Point-of-care measured platelet inhibition correlates with a reduced risk of an adverse cardiac event after percutaneous coronary intervention: results of the GOLD (AU-Assessing Ultegra) multicenter study.

BACKGROUND: The optimal level of platelet inhibition with a glycoprotein (GP) IIb/IIIa antagonist necessary to minimize thrombotic complications in patients undergoing a percutaneous coronary intervention (PCI) is currently unknown. METHODS AND RESULTS: Five hundred patients undergoing a PCI with the planned use of a GP IIb/IIIa inhibitor had platelet inhibition measured at 10 minutes, 1 hour, 8 hours, and 24 hours after the initiation of therapy with the Ultegra Rapid Platelet Function Assay (Accumetrics). Major adverse cardiac events (MACES: composite of death, myocardial infarction, and urgent target vessel revascularization) were prospectively monitored, and the incidence correlated with the measured level of platelet function inhibition at all time points. One quarter of all patients did not achieve >/=95% inhibition 10 minutes after the bolus and experienced a significantly higher incidence of MACEs (14.4% versus 6.4%, P=0.006). Patients whose platelet function was <70% inhibited at 8 hours after the start of therapy had a MACE rate of 25% versus 8.1% for those >/=70% inhibited (P=0.009). By multivariate analysis, platelet function inhibition >/=95% at 10 minutes after the start of therapy was associated with a significant decrease in the incidence of a MACE (odds ratio 0.46, 95% CI 0.22 to 0.96, P=0.04). CONCLUSIONS: Substantial variability in the level of platelet function inhibition is achieved with GP IIb/IIIa antagonist therapy among patients undergoing PCI. The level of platelet function inhibition as measured by a point-of-care assay is an independent predictor for the risk of MACEs after PCI.

Combined accelerated tissue-plasminogen activator and platelet glycoprotein IIb/IIIa integrin receptor blockade with Integrilin in acute myocardial infarction. Results of a randomized, placebo-controlled, dose-ranging trial. IMPACT-AMI Investigators.

BACKGROUND: Platelet activation and aggregation may be key components of thrombolytic failure to restore and maintain perfusion in acute myocardial infarction. We performed a placebo-controlled, dose-ranging trial of Integrilin, a potent inhibitor of platelet aggregation, with heparin, aspirin, and accelerated alteplase. METHODS AND RESULTS: We assigned 132 patients in a 2:1 ratio to receive a bolus and continuous infusion of one of six Integrilin doses or placebo. Another 48 patients were randomized in a 3:1, double-blind fashion to receive the highest Integrilin dose from the first phase or placebo. All patients received accelerated alteplase, aspirin, and intravenous heparin infusion; all but two groups also received an intravenous heparin bolus. The highest Integrilin dose group from the nonrandomized phase and the randomized patients were pooled for analysis and compared with placebo-treated patients. The primary end point was Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow at 90-minute angiography. Secondary end points were time to ST-segment recovery, an in-hospital composite (death, reinfarction, stroke, revascularization procedures, new heart failure, or pulmonary edema), and bleeding variables. The highest Integrilin dose groups had more complete reperfusion (TIMI grade 3 flow, 66% versus 39% for placebo-treated patients; P = .006) and a shorter median time to ST-segment recovery (65 versus 116 minutes for placebo; P = .05). The groups had similar rates of the composite end point (43% versus 42% for placebo-treated patients) and severe bleeding (4% versus 5%, respectively). CONCLUSIONS: The incidence and speed of reperfusion can be enhanced when a potent inhibitor of the glycoprotein IIb/IIIa integrin receptor, such as Integrilin, is combined with accelerated alteplase, aspirin, and intravenous heparin.

Effects of integrelin, a platelet glycoprotein IIb/IIIa receptor antagonist, in unstable angina. A randomized multicenter trial.

BACKGROUND: Although aspirin is beneficial in patients with unstable angina, it is a relatively weak inhibitor of platelet aggregation. The effect of Integrelin, which inhibits the platelet fibrinogen receptor glycoprotein (GP) IIb/IIIa, on the frequency and duration of Holter ischemia was evaluated in 227 patients with unstable angina. METHODS AND RESULTS: Patients received intravenous heparin and standard ischemic therapy and were randomized to receive oral aspirin and placebo Integrelin; placebo aspirin and low-dose Integrelin. 45 micrograms/kg bolus followed by a 0.5 microgram.kg-1. min-1 continuous infusion; or placebo aspirin and high-dose Integrelin, 90 micrograms/kg bolus followed by a 1.0-microgram.kg-1, min-1 constant infusion. Study drug was continued for 24 to 72 hours, and Holter monitoring was performed. Patients randomized to high-dose Integrelin experienced 0.24 +/- 0.11 ischemic episodes (mean +/- SEM) on Holter lasting 8.41 +/- 5.29 minutes over 24 hours of study drug infusion. Patients randomized to aspirin experienced a greater number (1.0 +/- 0.33, P < .05) and longer duration (26.2 +/- 9.8 minutes, P = .01) of ischemic episodes than the high-dose Integrelin group. There was no evidence of rebound ischemia after withdrawal of study drug. In 46 patients, platelet aggregation was rapidly inhibited by Integrelin in a dose-dependent fashion. The number of clinical events was small, and there were no bleeding differences in the three treatment arms. CONCLUSIONS: Intravenous Integrelin is well tolerated, is a potent reversible inhibitor of platelet aggregation, and added to full-dose heparin reduces the number and duration of Holter ischemic events in patients with unstable angina compared with aspirin.

Lesion-directed administration of alteplase with intracoronary heparin in patients with unstable angina and coronary thrombus undergoing angioplasty.

Percutaneous coronary revascularization in patients with unstable angina and coronary thrombus carries a high complication rate. A new strategy to reduce thrombus burden before revascularization was tested in a multicenter prospective trial. Patients with unstable angina and coronary thrombus (n = 45) received alteplase through an infusion catheter at the proximal aspect of the target lesion and concomitant intracoronary heparin via a standard guiding catheter. Angiography was performed before and alter lesion-directed therapy and post-intervention. Systemic fibrinogen depletion and thrombin activation were not observed, while fibrinolysis was evident for > or = 4 hr after treatment. Target lesion stenosis did not change significantly after lesion-directed therapy, but thrombus score was reduced, particularly among patients who had large thrombi (mean 2.2 vs. 1.6, P = 0.02). Revascularization was successful in 89% of patients. Median final stenosis was 30% and mean final thrombus score was 0.4. Complications included recurrent ischemia (11%), MI (7%), abrupt closure (7%), severe bleeding (4%), and repeat emergency angioplasty (2%). Patients with overt thrombus appeared to derive the most angiographic benefit from lesion-directed alteplase plus intracoronary heparin. Later revascularization was highly successful. This strategy may be a useful adjunct to percutaneous revascularization for patients with unstable angina and frank intracoronary thrombus.

Multicenter, randomized, double-blind, placebo-controlled trial of the platelet integrin glycoprotein IIb/IIIa blocker Integrelin in elective coronary intervention. IMPACT Investigators.

BACKGROUND: Platelet aggregation and thrombosis have been implicated in the pathogenesis of coronary angioplasty complications. Integrelin, a synthetic cyclic heptapeptide with high affinity and marked specificity for platelet integrin glycoprotein IIb/IIIa, effectively blocks ADP-induced platelet aggregation. METHODS AND RESULTS: In 150 patients undergoing elective percutaneous coronary intervention, random assignment was made to one of three treatment regimens: placebo; a 90-micrograms/kg bolus of Integrelin before angioplasty followed by a 1.0-micrograms.kg-1.min-1 infusion of Integrelin for 4 hours; or a 90-micrograms/kg bolus followed by a 1.0-microgram.kg-1.min-1 infusion of Integrelin for 12 hours. Patients were followed to 30 days for the composite occurrence of myocardial infarction, stent implantation, repeat urgent or emergency percutaneous intervention or coronary bypass surgery, or death. Pharmacodynamic data were obtained in a subset of 31 patients. Administration of a 90-micrograms/kg bolus of Integrelin achieved an 86% inhibition of platelet aggregation, and this inhibition was maintained by a 1.0-microgram.kg-1.min-1 infusion. There was a trend toward reduction in end-point events from 12.2% (placebo) to 9.6% (4-hour infusion) to 4.1% (12-hour infusion), although these differences were not statistically significant (P = .13 for the 12-hour group compared with placebo). Major bleeding occurred in 8%, 8%, and 2% of patients, while minor bleeding was observed in 14%, 33%, and 47% of patients, respectively. There was no difference in bleeding index among groups (1.5, 1.7, and 1.3, respectively), defined as [(change in hematocrit/3)+red blood cell units transfused]. CONCLUSIONS: This first clinical investigation of Integrelin during routine, elective, low- and high-risk coronary intervention supports the potential efficacy of Integrelin in routine coronary interventions. Pharmacodynamic analyses demonstrate that profound and sustained inhibition of platelet function is achieved, although a higher bolus dose may be required. Definitive assessment of efficacy and safety will need to await a large-scale study powered to achieve statistical significance.

Predicting the risk of abrupt vessel closure after angioplasty in an individual patient.

OBJECTIVES: We proposed to examine the relation between angiographic morphologic characteristics and abrupt closure after coronary angioplasty and to develop an empirically based risk stratification system. BACKGROUND: Certain lesion morphologic characteristics are associated with higher rates of abrupt closure after coronary angioplasty. Previous approaches have been limited by relatively small sample sizes and an inability to combine multiple characteristics to predict risk in an individual patient. METHODS: Lesion morphology was determined for 779 lesions in 658 patients undergoing an elective first angioplasty. Abrupt closure occurred in 63 lesions (8.1%). Variables associated with abrupt closure were identified by univariate and stepwise multiple logistic regression analysis, and internal validity was assessed by use of bootstrapping. An empirically based scoring system was developed by assigning different weights to each predictive characteristic and was then validated. RESULTS: Almost all lesion characteristics previously labeled "adverse" were associated with an increased risk of abrupt closure, but only total occlusion, location at a branch point, increasing lesion length, evidence for thrombus and right coronary artery location were statistically significant independent predictors. Despite the large sample size, the study was underpowered to detect even a 50% increase in risk with many characteristics. Using a scoring system, we assigned each lesion a specific risk of abrupt closure. The distribution of risk was broad, with 20% of patients having < or = 2.5% risk and 25% having > 10% risk. Internal validation techniques revealed that when 10% of patients were randomly eliminated from the sample in multiple iterations, the risk estimates varied, again pointing to the need for a larger sample. CONCLUSIONS: Empirically based weighting of lesion characteristics could quantify the risk of abrupt closure for individual patients, but a very large sample will be required to understand the interplay of complex lesion characteristics in altering expected outcomes.

Safety and antiplatelet effect of murine monoclonal antibody 7E3 Fab directed against platelet glycoprotein IIb/IIIa in patients undergoing elective coronary angioplasty.

BACKGROUND: Excessive platelet deposition at the site of arterial damage due to coronary angioplasty plays an important role in the pathophysiology of both abrupt closure and restenosis after that procedure. Even aspirin, a relatively weak platelet antagonist, decreases the complications of coronary angioplasty. This study was designed to provide preliminary safety and efficacy data on the use of a much more powerful antiplatelet agent, m7E3 Fab, a prototype murine monoclonal antibody fragment that binds directly to the platelet glycoprotein IIb/IIIa receptor mediating aggregation in patients undergoing coronary angioplasty. METHODS: Twenty-three patients referred for elective coronary angioplasty who met prespecified criteria designed to minimize risk of bleeding received, in groups of four to six patients, escalating bolus doses of 0.15 to 0.35 mg/kg of this agent immediately before coronary angioplasty. Heparin was administered in the usual manner, but aspirin was withheld for 24 hours before coronary angioplasty and until bleeding times and platelet aggregation had returned to normal after angioplasty. Glycoprotein IIb/IIIa binding site occupation, platelet aggregation response to 20 microM of adenosine diphosphate, and data on bleeding times were acquired at baseline and at 2, 6, 24, 48 and 72 hours after m7E3 Fab administration. Clinical safety and efficacy were also monitored throughout the time of hospitalization, and delayed antimurine immune responses were assayed. Five similar patients received aspirin (325 mg orally per day) but otherwise received the same treatment, thus serving as controls. RESULTS: Treatment with m7E3 Fab resulted in a dose-dependent occupation of binding sites to a maximum of 93% at 2 hours in the highest-dose groups, with an associated graded inhibition of platelet aggregation and increase in bleeding time significantly exceeding that seen in control patients, with a gradual recovery over 6 to 48 hours. Percutaneous transluminal coronary angioplasty was successfully performed in 18 of 21 patients (86%) in whom it was attempted. Arterial and venous sheath removal 24 hours after m7E3 Fab dosing was largely uneventful. No thrombotic complications were seen, and only one patient (excluding a patient who underwent uneventful urgent bypass surgery) had bleeding severe enough to require packed red cell transfusion. Eight patients (36%) developed late antibody titers against m7E3 Fab. CONCLUSIONS: This murine monoclonal antibody provides potent antiaggregatory action and thus may be useful in preventing thrombotic complications of coronary angioplasty, but studies of its safety and efficacy during longer infusions and with larger numbers of patients are needed. Less immunogenic forms of the antibody may be more clinically useful.

Acute myocardial infarction associated with initial cocaine use.

We have described a young man who had acute myocardial infarction after his first use of cocaine. This case demonstrates that potentially lethal myocardial infarctions may be associated with such initial "experimentation" with cocaine even in relatively small doses. Cocaine intoxication should be considered in young patients with acute myocardial ischemia or necrosis. We recommend that cocaine metabolites be checked in the urine if a drug history is unreliable in such patients.

Single-channel studies on linear gramicidins with altered amino acid side chains. Effects of altering the polarity of the side chain at position 1 in gramicidin A.

The modulation of gramicidin A single-channel characteristics by the amino acid side chains was investigated using gramicidin A analogues in which the NH2 terminal valine was chemically replaced by other amino acids. The replacements were chosen such that pairs of analogues would have essentially isosteric side chains of different polarities at position 1 (valine vs. trifluorovaline or hexafluorovaline; norvaline vs. S-methyl-cysteine; and norleucine vs. methionine). Even though the side chains are not in direct contact with the permeating ions, the single-channel conductances for Na+ and Cs+ are markedly affected by the changes in the physico-chemical characteristics of the side chains. The maximum single-channel conductance for Na+ is decreased by as much as 10-fold in channels formed by analogues with polar side chains at position 1 compared with their counterparts with nonpolar side chains, while the Na+ affinity is fairly insensitive to these changes. The relative conductance changes seen with Cs+ were less than those seen with Na+; the ion selectivity of the channels with polar side chains at position 1 was increased. Hybrid channels could form between compounds with a polar side chain at position 1 and either valine gramicidin A or their counterparts with a nonpolar side chain at position 1. The structure of channels formed by the modified gramicidins is thus essentially identical to the structure of channels formed by valine gramicidin A. The polarity of the side chain at position 1 is an important determinant of the permeability characteristics of the gramicidin A channel. We discuss the importance of having structural information when interpreting the functional consequences of site-directed amino acid modifications.