Frank I. Navetta

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

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.

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.

Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of the Platelet Integrin Glycoprotein IIb/IIIa Blocker Integrelin in Elective Coronary Intervention

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-μg/kg bolus of Integrelin before angioplasty followed by a 1.0-μg · kg−1 · min−1 infusion of Integrelin for 4 hours; or a 90-μg/kg bolus followed by a 1.0-μg · 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-μg/kg bolus of Integrelin achieved an 86% in...

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.

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

BackgroundExcessive 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 llb/llla receptor mediating aggregation in patients undergoing coronary angioplasty. MethodsTwenty-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 llb/llla binding site occupation, platelet aggregation response to 20 μM 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. ResultsTreatment 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. ConclusionsThis 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.

Effects of profound platelet inhibition with c7E3 before coronary angioplasty on complications of coronary bypass surgery

Abstract In conclusion, this report of 58 patients undergoing emergency bypass surgery after coronary angioplasty demonstrates that surgery can be performed after treatment with c7E3, with acceptable mortality and bleeding complications.

Abciximab and bleeding during coronary surgery: results from the EPILOG and EPISTENT trials ∗

BACKGROUND Abciximab during percutaneous coronary revascularization reduces ischemic complications, but concern exists regarding increased bleeding risk should emergency coronary surgical procedures be required. METHODS Outcomes were assessed among 85 patients who required coronary artery bypass grafting operations after coronary intervention in two randomized placebo-controlled trials of abciximab. Comparisons were made between patients in the pooled placebo and abciximab groups. RESULTS The incidence of coronary surgical procedures was 2.17% and 1.28% among patients randomized to placebo and abciximab, respectively (p = 0.021). Platelet transfusions were administered to 32% and 52% of patients in the placebo and abciximab groups, respectively (p = 0.059). Rates of major blood loss were 79% and 88% in the placebo and abciximab groups, respectively (p = 0.27); transfusions of packed red blood cells or whole blood were administered in 74% and 80% of patients, respectively (p = 0.53). Surgical reexploration for bleeding was required in 3% and 12% of patients, respectively. Death and myocardial infarction tended to occur less frequently among patients who had received abciximab. CONCLUSIONS Urgent coronary artery bypass grafting operations can be performed without an incremental increase in major hemorrhagic risk among patients on abciximab therapy.

A randomized trial of intravenous heparin in conjunction with anistreplase (anisoylated plasminogen streptokinase activator complex) in acute myocardial infarction : the Duke university clinical cardiology study (DUCCS) 1

OBJECTIVES We designed a randomized trial to evaluate the effects of heparin administration in conjunction with anistreplase (anisoylated plasminogen streptokinase activator complex [APSAC]) on arterial patency and clinical end points. BACKGROUND The role of conjunctive intravenous heparin therapy with APSAC has not been tested despite the recommendations that intravenous heparin should be used. METHODS Four hours after APSAC administration, 250 patients with acute myocardial infarction were randomly assigned to receive 325 mg of either aspirin alone or aspirin and a continuous infusion of heparin (15 IU/kg body weight per h). Clinical ischemic events and bleeding complications were monitored. On hospital day 5, coronary arteriography and left ventriculography were performed. RESULTS The primary end point of the trial (the combined outcome of death, reinfarction, recurrent ischemia and occlusion of the infarct-related artery) occurred in 42% of the heparin-treated group versus 43% of the group treated without heparin (p = 0.94). A patent infarct-related artery was present in 80% of the patients treated with heparin and in 73% of those treated without heparin (p = 0.26). Left ventricular function, as measured by ejection fraction, was well preserved in both groups (52% vs. 50.5%, respectively, p = 0.29). The overall bleeding rate was higher in patients with (32%) than without (17.2%) heparin (p = 0.006). CONCLUSIONS Weight-adjusted intravenous heparin therapy after APSAC in acute myocardial infarction does not reduce the combined incidence of death, reinfarction, recurrent ischemia and occlusion of the infarct-related artery. Furthermore, withholding intravenous heparin therapy is associated with a 46% reduction in bleeding complications. Our findings do not support the addition of intravenous heparin after APSAC therapy, as currently recommended, and suggest that a strategy of withholding heparin is simpler and safer and does not place the patient at increased risk for ischemic complications after myocardial infarction.

Effects of atrial natriuretic peptide on the coronary arterial vasculature in humans.

The effects of the synthetic 28-amino-acid alpha-human atrial natriuretic peptide (ANP) on the proximal coronary arteries and coronary blood flow were evaluated in 17 patients. Proximal coronary dimension was quantitated by digital angiography, and coronary flow was quantitated with 3F Doppler flow catheters. ANP, when given as a 2.5-micrograms/kg bolus in the left ventricle, caused sustained significant proximal coronary dilations from 3.49 +/- 0.57 to 4.09 +/- 0.76 mm, lasting more than 30 minutes. The proximal coronary diameter did not increase further after intracoronary injection of 0.3 mg nitroglycerin (4.08 +/- 0.79 mm). Coronary flow (resistance coronary dilation) was not significantly increased at 5 minutes after ANP (87 +/- 55 to 102 +/- 54 vol flow units), indicating that the proximal coronary dilations were not flow dependent. The persistent proximal coronary dilations were associated with minor and transient decreases in aortic pressure and left ventricular end-diastolic pressure and with minor and transient increases in heart rate, cardiac output, and left ventricular contractility. Plasma ANP level increased significantly by more than sixfold from 39.8 +/- 8.8 to 245.8 +/- 168.5 pg/ml. The time course of proximal coronary dilations was related more closely to the time course of increase in plasma cyclic guanosine monophosphate than that of plasma ANP. This study demonstrates that bolus injection of ANP (2.5 micrograms/kg), an endogenous vasodilator, caused marked sustained preferential proximal coronary dilations and brief minor changes in cardiac and systemic hemodynamics. Although additional studies are needed to assess its clinical efficacy as a coronary dilator in the treatment of coronary artery disease, these data suggest a potential of ANP in the therapy of ischemia.

Percutaneous transluminal coronary angioplasty in octogenarians as an effective therapy for angina pectoris

There are limited data regarding percutaneous transluminal coronary angioplasty (PTCA) in patients aged >80 years, a rapidly expanding population that has a 20% prevalence of symptomatic coronary artery disease.1–3 Two studies have reported relatively low success rates, high procedural morbidity and mortality, and no data on restenosis,4,5 whereas a third reported a higher success rate, but had limited angiographic follow-up—only in symptomatic patients.6 We therefore undertook a study to assess the early and long-term outcome of octogenarian patients treated with PTCA.