artery disease.2 Several large, randomized clinical trials have shown
that inhibition of platelet aggregation with platelet glycoprotein (Gp) IIb/IIIa
receptor antagonists improves outcomes in patients presenting with acute coronary
syndromes and after PCI.3,4 These
agents mitigate the thrombotic cascade both by blocking Gp IIb/IIIa, the primary
surface-membrane receptor responsible for platelet aggregation, and by indirectly
inhibiting the generation of thrombin.5-11
Eptifibatide is an intravenous, rapidly reversible, competitive inhibitor
of Gp IIb/IIIa. Therapy with eptifibatide has been shown to reduce short-term
adverse cardiac events in several coronary indications, including PCI,12 AMI with13 or without14 ST-segment elevation, and unstable angina.14 In the Enhanced Suppression of the Platelet IIb/IIIa
Receptor with Integrilin Therapy (ESPRIT) trial, high-dose, double-bolus eptifibatide
was evaluated in nonurgent coronary stenting. This trial was terminated early
for efficacy in February 2000.15 Final analysis
of the primary composite end point—death, MI, need for urgent target
vessel revascularization, or crossover to Gp IIb/IIIa inhibitor therapy for
thrombosis within 48 hours—showed a 37% relative risk reduction with
treatment (10.5% with placebo vs 6.6% with eptifibatide; P = .002). At 30 days, the key secondary composite end point of death,
MI, or urgent target vessel revascularization was reduced by a relative 35%
(10.4% vs 6.8%; P = .003).15
The purpose of the present analysis was to determine whether these benefits
continued at 6 months for patients enrolled in the ESPRIT trial.
The design and methods of the ESPRIT trial have been described.15,16 Briefly, 92 centers in the United
States and Canada enrolled patients who were scheduled to undergo nonurgent
coronary stenting. Enrollment of 2064 patients occurred from June 1999 through
February 2000. The primary inclusion criterion was intent to treat a native
coronary artery with stent implantation without planned use of a Gp IIb/IIIa
inhibitor. Exclusion criteria included MI within 24 hours before randomization
and ongoing chest pain precipitating urgent referral for PCI. Other exclusion
criteria included PCI within the previous 90 days, previous stent implantation
at the target location, staged PCI anticipated less than 30 days after randomization,
treatment with a Gp IIb/IIIa inhibitor or a thienopyridine within 30 days
before randomization, stroke or transient ischemic attack within 30 days before
randomization, history of hemorrhagic stroke, history of bleeding diathesis
or evidence of abnormal bleeding within 30 days before randomization, major
surgery within the previous 6 weeks, uncontrolled hypertension (>200/100 mm
Hg), documented thrombocytopenia (platelet count <100 × 103/µL), or a serum creatinine level of more than 4.0 mg/dL (350
µmol/L).
Patients were randomized in a 1:1 ratio to receive either placebo or
eptifibatide (Integrilin, COR Therapeutics, South San Francisco, Calif, and
Schering-Plough Research Institute, Kenilworth, NJ), started immediately prior
to PCI. The randomization allocation code was generated using random permuted
blocks within each investigative site. Each site kept a randomization schedule
unique to that site. Study drug kits were prepared only after the guiding
scout images had been obtained in the catheterization laboratory in preparation
for intervention. Patients were considered randomized at the time of any administration
of study drug. If the clinician decided not to give the study drug for any
reason, the patient was not randomized and was not considered part of the
study. If a kit was prepared but not used, unblinding did not occur and replacement
kits were used to reestablish the correct sequence in the randomization list
for the next eligible patient. Once study drug was given, a patient's participation
in the study was communicated to the coordinating center within 30 minutes
of randomization. This strategy served to minimize the number of patients
randomized but not actually treated in ESPRIT.
Study drug kits were packaged to be indistinguishable, regardless of
content. Any drug kit that became unusable was replaced with another uniquely
numbered kit of the same treatment. This kit then was given to the next patient
enrolled at that site. Eptifibatide was given as two 180-µg/kg boluses
10 minutes apart and as a continuous infusion of 2.0 µg/kg per minute
(1.0 µg/kg per minute in patients with a serum creatinine level >2.0
mg/dL [177 µmol/L]) started with the first bolus and continued for 18
to 24 hours. All patients received concomitant aspirin, and a weight-adjusted
heparin regimen was recommended (initial bolus of 60 U/kg), with a target
activated clotting time of 200 to 300 seconds. Treatment with ticlopidine
or clopidogrel was permitted on the day of the procedure but not beforehand;
the choice of loading dose was decided by the treating physician. The PCI
was performed according to local standards, and any approved stent could be
implanted.
To provide emergency, open-label Gp IIb/IIIa inhibitor therapy (for
direct treatment of abrupt closure, no reflow, coronary thrombosis, or similar
complications of PCI), "bailout" kits were supplied to the sites. These kits
contained 2 bolus vials of either eptifibatide (for patients allocated to
the placebo group) or placebo (for patients allocated to the eptifibatide
group). Once the bolus bailout treatment had begun, the study drug infusion
was discontinued and open-label eptifibatide infusion was initiated. Bailout
use of Gp IIb/IIIa inhibition did not result in unblinding of treatment assignment.
The protocol was approved by the institutional review board at each
clinical site, and patients gave informed consent for participation in the
trial and follow-up for 1 year. Masking of study drug allocation was maintained
through 1 year of follow-up.
Outcomes at 6 months, including death, MI, and target vessel revascularization,
were prospectively defined secondary end points of the trial. Target vessel
revascularization was defined as coronary artery bypass grafting or a second
PCI deemed by the site investigator to involve the original target vessel.
All other revascularizations were reviewed by a clinical events committee
(CEC) to determine whether the procedure met the criteria for target vessel
revascularization.
An end-point MI could occur by 1 of 2 criteria. The first criterion
was elevation of the creatine kinase–MB isoenzyme (CK-MB), assessed
by the enzymatic core laboratory in at least 2 samples, to at least 3 times
the upper limit of normal within 24 hours after PCI. The other criterion included
MIs reported by an investigator and adjudicated as end-point MIs by the CEC.
This required corroboration in the form of a clinical syndrome consistent
with MI (symptoms and signs of cardiac chest pain, other anginal equivalent,
or acute shortness of breath with features of new-onset pulmonary edema or
hypotension) and supportive electrocardiographic (ECG) or cardiac marker data.
Supportive ECG findings included development of Q waves (≥0.04 seconds)
in at least 2 contiguous leads or new left bundle-branch block. Supportive
cardiac marker findings included (in order of precedence and to the exclusion
of the next value) an elevated level of CK-MB, troponin I, or troponin T;
or a total CK level elevated to at least twice the upper limit of normal.
In cases of repeat PCI or bypass surgery, cardiac marker elevations to at
least 3 times or 5 times the upper limit of normal were required, respectively.
The sample size for ESPRIT was calculated based on both the projected
reduction in the rate of a key secondary composite end point (death, MI, or
target vessel revascularization at 30 days) and the reduction in the rate
of the primary composite end point (death, MI, urgent target vessel revascularization,
or bailout Gp IIb/IIIa inhibitor use at 48 hours). The secondary end point
was used for power calculations because of its application in other trials
of Gp IIb/IIIa inhibitors in this setting. We expected a rate of the secondary
end point of 11% in the placebo group, reduced by 33% with treatment. With
86% power and a 2-tailed α level of .05, the projected sample size for
the study was 2400 patients.
An independent board monitored the safety of the trial. There was no
plan for interim analyses of efficacy because recruitment was anticipated
to be complete within 6 months. When enrollment continued beyond 8 months,
however, the board independently elected to evaluate both safety and efficacy,
using a prespecified criterion of P<.005 for the
reduction in death or MI at 48 hours for early termination of the trial.
Study coordinators collected data on case report forms at the sites.
All analyses were performed according to the intention-to-treat principle
(all randomized patients, as randomized). Survival analysis methods were used
for the 6-month analyses. Pairwise comparisons between the 2 treatment groups
were made using the log-rank test, with event rates calculated by the Kaplan-Meier
method. Two-sided P values are reported. Time to
first occurrence of any component of the composite end point is shown by Kaplan-Meier
survival curves. Treatment effects by subgroups are reported as hazard ratios
(HRs) with 95% confidence intervals (CIs), calculated using a Cox proportional
hazards model.
The 6-month follow-up database was locked on January 5, 2001. Follow-up
of all end-point clinical events, obtained by telephone contact or clinic
visit at 6 months after randomization, was available for 988 of 1040 patients
assigned to receive eptifibatide (95.0%) and 977 of 1024 patients assigned
to receive placebo (95.4%); mortality status was available for 1023 (98.4%)
and 1010 (98.6%), respectively (Figure 1).
Among the 2064 patients enrolled in the study, baseline demographic
and angiographic characteristics were balanced and did not differ significantly
between treatment groups.15 The cohort had
a median age of 62 years, about 73% were male, 20% had diabetes, 23% were
current smokers, about one third had had a prior MI, and slightly more than
half of the patients in both treatment groups had hypertension and hyperlipidemia.
Almost 20% of patients had an acute coronary syndrome within 48 hours or acute
ST-segment elevation MI within 7 days before intervention. More than 98% of
patients randomized into the trial underwent PCI, at least 1 stent was placed
in 97.2% of patients who underwent PCI, and more than 97% of patients received
a thienopyridine, predominantly clopidogrel.15
The 6-month composite end point of death or MI occurred in 11.5% of
placebo-treated patients and in 7.5% of eptifibatide-treated patients (HR,
0.63; 95% CI, 0.47-0.84; P = .002; Figure 2A; Table 1). There was consistency in the direction of treatment effect of
eptifibatide with regard to this end point across patient subgroups defined
by age, weight, sex, presence or absence of diabetes, and clinical condition
(Figure 3). However, as can be seen
from the wide CIs in some of the analyses in Figure 3, the study did not have power to test the treatment effect
in these predefined subgroups. In additional analyses that tested for treatment-by-subgroup
interactions, an increased benefit of eptifibatide was seen with increasing
age (P = .03). The composite end point of death,
MI, or target vessel revascularization at 6 months also differed significantly
between treatment groups (Figure 2B).
The incidence of the individual components varied. The only significant effect
was observed in reduction of MI. Mortality was reduced, but not to a significant
extent. Finally, target vessel revascularization was not substantially affected
(Table 1).
Event rates for the composite end point of death, MI, or target vessel
revascularization and selected individual end points at 48 hours, 30 days,
and 6 months are shown in Table 2.
About 83% of the 4.1% benefit of eptifibatide in reducing this end point at
6 months was achieved in the first 48 hours, during which an absolute reduction
of 3.4% occurred. However, an additional 17% of the absolute difference between
groups at 6 months was manifested after the first 48 hours.
For mortality, the rate of death between 30 days and 6 months with placebo
was nearly twice that with eptifibatide treatment (1.4% vs 0.8%; P = .19). Furthermore, the Kaplan-Meier curves continued to separate
over time; about two thirds of the absolute difference accrued between 30
days and 6 months (Figure 2C). However,
only 14 and 8 deaths had occurred by 6 months in the placebo and eptifibatide
groups, respectively, and this difference was not statistically significant.
The rate of target vessel revascularization also was lower in the eptifibatide
group, but the difference was small and not significant at any of the time
points. The absolute treatment benefit for the composite end point of MI and
death also showed that most of the benefit accrued early and was at least
maintained over the ensuing 6 months.
The acute benefits of eptifibatide have been established in several
settings, including treatment of patients with acute coronary syndromes and
as adjunctive therapy for patients undergoing PCI. The 6-month follow-up of
patients in the ESPRIT trial shows the efficacy of eptifibatide in coronary
stenting to be clinically relevant, statistically significant, and durable
over time. Adjunctive treatment with eptifibatide had the greatest effect
on MI and reduced the composite incidence of death or MI, as well as its components,
and that of death, MI, and target vessel revascularization. Of interest, benefit
continued to accrue between 48 hours and 6 months, well beyond the 18 to 24
hours of initial treatment. The suggestion that treatment with eptifibatide
may be associated with lower mortality at 6 months (a nonsignificant 44% reduction
in this study) supports the concept of the complementary effects of stenting
and Gp IIb/IIIa inhibition in improving this fundamental adverse outcome in
patients with ischemic heart disease.17
Until this report, abciximab had been the only Gp IIb/IIIa inhibitor
shown to reduce ischemic complications of PCI over the long term.17 Accordingly, much of the discussion of putative mechanisms
by which abciximab improves long-term outcomes compared with smaller, competitive
Gp IIb/IIIa inhibitors (such as eptifibatide) had focused on the unique pharmacodynamic
and pharmacokinetic properties of abciximab. The avid binding of abciximab
to platelets for up to 2 weeks after administration and its cross-reactivity
with other receptors, including ανβ3 (vitronectin)
and Mac-1, were forwarded as hypotheses to explain the differences observed
in clinical trials.17-20
The ESPRIT results suggest that long-term benefits can be explained more simply
by appropriate use of high-level inhibitors of platelet Gp IIb/IIIa integrin
during PCI. In the Integrilin to Minimize Platelet Aggregation and Coronary
Thrombosis (IMPACT-II) study, a 135-µg/kg bolus and either a 0.5- or
0.75-µg/kg-per-minute infusion were studied in coronary intervention.
There was only a borderline significant 16% to 22% reduction in the composite
end point of death, MI, or urgent target vessel revascularization at 30 days
with eptifibatide treatment, with maintenance (but not augmentation) of the
results at 6 months.12 The results of the ESPRIT
study, which used a dose of eptifibatide some 3 to 4 times higher than that
studied in IMPACT-II, lend credence to the need for greater inhibition of
platelet aggregation during PCI to maximize both short- and long-term outcomes.
That benefits continued to accrue over time is a provocative and unexplained
observation. Although eptifibatide treatment reduced epicardial thrombosis
resulting in abrupt closure and urgent target vessel revascularization within
the first 48 hours, this phenomenon accounted for only a small proportion
of the long-term benefit. In particular, the treatment effect on mortality
appears to be a delayed phenomenon—the difference in mortality between
the placebo and eptifibatide groups tripled, from 0.2% to 0.6%, between 30
days and 6 months. Clearly, these numbers are small (and the differences are
not statistically significant); there were only 22 deaths across both treatment
arms at 6 months, and the outcomes of patients lost to follow-up in the 2
treatment arms are unknown. Nevertheless, these data are consistent with the
observations for mortality at the same follow-up point in the Evaluation of
c7E3 for Prevention of Ischemic Complications (EPIC),18
Evaluation in PTCA to Improve Long-term Outcomes with abciximab Gp IIb/IIIa
blockade (EPILOG),19 and the Evaluation of
Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT) trials of abciximab.20
Recent studies have suggested additional mechanisms by which platelet
Gp IIb/IIIa blockade might indirectly improve long-term outcomes. Periprocedural
MI, as evidenced by increases in CK-MB levels, long has been associated with
increased mortality and other adverse cardiac events.21,22
In an angiographic substudy of the ESPRIT trial, Gibson et al23
found that eptifibatide administration was associated with significantly increased
coronary flow reserve and a trend toward increased microvascular perfusion
after stent placement. In that study, poor myocardial perfusion was the strongest
predictor of release of CK-MB. Reductions in release of inflammatory factors,
such as CD-40 ligand (David Phillips, PhD, written communication, March 2001),
and of vascular mediators, such as platelet-derived growth factor and transforming
growth factor β, by Gp IIb/IIIa inhibition is another possible mechanism
that might improve long-term vascular responses.
In summary, these data, particularly when coupled with the antecedent
clinical trials of Gp IIb/IIIa inhibition in PCI, argue strongly that all
patients undergoing PCI should be considered for treatment with an inhibitor
of the platelet Gp IIb/IIIa integrin. Across a series of randomized trials
involving different intravenous Gp IIb/IIIa antagonists, benefits have been
observed among patients of all risk categories and with all approved interventional
devices. The strategy of maximal inhibition beginning just before the procedure
and maintained throughout the infusion, especially in the early hours immediately
after PCI, appears to be critical to imparting long-term benefits. This study
adds to the evidence that outcomes of PCI can be improved through inhibition
of the platelet Gp IIb/IIIa integrin.
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