Pharmacodynamic profile of the direct thrombin antagonist bivalirudin given in combination with the glycoprotein IIb/IIIa antagonist eptifibatide

Background Because of the adverse characteristics associated with heparin, direct antagonists of thrombin have been investigated as anticoagulants during percutaneous coronary interventions. However, the hematologic and clinical interactions between direct thrombin antagonists and inhibitors of platelet glycoprotein IIb-IIIa are incompletely explored. Methods Forty-two patients who underwent elective percutaneous coronary intervention were randomized to receive a bivalirudin 1.0 mg/kg bolus followed by a 4-hour infusion at 2.5 mg/kg/h; a bivalirudin 0.75 mg/kg bolus followed by a 4-hour infusion at 1.75 mg/kg; or a heparin 60 U/kg bolus. All the patients also received eptifibatide, given as 2 sequential boluses of 180 μg/kg followed by a 2 μg/kg/min infusion for 18 to 24 hours, and aspirin. Results After the bolus dose of the study drug, turbidimetric platelet aggregation in response to 5 μmol/L adenosine diphosphate increased in patients assigned to heparin but not those assigned to bivalirudin. After eptifibatide, platelet aggregation was eliminated in all 3 treatment groups. The effect of heparin and the effects of both bivalirudin regimens on the formation of thrombin antithrombin complexes and prothrombin fragment 1.2 were comparable. Neither agent affected the formation of platelet-monocyte complexes or expression of CD 63 lysosomal antigen. There were no major bleeding events, and a single non-Q-wave myocardial infarction (MI) occurred in a patient treated with bivalirudin. Conclusion These findings show the feasibility of combining the direct thrombin antagonist bivalirudin with a potent antagonist of platelet glycoprotein IIb-IIIa. Clinical trials are needed to assess the safety and efficacy of this combination. (Am Heart J 2002;143:585-93.)     

Pharmacodynamic profile of short-term readministration of abciximab in healthy subjects

Objective The purpose of the study was to establish a rebolus regimen for abciximab that restores pharmacologic glycoprotein (GP) IIb/IIIa receptor blockade within a short time frame (up to 48 hours) after completion of an initial treatment. Methods and Results The study was a single-center, nonrandomized, open-label dose escalation trial in healthy volunteers (n = 30). Each subject received a 0.25 mg/kg bolus and a 0.125 μg/kg per minute infusion of abciximab, followed by incremental bolus doses of the agent at 15-minute intervals up to 48 hours (10 per group) after completion of the infusion, (maximal cumulative rebolus dose of 0.25 mg/kg). Pharmacodynamic measurements (GP IIb/IIIa receptor blockade, turbidimetric and whole blood platelet aggregation with use of a rapid platelet function assay [RPFA]) were obtained at periodic intervals during and after administration of the abciximab bolus and infusion. At the time of the first rebolus, pharmacodynamic measurements were attained immediately before administration of each rebolus and 15 minutes after the last rebolus dose. In subjects who received reboluses 12 hours after infusion, a cumulative dose of 0.05 mg/kg restored >80% blockade of GP IIb/IIIa receptors and >80% inhibition of turbidimetric (5 and 20 μmol/L adenosine diphosphate) and RPFA aggregation in 10 of 10 subjects. At 24 hours after treatment, a cumulative abciximab bolus dose of 0.1 mg/kg restored >80% blockade of all 4 pharmacodynamic measurements in 10 of 10 subjects. At 48 hours after treatment, a cumulative bolus dose of 0.15 mg/kg restored >80% blockade of all 4 pharmacodynamic measurements in 10 of 10 subjects. Conclusions A fraction of the bolus of abciximab restored pharmacologic (>80%) GP IIb/IIIa receptor blockade when readministered at various postinfusion time points. These observations suggest that in the setting where acute readministration of abciximab is required less than a full bolus dose of the agent is warranted. (Am Heart J 2002;143:87-94.)     

A randomized two‐by‐two comparison of high‐dose bolus tirofiban versus abciximab and unfractionated heparin versus bivalirudin during percutaneous coronary revascularization and stent placement: The tirofiban evaluation of novel dosing versus abciximab with clopidogrel and inhibition of thrombin (TENACITY) study trial

Background : In the absence of high‐dose thienopyridines, placebo‐controlled trials have demonstrated a reduction in ischemic events with intravenous glycoprotein IIb/IIIa antagonists during percutaneous coronary intervention (PCI). One head‐to‐head trial comparing abciximab and tirofiban among PCI patients found tirofiban to be inferior, and laboratory evidence confirmed that the bolus dose of tirofiban tested in that trial to be less effective than abciximab. Whether a higher bolus dose of tirofiban would be as efficacious as abciximab during PCI is uncertain. Methods and Results : Patients undergoing PCI were randomized equally to abciximab or to tirofiban, given as high‐dose bolus (25 μg/kg) plus 12‐hr infusion (0.15 μg/kg/min). All patients received aspirin and clopidogrel and were additionally randomized to unfractionated heparin or bivalirudin. Approximately 8,000 patients were to be studied, but after 383 were enrolled, the study sponsor discontinued the trial for financial reasons. The primary endpoint of 30‐day death, myocardial infarction, or urgent target vessel revascularization occurred in 8.8% of patients randomized to abciximab and 6.9% of those randomized to tirofiban. The respective rates of major bleeding were 1.5 and 1.6%. Additionally, the primary endpoint occurred in 8.1% of patients randomized to unfractionated heparin and 7.6% of those randomized to bivalirudin. The respective rates of major bleeding were 2.5% and 0.5%. Conclusion : With limited assessment, this direct comparison of high‐dose bolus tirofiban versus abciximab produced encouraging results and suggests that further study of this tirofiban dose regimen is warranted. The limited assessments comparing heparin and bivalirudin are consistent with prior observations. © 2010 Wiley‐Liss, Inc.     

Comparison of bivalirudin versus heparin during percutaneous coronary intervention (the Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical Events [REPLACE]-1 trial)

To assess the efficacy of the direct thrombin inhibitor bivalirudin relative to heparin during contemporary coronary intervention, 1,056 patients who underwent elective or urgent revascularization were randomized in a large-scale pilot study to receive heparin (70 U/kg initial bolus) or bivalirudin (0.75 mg/kg bolus, 1.75 mg/kg/hour infusion during the procedure). All patients received aspirin; pretreatment with clopidogrel was encouraged, and glycoprotein (GP) IIb/IIIa blockade was at the physician's discretion. Stents were placed in 85% of patients; 72% received a GP IIb/IIIa inhibitor, and 56% were pretreated with clopidogrel. Activated clotting times were higher among patients randomized to bivalirudin than among those given heparin before device activation (median 359 vs 293 seconds, p <0.001). The composite efficacy end point of death, myocardial infarction, or repeat revascularization before hospital discharge or within 48 hours occurred in 5.6% and 6.9% of patients in the bivalirudin and heparin groups, respectively (p = 0.40). Major bleeding occurred in 2.1% versus 2.7% of patients randomized to bivalirudin or heparin, respectively (p = 0.52). This trial represents the largest prospective dataset of bivalirudin administered concomitantly with planned GP IIb/IIIa blockade and provides evidence of the safety and efficacy of this combined antithrombotic approach.     

Combination reperfusion therapy with abciximab and reduced dose reteplase: results from TIMI 14. The Thrombolysis in Myocardial Infarction (TIMI) 14 Investigators.

Aims Abciximab has previously been shown to enhance thrombolysis and improve myocardial perfusion when combined with reduced doses of alteplase. The purpose of the reteplase phase of TIMI 14 was to evaluate the effects of abciximab when used in combination with a reduced dose of reteplase for ST-elevation myocardial infarction. Methods and Results Patients (n=299) with ST-elevation myocardial infarction were treated with aspirin and randomized to a control arm with standard dose reteplase (10+10 U given 30 min apart) or abciximab (bolus of 0.25 mg. kg(-1)and 12-h infusion of 0.125 microg. kg(-1). min(-1)) in combination with reduced doses of reteplase (5+5 U or 10+5 U). Control patients received standard weight-adjusted heparin (bolus of 70 U. kg(-1); infusion of 15 U. kg(-1). h(-1)), while each of the combination arms with abciximab and reduced dose reteplase received either low dose heparin (bolus of 60 U. kg(-1); infusion of 7 U. kg(-1). h(-1)) or very low dose heparin (bolus of 30 U. kg(-1); infusion of 4 U. kg(-1). h(-1)). The rate of TIMI 3 flow at 90 min was 70% for patients treated with 10+10 U of reteplase alone (n=87), 73% for those treated with 5+5 U of reteplase with abciximab (n=88), and 77% for those treated with 10+5 U of reteplase with abciximab (n=75). Complete (>/=70%) ST resolution at 90 min was seen in 56% of patients receiving a reduced dose of reteplase in combination with abciximab compared with 48% of patients receiving reteplase alone.Conclusions Reduced doses of reteplase when administered in combination with abciximab were associated with higher TIMI 3 flow rates than reported previously for reduced doses of reteplase without abciximab and were at least as high as for full dose reteplase alone Copyright 2000 The European Society of Cardiology.     

The anticoagulant therapy with bivalirudin to assist in the performance of percutaneous coronary intervention in patients with heparin-induced thrombocytopenia (ATBAT) study: main results

Up to 5% of patients given heparin develop heparin-induced thrombocytopenia (HIT). These patients may need anticoagulation for acute coronary syndromes (ACS) or percutaneous coronary intervention (PCI), a clinical challenge given the limited alternatives. In a prospective, open-label study, we evaluated the safety and efficacy of bivalirudin in patients with HIT or HIT with thrombotic syndrome (HITTS) undergoing PCI. Patients aged 18 years were enrolled in 24 centers in 2 countries. Bivalirudin was given 5 minutes before PCI (1 mg/kg bolus; 2.5 mg/kg/hour infusion for 4 hours [high-dose group] or 0.75 mg/kg bolus; 1.75 mg/kg/hour infusion [low-dose group]). Clinical and hematological measures were assessed within 24 hours after starting bivalirudin, just before PCI, just before sheath removal, and 48 hours after treatment or at discharge, whichever occurred first. The primary endpoint was major bleeding 48 hours after discontinuation or until discharge, whichever occurred first. From July 1999 to February 2003, 52 patients were recruited. Procedural success (TIMI grade 3 flow and < 50% stenosis) was achieved in 98% of patients, and clinical success (absence of death, emergency bypass surgery, or Q-wave infarction) was achieved in 96%. One high-dose patient who underwent elective bypass surgery had major bleeding (1.9%; 95% CI: 0.05 10.65%), and 7 patients had minor bleeding. No patient had significant thrombocytopenia (platelet count < 50 109/L) after treatment. One patient in the low-dose group died from cardiac arrest ~46 hours after uncomplicated PCI. Bivalirudin appeared safe and provided effective anticoagulation during PCI. These data, and extensive experience with bivalirudin in PCI, support its use in high-risk patients with HIT requiring PCI.     

Quantification of abciximab-induced platelet inhibition is assay dependent: a comparative study in patients undergoing percutaneous coronary intervention

Background The best method for measuring the degree of platelet inhibition with glycoprotein (GP) IIb-IIIa antagonists during percutaneous coronary intervention (PCI) and the optimal degree of periprocedural inhibition is uncertain. Low molecular weight heparins have been reported to cause less platelet activation than unfractionated heparin. Therefore, compared with unfractionated heparin (UHF), a low molecular weight heparin could enhance measured platelet inhibition. In this study, we compared 3 methods of measuring platelet inhibition and investigated the effects of half doses of abciximab in combination with either UFH or the low molecular weight heparin dalteparin in patients undergoing PCI with planned abciximab administration. Methods Abciximab-induced platelet inhibition was measured serially by means of 3 assays: 1) GP IIb-IIIa receptor occupancy, 2) binding of the activated GP IIb—IIIa-specific monoclonal antibody PAC1, and 3) agglutination of platelets with fibrinogen-coated beads (RPFA). Forty patients were randomly allocated to receive either UFH (70 U/kg) or dalteparin (60 IU/kg), followed by a half dose of abciximab (0.125 mg/kg) administered twice at 10-minute intervals. Assays were obtained 10 minutes after each half dose of abciximab and 8 to 10 and 24 hours after abciximab administration. Results No differences between UFH and dalteparin were observed. At each time-point measured, the mean percent platelet inhibition as determined by means of the receptor occupancy assay and PAC1 binding assay was less than the degree of inhibition determined by means of the RPFA. Conclusions The results of targeted levels of platelet inhibition cannot be extrapolated between different clinical trials of GP IIb-IIIa antagonists unless the same assay is used. Dalteparin, compared with UFH, does not enhance platelet inhibition or receptor occupancy by abciximab, as demonstrated by means of 3 separate assays. (Am Heart J 2003;145:e6.)     

Association of prerandomization anticoagulant switching with bleeding in the setting of percutaneous coronary intervention (A REPLACE-2 analysis)

The REPLACE-2 trial of patients who underwent urgent or elective percutaneous coronary intervention (PCI) demonstrated a significantly lower bleeding risk with bivalirudin plus provisional glycoprotein IIb/IIIa inhibitor compared with unfractionated heparin with planned glycoprotein IIb/IIIa inhibitor. The goal of this analysis was to evaluate whether a hazard existed when unfractionated heparin or low-molecular-weight heparin was administered before study medication in the REPLACE-2 trial. The REPLACE-2 trial randomized 6,010 patients undergoing PCI to receive bivalirudin plus provisional glycoprotein IIb/IIIa inhibitor or unfractionated heparin plus planned glycoprotein IIb/IIIa inhibitor. The present study compared bleeding among patients treated with or without antithrombin therapy in the 48 hours before study treatment. Among patients treated with bivalirudin, there was no difference in protocol-defined major or minor bleeding, bleeding according to Thrombolysis In Myocardial Infarction criteria, or noncoronary artery bypass graft blood transfusions between the patients treated with versus without antithrombin therapy (p=NS). However, in patients treated with unfractionated heparin plus planned glycoprotein IIb/IIIa inhibitor, there was a significant increase in the composite of protocol-defined major or minor bleeding and in noncoronary artery bypass graft blood transfusions (p<0.05 for 3-way comparison vs no unfractionated heparin and for 2-way comparisons of no unfractionated heparin vs unfractionated heparin or low-molecular-weight heparin). In conclusion, in patients treated with bivalirudin, pretreatment with antithrombin therapy was not associated with increased bleeding. In contrast, among patients randomized to receive unfractionated heparin and planned glycoprotein IIb/IIIa, pretreatment with antithrombin therapy was associated with increased protocol-defined composite major or minor bleeding and increased need for transfusion.     

Reduced inhibition by abciximab in platelets with the Pl polymorphism

Background The Pl^A2 polymorphism of the glycoprotein IIb/IIIa (fibrinogen) receptor has been associated with increased restenosis and stent thrombosis. We postulated that this allele could alter the antiplatelet effect of abciximab in patients undergoing percutaneous coronary intervention. Methods Optical platelet aggregation assays, Ultegra (Accumetrics, San Diego) rapid platelet function assays, and radiometric abciximab binding assays were performed in 66 Pl^A1/A1 and 21 Pl^A1/A2 patients undergoing percutaneous coronary interventions. The affinity of abciximab for the Pl^A1 and Pl^A2 receptors was determined with use of transfected cells. Results Compared with Pl^A1/A1 homozygotes, Pl^A1/A2 platelets were less completely inhibited after abciximab bolus (P = .002) and at 24 hours (P = .02) as assessed by the rapid platelet function assays. Optical aggregation assays confirmed that Pl^A1/A2 platelets were less completely inhibited after abciximab bolus (P = .05). The radiometric abciximab binding assay demonstrated that the Pl^A1/A2 platelets had fewer baseline fibrinogen receptors than did the Pl^A1/A1 platelets (P = .04) and more free fibrinogen receptors at 24 hours (P = .008). Cells transfected to express homozygous Pl^A1 or Pl^A2 demonstrated a nonsignificant trend (P = .12) for reduced abciximab affinity for Pl^A2. Conclusions Pl^A1/A2 platelets are less completely inhibited with abciximab, contributing to the observed interindividual variability in platelet function inhibition. Because the extent of platelet inhibition is an independent predictor for the risk of major adverse coronary events after percutaneous coronary intervention, the relative resistance of Pl^A2-positive platelets may contribute to a less favorable outcome in these patients. (Am Heart J 2002;143:76-82.)     

Effect of bivalirudin compared with unfractionated heparin plus abciximab on infarct size and myocardial recovery after primary percutaneous coronary intervention: the horizons-AMI CMRI substudy

Background : Myocardial infarct size is a strong independent predictor of mortality in patients with ST‐elevation myocardial infarction (STEMI). In the Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction (HORIZONS‐AMI) trial, bivalirudin compared with unfractionated heparin plus a glycoprotein IIb/IIIa inhibitor reduced cardiac mortality in STEMI patients, which was attributed to reduced major bleeding. Whether a possible reduction in infarct size with bivalirudin may have contributed to the enhanced survival with this agent is unknown. Methods : Cardiac magnetic resonance imaging was performed within 7 days and after 6 months in 51 randomized patients from a single center in HORIZONS‐AMI trial (N = 28 bivalirudin, N = 23 heparin plus abciximab). Infarct size, microvascular obstruction (MVO), left ventricular ejection fraction (LVEF), and LV end‐diastolic and end‐systolic volume indices were evaluated. Results : Infarct size was not significantly different after treatment with bivalirudin compared with heparin plus abciximab either within 7 days (median 9.3% [interquartile range 4.9%, 26.6%] vs. 20.0% [5.9%, 28.2%], P = 0.28) or at 6 months 6.7% [3.8%, 20.0%] vs. 8.2% [1.8%, 16.5%], P = 0.73). MVO was present in 28.6% versus 34.8% of patients respectively (P = 0.63). LVEF and LV volume indices also did not significantly differ between the two groups at either time period, nor were differences in myocardial recovery evident. Conclusions : In conclusion, in the HORIZONS‐AMI Cardiac magnetic resonance imaging (CMRI) substudy, cardiac magnetic resonance imaging within 7 days and at 6 months after primary percutaneous coronary intervention (PCI) did not demonstrate significant differences in infarct size, MVO, LVEF, or LV volume indices in patients treated with bivalirudin compared with unfractionated heparin plus abciximab. © 2011 Wiley Periodicals, Inc.     

Comparison of bivalirudin versus heparin on radial artery occlusion after transradial catheterization

Background : Anticoagulant therapy is required to prevent radial artery occlusion (RAO) after transradial catheterization. There is no data comparing bivalirudin to standard heparin. Methods : We studied 400 consecutive patients. In case of diagnostic angiography‐only (n = 200), they received an intravenous bolus of heparin (70 U kg^?1) immediately before sheath removal whereas in case of angiography followed by ad hoc percutaneous coronary intervention (n = 200), they received bivalirudin (bolus 0.75 mg kg^?1, followed by infusion at 1.75 mg/kg/h). RAO was assessed 4–8 weeks later using two‐dimensional echography‐doppler and reverse Allen's test with pulse oximetry. Results : At follow‐up, 21 of the 400 (5.3%) patients were found to have RAO with no significant difference between the two groups (3.5% bivalirudin vs. 7.0% heparin, P = 0.18). Patients with RAO had a significantly lower weight compared to patients without RAO (78 ± 13 kg vs. 86 ± 18 kg, P = 0.011). By multivariate analysis, a weight <84 kg (OR: 2.78, 95% CI 1.08–8.00, P = 0.032) and a procedure duration ≤20 min (OR: 7.52, 95% CI 1.57–36.0, P = 0.011) remained strong independent predictors of RAO. All cases of radial occlusion were asymptomatic and without clinical sequelae. Conclusion : Delayed administration of bivalirudin or heparin for transradial catheterization provides similar efficacy in preventing RAO. Because of its low cost, a single bolus of heparin can be preferred in case of diagnostic angiography whereas bivalirudin can be contemplated in case of ad hoc percutaneous coronary intervention. © 2010 Wiley‐Liss, Inc.     

Long term efficacy of abciximab bolus‐only compared to abciximab bolus and infusion after transradial coronary stenting

Background: No data are available on the long term efficacy of abciximab bolus‐only with aspirin and clopidogrel pretreatment and systematic coronary stenting. Our objective was to evaluate the 3‐year clinical outcomes in the EASY trial. Methods: After a bolus of abciximab (0.25 mg/kg) and uncomplicated transradial coronary stenting, 1,005 patients were randomized either to same‐day home discharge and no infusion (bolus‐only group, n = 504) or to overnight hospitalization and 12 hours abciximab infusion (bolus + infusion group, n = 501). In contrast, 343 patients were not randomized after stenting for safety reasons and received abciximab bolus and infusion (not‐randomized group). The rate of major adverse cardiovascular events (MACE), including death, myocardial infarction (MI) and target vessel revascularization (TVR) after percutaneous coronary intervention (PCI) was evaluated. Results: Up to 3 years, the incidence of MACE remained similar in the two randomized groups, 14% in bolus‐only vs. 17% in bolus + infusion (P = 0.38). Similar efficacy was observed in subgroups analysis including higher‐risk patients such as those with diabetes, unstable angina or non‐ST elevation MI. Conversely, the incidence of MACE remained significantly higher in patients not‐randomized post‐PCI at all time intervals (P < 0.0001). The difference in outcomes between randomized and not‐randomized patients was mostly accounted by the higher rates of MI, TVR as survival rate remained similar. Conclusion: In patients pretreated with aspirin and clopidogrel and undergoing uncomplicated coronary artery stenting, abciximab bolus‐only was associated with similar outcomes compared with bolus followed by infusion, up to 3 years after PCI. Conversely, patients with suboptimal results or clinical complications during PCI remained at higher risk of late revascularization or MI. © 2009 Wiley‐Liss, Inc.     

Bivalirudin compared with IIb/IIIa inhibitors in patients with in-stent restenosis undergoing intracoronary brachytherapy

BACKGROUND: Bivalirudin is replacing heparin in percutaneous coronary interventions (PCIs), including vascular brachytherapy (VBT). The aim of the study was to compare bivalirudin with eptifibatide in patients with in-stent restenosis (ISR) undergoing PCI and VBT. METHODS: One hundred forty-four patients treated with bivalirudin as a single antithrombotic agent were compared with 150 patients treated with eptifibatide. Bivalirudin as a bolus of 0.75 mg/kg followed by 1.75 mg/kg/h infusion until the end of the procedure, and eptifibatide as a double bolus of 180 microg/kg followed by 2 microg/kg/min infusion for 18 h after the procedure were used. The main outcome measures were in-hospital events and 30-day clinical outcomes. RESULTS: Baseline clinical characteristics were similar except that patients in the eptifibatide group were younger (P=.02) and had more saphenous vein graft lesions (P<.001). Patients in the bivalirudin group had a higher number of lesions in the right coronary artery (P<.001) and a higher number of vessels treated (P<.001). Postprocedure creatinine phosphokinase (CPK)-MB levels were significantly lower in the bivalirudin group (P<.03). In-hospital events showed significantly less minor bleeding (P=.01) and a trend toward lower major bleeding and major adverse cardiac events (MACE) in the bivalirudin group (P=.06). Thirty-day outcomes showed a significantly lower incidence of non-Q-wave myocardial infarction (MI) in the bivalirudin group (P=.004). CONCLUSION: Bivalirudin, as a single antithrombotic agent during PCI and VBT, is associated with significantly lower postprocedural CPK-MB elevation, minor bleeding complications, 30-day non-Q-wave MI rates, and a trend toward lower major bleeding and in-hospital MACE when compared with eptifibatide.     

Effect of prolonged Bivalirudin infusion on ST-segment resolution following primary percutaneous coronary intervention (from the PROBI VIRI 2 study)

Bivalirudin is widely used as an anticoagulant during percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction. However, an increase in acute stent thrombosis rates has been found in the HORIZONS-AMI trial. A prolonged infusion after PCI has been shown to be a safe and effective tool in patients undergoing urgent or elective PCI in the PROBI VIRI study. We examined the effects of prolonged drug infusion after primary PCI. From databases of 5 high-volume centers we compared a group of patients treated with a 4-hour prolonged infusion after PCI to 2 groups treated with a peri-PCI infusion and heparin plus abciximab. The primary study end point was >70% ST-segment resolution within 90 minutes after PCI; secondary end points were partial (>50%) ST-segment resolution within 90 minutes and intrahospital major and minor bleedings on the Acuity scale. The study population consisted of 264 patients undergoing primary PCI who were pretreated with aspirin and clopidogrel. The 3 study groups did not differ significantly by baseline characteristics. The primary end point was achieved in 69.8%, 48.8%, and 69.6% of patients in the prolonged bivalirudin, bivalirudin, and heparin/abciximab groups, respectively (p = 0.048 for prolonged vs standard infusion, p = 0.98 for prolonged infusion vs abciximab). Major bleedings and other secondary study end points were not significantly different among study groups. In conclusion, a strategy of prolonged bivalirudin infusion after primary PCI seems equivalent to a strategy with heparin plus abciximab, with an improvement in standard infusion in obtaining early microvascular reperfusion.     

The Ultegra rapid platelet-function assay: comparison to standard platelet function assays in patients undergoing percutaneous coronary intervention with abciximab therapy

Background Despite the proven benefit of glycoprotein IIb/IIIa inhibitors during percutaneous coronary intervention, significant interpatient variability exists in antiplatelet response. Furthermore, a diminished degree of platelet inhibition is an independent predictor of adverse cardiac events, highlighting the need for accurate and precise monitoring of platelet function. Methods Patients (n = 192) who underwent elective percutaneous coronary intervention at 4 centers were enrolled. The following 3 time points were studied: 1, baseline, before abciximab bolus administration; 2, during, within 1 hour of abciximab bolus administration; and 3, post, 24 hours after abciximab bolus administration or at the time of patient discharge, whichever occurred first. The following 3 assays were compared at all time points: Ultegra rapid platelet-function assay (Ultegra RPFA), conventional turbidometric platelet aggregometry, and receptor binding assay with [¹²⁵I]-abciximab. Variability in Ultegra RPFA measurements between operators was determined with performance of the assays at the point of care and in the laboratory. A sub-study of 22 patients at 1 center was performed in which the laboratory scientist performed all 3 assays in duplicate at each time point. Results Comparison with the receptor binding assay and conventional platelet aggregometry in 120 patients showed that the Ultegra RPFA correlated with aggregometry (r = 0.89) and with the receptor binding assay (r = 0.89). There was good agreement (r = 0.80) between values obtained by intended users and those obtained by laboratory scientists. Furthermore, Ultegra RPFA values had equivalent precision to the standard assays. Conclusion The Ultegra RPFA has equivalent accuracy and precision when compared with the 2 reference assays studied. Ultegra RPFA measurements are not operator-dependent and are not influenced by concomitant medications, hematologic parameters, or demographics. (Am Heart J 2002;143:602-11.)     

Antiplatelet effects of abciximab, tirofiban and eptifibatide in patients undergoing coronary stenting

OBJECTIVES: We sought to investigate whether abciximab, tirofiban and eptifibatide achieve comparable antiplatelet effects with coronary stenting. BACKGROUND: The glycoprotein (GP) IIb/IIIa antagonists abciximab, tirofiban and eptifibatide differ in chemical structure, binding site and pharmacokinetics. METHODS: Sixty patients undergoing coronary stenting were randomly assigned to abciximab (bolus 0.25 mg/kg body weight, infusion 10 microg per min for 12 h), tirofiban (bolus 10 microg/kg, infusion 0.15 microg/kg per min for 72 h) or eptifibatide (bolus 180 microg/kg, infusion 2 microg/kg per min for 72 h). We took serial blood samples to analyze platelet function by using flow cytometry, turbidimetric aggregometry and the rapid platelet-function assay (RPFA). RESULTS: As assessed by RPFA, platelet aggregation after 2 h of infusion was reduced to 5.9 +/- 7.8% (mean +/- SD) of baseline by abciximab, to 5.0 +/- 5.4% by tirofiban and to 7.8 +/- 7.1% by eptifibatide (p = 0.42). Turbidimetric aggregometry with adenosine diphosphate stimulation yielded similar results, whereas percent inhibition of platelet aggregation after thrombin receptor stimulation was 45.8 +/- 16.8% with abciximab, 51.3 +/- 17.6% with tirofiban and 52.9 +/- 14.8% with eptifibatide (p = 0.37). Tirofiban and eptifibatide maintained their level of platelet inhibition during infusion. Flow cytometry revealed that the reduction in the monocyte-platelet interaction by abciximab, tirofiban and eptifibatide was not significantly different (20.0 +/- 21.9%, 23.8 +/- 18.2% and 21.0 +/- 19.8%, respectively; p = 0.87). CONCLUSIONS: Abciximab, tirofiban and eptifibatide, at currently recommended doses, achieved similar levels of inhibition of platelet aggregation and a similar reduction in the platelet-monocyte interaction.     

Enoxaparin and abciximab adjunctive pharmacotherapy during percutaneous coronary intervention

Randomized controlled trials of patients with non-ST segment elevation acute coronary syndromes have established the superiority of enoxaparin (versus unfractionated heparin) for reducing adverse ischemic outcomes. Furthermore, adjunctive abciximab therapy during percutaneous coronary intervention (PCI) is associated with improved clinical outcomes. Since algorithms for integrating these pharmacotherapies have not been determined, patients undergoing elective PCI were enrolled into 2 distinct and separate studies conducted by the National Investigators Collaborating on Enoxaparin (NICE) study groups (NICE 1 and NICE 4 studies). Patients in NICE 1 were administered enoxaparin 1.0 mg/kg intravenously (without abciximab) and those enrolled in NICE 4 were administered a reduced dose (0.75 mg/kg) of enoxaparin in combination with standard-dose abciximab intravenously during PCI. Bleeding events and ischemic outcomes assessed in-hospital and at 30-days post-PCI were infrequent with either pharmacologic regimen. In the dose regimens studied, enoxaparin with or without abciximab appears to provide safe and effective anticoagulation during PCI. The combination of reduced-dose enoxaparin and abciximab was associated with a low incidence of adverse outcomes (bleeding or ischemic events). Additional studies may be required to establish the relative safety and efficacy of this new adjunctive pharmacologic strategy when compared with the combination of low-dose, weight-adjusted unfractionated heparin and abciximab.     

Single center experience with provisional abciximab therapy in complex lower limb interventions

Background: Abciximab, a glycoprotein IIb/IIIa antagonist has been shown to improve patency and clinical outcome in patients undergoing endovascular recanalization of femoro-popliteal occlusions. However, data on abciximab therapy in complex peripheral catheter interventions of lower limbs are quite limited. The objective of this retrospective study was to evaluate the clinical and hemodynamic outcomes of patients treated with provisional abciximab during complex peripheral catheter interventions. Patients and methods: Analysis of a consecutive series of 44 patients with provisional abciximab therapy in complex peripheral catheter interventions with imminent risk of early rethrombosis defined as revascularization of arterial occlusions associated with one or more of the following additional circumstances named as time-consuming intervention > 3 hours, compromised contrast flow not solved by stenting, distal embolization not solved by mechanical thromboembolectomy, and peri-interventional notice of thrombus evolution despite adequate heparin adjustment of lower limbs. Adjunctive abciximab therapy was started in accordance to percutaneous coronary bailout situations. The decision to add abciximab was based on the decision of the operator and went along with the judgement that there is a rising risk of reocclusion due to the progressive complexity of an individual intervention. A bolus of 0.25 mg per kilogram of body weight, followed by a maintenance infusion of 0.125 mug/kg/min (up to a maximum dosage of 10 mug/min) for 12 hours was administered. Clinical and hemodynamic outcome was prospectively assessed at discharge, three and six months after the index procedure. Results: The occluded artery of 44 limbs was in the iliac (2%), in the femoro-popliteal (73%) or below the knee segment (25%). Overall, occlusion length was 11.5 +/- 6.5 cm. Technical success rate was 95%. Mean ABI increased from 0.5 +/- 0.16 to 0.88 +/- 0.19 (p < 0.001) with immediate hemodynamic improvement of 91%. Overall, sustained clinical improvement was 84% and 66% at three and six months follow-up, with best results in iliac (100%), followed by below the knee (73%) and by femoro-popliteal segment (63%) at six months, respectively. Overall, secondary clinical improvement was 86% at six months. Minor and major bleeding complications were 16% and 9%, respectively. Conclusion: Abciximab should be noticed as medical adjunct in the interventional armamentarium to prevent imminent rethrombosis in complex peripheral catheter interventions.     

Prophylactic intravenous use of milrinone after cardiac operation in pediatrics (PRIMACORP) study

Background Many pediatric patients undergoing cardiac surgery involving cardiopulmonary bypass have a predictable fall in the cardiac index 6 to18 hours after surgery, the so-called low cardiac output syndrome (LCOS). Because patients who have LCOS require more monitoring and support and have a prolonged stay in the intensive care unit, the syndrome is associated with a costly morbidity. Milrinone, a phosphodiesterase III inhibitor, improves cardiac muscle contractile force and vascular muscle relaxation through positive inotropic and vasodilatory effects. The purpose of the Prophylactic Intravenous Use of Milrinone After Cardiac Operation in Pediatrics (PRIMACORP) study is to evaluate the safety and efficacy of the prophylactic use of milrinone in pediatric patients at high risk for development of LCOS after undergoing cardiac surgery. Methods Patients in the multicenter, randomized, double-blind, placebo-controlled, parallel treatment study will be randomized to 1 of 3 treatment arms: (1) low-dose milrinone (25 μg/kg intravenous bolus over 60 minutes followed by a 0.25 μg/kg/min infusion for 35 hours), (2) high-dose milrinone (75 μg/kg intravenous bolus over 60 minutes followed by a 0.75 μg/kg/min infusion for 35 hours), or (3) placebo. Results The primary end point for efficacy evaluation will be based on a composite variable consisting of death or development of LCOS requiring additional mechanical or pharmacologic support, up to 36 hours after randomization. A 2-sided test with a 0.025 type I error will be used for the primary end point analysis. The PRIMACORP study will enroll a total of 240 patients. Six additional secondary end points will be analyzed. Conclusions The PRIMACORP study will address several questions regarding the safety and efficacy of prophylactic milrinone use in pediatric patients at high risk for development of LCOS after cardiac surgery. (Am Heart J 2002;143:15-21.)     

Antithrombotic efficacy of bivalirudin compared to unfractionated heparin during percutaneous coronary intervention for acute coronary syndrome

Bivalirudin is associated with an increased risk of acute stent thrombosis (AST) compared to unfractionated heparin (UFH) in acute coronary syndrome patients (ACS) during short-duration percutaneous coronary intervention (PCI). The mechanisms involved are unknown. We aimed to investigate the antithrombotic efficacy of bivalirudin compared to UFH during PCI. In a monocenter study, we prospectively enrolled 30 patients undergoing PCI for a non–ST elevation ACS. They were randomly assigned to a single intravenous (IV) bolus of UFH (70 IU/kg) or an IV bolus of bivalirudin 0.75 mg/kg followed by a 1.75 mg/kg/h infusion during PCI. All patients received a loading dose (LD) of 180 mg of ticagrelor at the time of PCI. The VASP index and activated partial thromboplastin time (aPTT) were used to assess the course of platelet reactivity (PR) and antithrombotic activity. The two groups were similar regarding baseline, angiographic, and interventional characteristics. There was no difference between the two groups in the course of PR following ticagrelor LD. An optimal PR inhibition was obtained 4 h after the LD of ticagrelor. The level of antithrombotic activity was significantly lower in the bivalirudin group compared to the UFH group (p < 0.001) during PCI but similar at 2 and 4 h post-PCI. We observed that, in ACS undergoing PCI, the antithrombotic efficacy of an IV bolus of bivalirudin is significantly lower than that of a 70-IU/kg UFH bolus. This could contribute to the excess in thrombotic acute events observed during short-duration PCI.