Eptifibatide in percutaneous coronary intervention. A review.

Percutaneous coronary angioplasty and stenting is widely used for the treatment of patients with coronary artery disease. Glycoprotein (GP) IIb-IIIa inhibitors represent a new class of drugs with proven efficacy in reducing ischemic complications of patients undergoing percutaneous coronary intervention (PCI). One of these, eptifibatide (Integrilin feminine, COR), is a small molecule inhibitor of glycoprotein IIb-IIIa receptors which has been studied extensively in patients undergoing PCI. In both IMPACT II and ESPRIT trials, patients treated with eptifibatide experienced a reduction in the rate of ischemic complications compared to those treated with placebo. These landmark studies, which are the focus of this review, emphasize the importance of considering the use of GP IIb-IIIa inhibitors in all patients undergoing PCI.

Clinical pharmacology of higher dose eptifibatide in percutaneous coronary intervention (the PRIDE study).

This study describes the dose-exploration phase of the PRIDE trial, an investigation of the clinical pharmacology of higher dose eptifibatide in patients who underwent elective percutaneous coronary intervention (PCI). Outcomes of treatment with the platelet glycoprotein IIb/IIIa inhibitors were dependent upon proper dosing selection. In this multicenter, placebo-controlled clinical study, 127 patients were randomized 1:1:2:2 into 1 of the following treatment groups: placebo; eptifibatide as a 135 microg/kg bolus followed by a 0.75 microg/kg/min infusion; eptifibatide as a 180 microg/kg bolus with a 2.0 microg/kg/min infusion; or eptifibatide as a 250 microg/kg bolus with a 3.0 microg/kg/min infusion. Light transmission aggregometry was used to determine platelet aggregation in response to 20 microM adenosine diphosphate, and platelet receptor occupancy was also determined. Eptifibatide exhibited linear pharmacokinetics over the dose range studied. Inhibition of platelet aggregation was greater in samples collected in sodium citrate compared with those collected in D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone. The 180/2.0 dosing regimen achieved 90% inhibition of platelet aggregation immediately (5 minutes) and at steady state (8 to 24 hours). At 1 hour, mean inhibition of platelet aggregation was 80%. Eptifibatide exhibited dose-dependent pharmacodynamics that were dependent upon choice of anticoagulant. A 180 microg/kg bolus followed by a 2.0 microg/kg/min infusion at steady state achieved >80% inhibition of platelet aggregation. With the single-bolus regimen, however, there was an early loss of the inhibition of platelet aggregation before steady state was reached. Additional dose-exploration studies may further optimize eptifibatide dosing.

Effect of glycoprotein IIb/IIIa receptor inhibition on angiographic complications during percutaneous coronary intervention in the ESPRIT trial.

OBJECTIVES: We sought to determine whether eptifibatide decreases the incidence of in-laboratory angiographic complications and to determine the relationship of angiographically evident complications to elevations of creatine kinase-MB (CK-MB) enzyme levels during percutaneous coronary intervention. BACKGROUND: In the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial, eptifibatide during coronary intervention was associated with decreased ischemic complications at 48 h and 30 days. METHODS: Patients (n = 2,064) were randomized to placebo versus eptifibatide (two 180 microg/kg boluses 10 min apart and as a continuous infusion of 2 microg/kg per min) during percutaneous coronary stenting. Angiographic complications including major dissection, distal embolization, residual thrombus, abrupt closure, residual stenosis >50% and side-branch occlusion were prospectively recorded by the operator. Creatine kinase-MB levels were measured after the procedure and every 6 h thereafter. The incidence of angiographic complications and CK-MB elevation was determined for eptifibatide versus placebo groups. RESULTS: Eptifibatide-treated patients demonstrated nonsignificant trends toward fewer angiographic complications (10 vs. 12% for placebo patients, p = 0.13) and, for patients with angiographic complications, fewer subsequent CK-MB elevations (43 vs. 50% for placebo patients, p = 0.31). In patients without any angiographic complications, the incidence of CK-MB elevation >3 times the normal was 7% with placebo and 4% with eptifibatide (p = 0.003). CONCLUSIONS: Eptifibatide during nonurgent coronary stent intervention only minimally (and insignificantly) reduces the incidence of angiographic complications and subsequent CK-MB elevations in patients developing an angiographic complication. The greater effect is to reduce myocardial infarction in patients undergoing otherwise uneventful coronary stent implantation as well as in the overall study population.

Pharmacodynamics and pharmacokinetics of higher-dose, double-bolus eptifibatide in percutaneous coronary intervention.

BACKGROUND: Pharmacodynamics of eptifibatide, a cyclic heptapeptide antagonist of platelet glycoprotein IIb/IIIa, are substantially altered by anticoagulants that chelate calcium, resulting in overestimation ex vivo of the in vivo effects of this agent. We conducted a dose-ranging study to characterize the pharmacodynamics and pharmacokinetics of eptifibatide under physiological conditions. METHODS AND RESULTS: Patients (n=39) undergoing elective percutaneous coronary intervention were randomly assigned to an eptifibatide bolus followed by an infusion (180-microgram/kg bolus followed by 2 microgram/kg per minute or 250-microgram/kg bolus followed by 3 microgram/kg per minute) for 18 to 24 hours. In a 2:1 ratio, these patients received either a second bolus of eptifibatide (90 microgram/kg or 125 microgram/kg for the initial 180-microgram/kg or 250-microgram/kg groups, respectively) or placebo 30 minutes after the initial bolus. Bleeding times, ex vivo platelet aggregation, receptor occupancy, and plasma eptifibatide levels at baseline and at 1, 2, 3, 4, 6, and 8 hours were evaluated. Platelet inhibition was dose dependent and >80% in all groups by steady state. The single-bolus regimens had a transient loss of inhibition at 1 hour, consistent with rapid distribution and drug elimination. Pharmacokinetic modeling suggested that optimal dosing of eptifibatide would be obtained with a 180-microgram/kg bolus and a 2-microgram/kg per minute infusion followed by a second 180-microgram/kg bolus 10 minutes later. CONCLUSIONS: A novel higher-dose, double-bolus regimen of eptifibatide in coronary intervention attains and maintains >90% inhibition of platelet aggregation in >90% of patients, providing the pharmacodynamic construct for the design of the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial of adjunctive eptifibatide in coronary stent implantation.

Platelet glycoprotein IIb/IIIa integrin blockade with eptifibatide in coronary stent intervention: the ESPRIT trial: a randomized controlled trial.

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-microg/kg boluses 10 minutes apart and continuous infusion of 2.0 microg/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.

Design and methodology of the ESPRIT trial: evaluating a novel dosing regimen of eptifibatide in percutaneous coronary intervention.

BACKGROUND: Clinical trials of the glycoprotein (GP) IIb/IIIa inhibitors have shown that these potent antiplatelet agents are effective in reducing the ischemic complications of percutaneous coronary interventions. However, even though stents are now implanted in >75% of percutaneous interventional procedures, only one study, a trial of the monoclonal antibody abciximab, has formally evaluated adjunctive GP IIb/IIIa inhibition in this setting. METHODS AND RESULTS: Eptifibatide, a nonimmunogenic and rapidly reversible inhibitor of the platelet receptor integrin IIb/IIIa, has also undergone evaluation as an adjunct to coronary intervention. In clinical trials performed heretofore, however, it has appeared to have less relative clinical efficacy than the monoclonal antibody abciximab. Since the early seminal trials, it has been recognized that the doses of eptifibatide previously used achieved only 30% to 50% of maximal platelet GP IIb/IIIa integrin inhibition. This is considerably less than the 80% level of receptor inhibition that has been proposed to prevent coronary thrombus formation in animal models and that has been achieved in clinical trials with abciximab. CONCLUSIONS: The Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial was designed to test the safety and efficacy of a high-dose, "180/2.0/180" double-bolus regimen of eptifibatide (a 180-microg/kg bolus followed 10 minutes later by a second 180-microg/kg bolus of eptifibatide combined with a 2.0-microg/kg per minute infusion) as an adjunct to nonacute percutaneous coronary intervention with stent implantation. In this report, we review the rationale, design, and methods of this clinical investigation.

Effects of 308 nanometer excimer laser energy on 316 L stainless-steel stents: implications for laser atherectomy of in-stent restenosis.

PURPOSE: To determine the effects of the incidental exposure of stents to pulsed 308 nanometer ultraviolet excimer laser energy. METHODS: Five types of 316 L stainless-steel coronary stents were subjected to two types of study. First, for endurance testing, sixty stents were deployed in 3.0Eth 4.0 mm polymer tubes in three geometries. Up to 1,000 laser pulses were delivered while advancing a 2.0 mm eccentric catheter through the lumen of the stent. These stents were next subjected to 400 million simulated heartbeats and then analyzed for metal etching and fatigue. Second, six additional stents were irradiated with 1,000 pulses underwater and then analyzed for particulates, anions and cations liberated from the stent. RESULTS: Photomicroscopy revealed surface etching on a number of stents. Two stent models exhibited multiple strut fractures at the strut joints in both test samples and controls. In no case was a break observed at the site of laser-stent interaction. Breakage frequency was not significantly different between lazed stents and controls. Lazed stents produced a mean of 14 micrograms of sodium and 4 micrograms of iron more than controls. No excess particulates were detected. CONCLUSION: Under model conditions typical of clinical use, excimer laser treatment does not alter stainless-steel stent endurance or liberate clinically significant material from the stent.

Nocturnal blood pressure dipping: a consequence of diurnal physical activity blipping?

This study was designed to describe the interaction between physical activity (PA), quantified objectively by electronic activity monitors, and ambulatory blood pressure (ABP), and to test the hypothesis that modifying daily PA can effect significant changes in the diurnal variation in blood pressure and may result in altered dipping/nondipping status of an individual. Initially, 70 individuals underwent simultaneous ABP and electronic activity monitoring (actigraph devices manufactured by Gaewihler Electronics, Switzerland) over a 24-h period. Then, in a prospective study, the dipping/nondipping status of 43 subjects was assessed using ABP recorded over two 24-h periods of differing activity levels. Of the 70 subjects (age 49 +/- 11 years, 42 male) the diurnal variation in systolic blood pressure (20 +/- 12%, step-up from night [120 +/- 12 mm Hg] to day [144 +/- 13 mm Hg]) and diurnal variation in PA score (increment from sleep, 44 +/- 17 units) correlated significantly (R2 = 0.29; P < .05). Of the 43 subjects who underwent ABP monitoring on a more active day, four had a nondipping BP profile; 12 of these same 43 subjects had a nondipping BP profile when monitored on a less active day (chi2 = 4.9; P < .05). These results provide a quantitative description of the contribution of PA, including the sleep/awake status, to blood pressure variation in a group of normotensive and hypertensive individuals. The magnitude of this effect underscores the importance of interpreting 24-h ABP data only in the presence of adequately quantified activity data.

Electronic activity-monitor-derived sleeping and awake times and diurnal variation of blood pressure.

BACKGROUND: Results of a number of studies have indicated that target-organ damage is more pronounced in non-dippers, those in whom the blood pressure falls by less than 10% with the onset of sleep, than it is in dippers with comparable clinic blood pressures. However, the standard use of arbitrarily defined daytime and night-time periods, rather than precise estimates of sleeping time and awake time, could limit the accuracy of estimates of diurnal variation of blood pressure and hence of dipping status. DESIGN AND METHODS: In this study of 102 consecutive patients undergoing ambulatory blood pressure monitoring we compared activity-derived estimates of sleeping and awake blood pressures using electronic activity monitoring and diary records with estimates determined using pre-defined day and night-time periods. The dipping/non-dipping status of each subject was assessed using these three different techniques for defining the awake/asleep time periods. RESULTS: The sleeping/awake times based on the activity monitor, diary and default data were 2356 h+/-55 min/0754 h+/-50 min, 2326 h+/-61 min/0722 h+/-72 min and 2300 h and 0700 h respectively. The percentage systolic/diastolic falls in blood pressure were 18+/-6/18+/-7% with six non-dippers (activity-monitor-derived data), 16+/-6/17+/-8% and 12 non-dippers (diary data) and 13+/-7/15+/-7% and 21 non-dippers (using the pre-set daytime and night-time periods). DISCUSSION: Results of this study demonstrate that the extent of the diurnal variation in blood pressure (and hence dipping status) can differ depending on the technique used to define periods of wakefulness and sleep.