J. Conor O'Shea

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.

Association of mortality with years of education in patients with ST-segment elevation myocardial infarction treated with fibrinolysis.

OBJECTIVES The purpose of this study was to examine the association between lower socioeconomic status (SES), as ascertained by years of education, and outcomes in patients with acute ST-segment elevation myocardial infarction (STEMI). BACKGROUND Previous studies have shown an inverse relationship between SES and coronary heart disease and mortality. Whether a similar association between SES and mortality exists in STEMI patients is unknown. METHODS We evaluated 11,326 patients with STEMI in the GUSTO-III (Global Use of Strategies to Open Occluded Coronary Arteries) trial study from countries that enrolled >500 patients. We evaluated clinical outcomes (adjusted using multivariate regression analysis) according to the number of years of education completed. RESULTS One-year mortality was inversely related to years of education and was 5-fold higher in patients with <8 years compared with those with >16 years of education (17.5% vs. 3.5%, p < 0.0001). The strength of the relationship between education and mortality varied among different countries. Nonetheless, years of education remained an independent correlate of mortality at day 7 (hazard ratio per year of increase in education: 0.86; 95% confidence interval: 0.83 to 0.88) and also between day 8 and 1 year (hazard ratio per year of increase in education: 0.96; 95% confidence interval: 0.94 to 0.98), even after adjustment for baseline characteristics and country of enrollment. CONCLUSIONS When the number of years of education was used as a measure of SES, there was an inverse relationship such that significantly higher short-term and 1-year mortality existed beyond that accounted for by baseline clinical variables and country of enrollment. Future studies should account for and investigate the mechanisms underlying this link between SES and cardiovascular disease outcomes.

Effect of operator and institutional volume on clinical outcomes after percutaneous coronary interventions performed in Canada and the United States: a brief report from the Enhanced Suppression of the Platelet glycoprotein IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) study.

BACKGROUND The Enhanced Suppression of the Platelet glycoprotein IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial compared the use of eptifibatide with placebo in 2064 coronary intervention patients. It was previously reported that Canadian patients had reduced rates of 30-day and one-year death, myocardial infarction (MI) or target vessel revascularization (TVR) compared with patients in the United States (US). OBJECTIVE To examine whether operator or institutional volume differences explain the regional variation in clinical outcome. METHODS AND RESULTS Each site received an operator and institutional volume survey. Fifty-seven sites (62%) returned complete data on 1338 patients. In this smaller cohort, Canadian patients had reduced rates of 30-day and one-year death, MI or TVR compared with US patients (6.3% versus 10.3% and 14.9% versus 20.1%, respectively; P<0.05 for both comparisons). Among 176 physicians with a median of 13 years experience, the median operator volume was 200 cases per year. Operators with fewer than 100 cases per year had higher rates of 30-day death, MI or TVR (13.2% versus 8.7%; P=0.18) and large MI (7.7% versus 3.3%; P=0.06) than those with 100 or more cases per year. The median institutional volume was 1064 cases per year. Canadian and US centres had similar operator and institutional volumes. By multivariate modelling, operator volume was not predictive of adverse clinical events. However, the rates of 30-day and one-year death, MI or TVR fell by 3% for every 100 patients treated by the institution (OR 0.97; P=0.058 and P=0.002, respectively). Enrollment in Canada was associated with improved outcomes at 30 days (OR 0.50; P=0.001) and one year (OR 0.66; P=0.001) despite inclusion of volume variables in the models. CONCLUSIONS In the ESPRIT study, institutional volume was associated with a modest reduction in risk of death, MI or TVR over short- and long-term follow-up periods. The Canadian and US investigators and institutions selected in ESPRIT had similar annual procedural volumes. Therefore, volume variables did not explain the differential risk of clinical events observed for patients enrolled in the two countries.

Stent Parameters Predict Major Adverse Clinical Events and the Response to Platelet Glycoprotein IIb/IIIa Blockade Findings of the ESPRIT Trial

Background—Only limited data describe relationships between stent parameters (length and diameter), adverse events after percutaneous coronary intervention, and effects of platelet glycoprotein IIb/IIIa blockade by stent parameters. Methods and Results—In this post hoc analysis of the 1983 patients receiving a stent in the Enhanced Suppression of the Platelet Glycoprotein IIb/IIIa Receptor with Integrilin Therapy randomized percutaneous coronary intervention trial of eptifibatide versus placebo, rates of the major adverse cardiac event (MACE) end point (death, myocardial infarction, urgent target-vessel revascularization, or thrombotic bailout) at 48 hours and 1 year were correlated with stent parameters and then analyzed by randomization to eptifibatide versus placebo. In the placebo group, MACE increased with number of stents implanted, total stent length (by quartiles of <15, 15 to <18, 18 to <30, and ≥30 mm), and total stented vessel area (by quartiles of area <141, 141 to <188, 188 to <292, and ≥292 mm2). By stent parameters, MACE at 48 hours was reduced in the eptifibatide group at stent lengths of 18 to <30 mm (odds ratio [OR], 0.55; 95% CI, 0.32 to 0.94; P=0.030) and ≥30 mm (OR, 0.43; 95% CI, 0.25 to 0.75; P=0.003), stent diameters of >2.5 to <3.5 mm (OR, 0.56; 95% CI, 0.39 to 0.82; P=0.002), and with 2 stents implanted (OR, 0.39; 95% CI, 0.22 to 0.69; P=0.001). In the placebo group, near-linear relationships were observed between both increasing stent length and increasing stented vessel area and MACE at 48 hours and 1 year (all, P<0.001); these gradients were flattened in the eptifibatide group (P=0.005 for stent length). Conclusions—Stent parameters predict MACE after percutaneous coronary intervention. Glycoprotein IIb/IIIa blockade mitigates much of the hazard of increasing procedural complexity.

Stent Parameters Predict Major Adverse Clinical Events and the Response to Platelet Glycoprotein IIb/IIIa BlockadeCLINICAL PERSPECTIVE

Background—Only limited data describe relationships between stent parameters (length and diameter), adverse events after percutaneous coronary intervention, and effects of platelet glycoprotein IIb/IIIa blockade by stent parameters. Methods and Results—In this post hoc analysis of the 1983 patients receiving a stent in the Enhanced Suppression of the Platelet Glycoprotein IIb/IIIa Receptor with Integrilin Therapy randomized percutaneous coronary intervention trial of eptifibatide versus placebo, rates of the major adverse cardiac event (MACE) end point (death, myocardial infarction, urgent target-vessel revascularization, or thrombotic bailout) at 48 hours and 1 year were correlated with stent parameters and then analyzed by randomization to eptifibatide versus placebo. In the placebo group, MACE increased with number of stents implanted, total stent length (by quartiles of <15, 15 to <18, 18 to <30, and ≥30 mm), and total stented vessel area (by quartiles of area <141, 141 to <188, 188 to <292, and ≥292 mm2). By stent parameters, MACE at 48 hours was reduced in the eptifibatide group at stent lengths of 18 to <30 mm (odds ratio [OR], 0.55; 95% CI, 0.32 to 0.94; P=0.030) and ≥30 mm (OR, 0.43; 95% CI, 0.25 to 0.75; P=0.003), stent diameters of >2.5 to <3.5 mm (OR, 0.56; 95% CI, 0.39 to 0.82; P=0.002), and with 2 stents implanted (OR, 0.39; 95% CI, 0.22 to 0.69; P=0.001). In the placebo group, near-linear relationships were observed between both increasing stent length and increasing stented vessel area and MACE at 48 hours and 1 year (all, P<0.001); these gradients were flattened in the eptifibatide group (P=0.005 for stent length). Conclusions—Stent parameters predict MACE after percutaneous coronary intervention. Glycoprotein IIb/IIIa blockade mitigates much of the hazard of increasing procedural complexity.

Stent Parameters Predict Adverse Clinical Outcomes and Response to Platelet Glycoprotein IIb/IIIa Blockade: Findings of the ESPRIT Trial

Background—Only limited data describe relationships between stent parameters (length and diameter), adverse events after percutaneous coronary intervention, and effects of platelet glycoprotein IIb/IIIa blockade by stent parameters. Methods and Results—In this post hoc analysis of the 1983 patients receiving a stent in the Enhanced Suppression of the Platelet Glycoprotein IIb/IIIa Receptor with Integrilin Therapy randomized percutaneous coronary intervention trial of eptifibatide versus placebo, rates of the major adverse cardiac event (MACE) end point (death, myocardial infarction, urgent target-vessel revascularization, or thrombotic bailout) at 48 hours and 1 year were correlated with stent parameters and then analyzed by randomization to eptifibatide versus placebo. In the placebo group, MACE increased with number of stents implanted, total stent length (by quartiles of <15, 15 to <18, 18 to <30, and ≥30 mm), and total stented vessel area (by quartiles of area <141, 141 to <188, 188 to <292, and ≥292 mm2). By stent parameters, MACE at 48 hours was reduced in the eptifibatide group at stent lengths of 18 to <30 mm (odds ratio [OR], 0.55; 95% CI, 0.32 to 0.94; P=0.030) and ≥30 mm (OR, 0.43; 95% CI, 0.25 to 0.75; P=0.003), stent diameters of >2.5 to <3.5 mm (OR, 0.56; 95% CI, 0.39 to 0.82; P=0.002), and with 2 stents implanted (OR, 0.39; 95% CI, 0.22 to 0.69; P=0.001). In the placebo group, near-linear relationships were observed between both increasing stent length and increasing stented vessel area and MACE at 48 hours and 1 year (all, P<0.001); these gradients were flattened in the eptifibatide group (P=0.005 for stent length). Conclusions—Stent parameters predict MACE after percutaneous coronary intervention. Glycoprotein IIb/IIIa blockade mitigates much of the hazard of increasing procedural complexity.

Stent Parameters Predict Major Adverse Clinical Events and the Response to Platelet Glycoprotein IIb/IIIa BlockadeCLINICAL PERSPECTIVE: Findings of the ESPRIT Trial

Background—Only limited data describe relationships between stent parameters (length and diameter), adverse events after percutaneous coronary intervention, and effects of platelet glycoprotein IIb/IIIa blockade by stent parameters. Methods and Results—In this post hoc analysis of the 1983 patients receiving a stent in the Enhanced Suppression of the Platelet Glycoprotein IIb/IIIa Receptor with Integrilin Therapy randomized percutaneous coronary intervention trial of eptifibatide versus placebo, rates of the major adverse cardiac event (MACE) end point (death, myocardial infarction, urgent target-vessel revascularization, or thrombotic bailout) at 48 hours and 1 year were correlated with stent parameters and then analyzed by randomization to eptifibatide versus placebo. In the placebo group, MACE increased with number of stents implanted, total stent length (by quartiles of <15, 15 to <18, 18 to <30, and ≥30 mm), and total stented vessel area (by quartiles of area <141, 141 to <188, 188 to <292, and ≥292 mm2). By stent parameters, MACE at 48 hours was reduced in the eptifibatide group at stent lengths of 18 to <30 mm (odds ratio [OR], 0.55; 95% CI, 0.32 to 0.94; P=0.030) and ≥30 mm (OR, 0.43; 95% CI, 0.25 to 0.75; P=0.003), stent diameters of >2.5 to <3.5 mm (OR, 0.56; 95% CI, 0.39 to 0.82; P=0.002), and with 2 stents implanted (OR, 0.39; 95% CI, 0.22 to 0.69; P=0.001). In the placebo group, near-linear relationships were observed between both increasing stent length and increasing stented vessel area and MACE at 48 hours and 1 year (all, P<0.001); these gradients were flattened in the eptifibatide group (P=0.005 for stent length). Conclusions—Stent parameters predict MACE after percutaneous coronary intervention. Glycoprotein IIb/IIIa blockade mitigates much of the hazard of increasing procedural complexity.

Small-Molecule Glycoprotein IIb/IIIa Inhibitors as Adjunctive Therapy in Percutaneous Coronary Interventions

The glycoprotein (GP) IIb=IIIa receptor is a calcium-dependent heterodimer consisting of two transmembrane proteins: a 136-kd a subunit, consisting of one heavy chain and one light chain, and a 92-kd b subunit. The surface of a typical platelet contains approximately 50,000 to 80,000 GP IIb=IIIa receptors [1]. Activation by agonists leads to conformational changes in the GP IIb=IIIa receptor, enabling adhesive proteins that contain the peptide sequence arginineglycine-aspartic acid (RGD) such as ®brinogen, von Willebrands factor, and vitronectin to bind to GP IIb=IIIa [2]. Of these adhesive molecules, ®brinogen appears to be the most important ligand in thrombosis because it exists in high concentrations in the blood and, because it is divalent, it can simultaneously bind to GP IIb=IIIa receptors on separate platelets, resulting in platelet aggregation [3]. There is considerable evidence from large-scale, randomized clinical trials that inhibitors of the GP IIb=IIIa receptor are effective in reducing the rates of ischemic complications associated with percutaneous coronary intervention (PCI) [4±8]. Bene®ts have been observed in patients of all risk strata and in a wide range of clinical settings, including elective coronary intervention, intervention related to acute coronary syndromes, and intervention during acute myocardial infarction (MI) and in conjunction with coronary stenting [9,10].