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.)     

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.)     

Comparison of GP IIB/IIIA Inhibitors and Their Activity as Measured by Aggregometry, Flow Cytometry, Single Platelet Counting, and the Rapid Platelet Function Analyzer

Background: GP IIb/IIIa inhibitors have primarily been used short-term e.g., during PTCA. They failed to show clinical benefit during long-term therapy. One reason might be the absence of a method to monitor inhibitor activity. This study compared platelet aggregometry, the rapid platelet function analyzer (RPFA) test, single platelet counting, and flow cytometric determination of receptor occupancy to measure GP IIb/IIIa-receptor inhibitor activity. Methods: Increasing doses of abciximab, tirofiban, and eptifibatide were added to whole blood in vitro. Whole blood was used for the RPFA, for single platelet counting and flow cytometry. Platelet rich plasma was prepared for aggregometry. Results: The correlation between aggregometry and RPFA results was linear for abciximab and eptifibatide. Tirofiban was a stronger inhibitor with the RPFA (IC₅₀ 7.7[emsp4 ]nM) than with aggregometry (IC₅₀ 19.6[emsp4 ]nM). The single platelet counting technique showed that even supratherapeutic concentrations of all three inhibitors could not completely suppress microaggregation. Abciximab concentrations that were equipotent to tirofiban with aggregometry were less potent with regards to the inhibition of microaggregation. This difference was more pronounced with TRAP induced microaggregation than with ADP. The flow cytometric receptor occupancy test showed that occupancy was 95[emsp4 ]% with 5[emsp4 ]g/ml abciximab and almost 97[emsp4 ]% with 10[emsp4 ]g/ml. Tirofiban reached a maximum receptor occupancy of 56[emsp4 ]%, eptifibatide 64[emsp4 ]%. Conclusions: While aggregometry is time consuming the RPFA provides results fast and with little variability. There is still a discrepancy between aggregometry and RPFA results for tirofiban. The single platelet counting technique detects the inhibition of microaggregation the relevance of which for the clinical outcome is not known. The flow cytometric receptor occupancy assay is best suited for abciximab.     

Promise of combined low-molecular-weight heparin and platelet glycoprotein IIb/IIIa inhibition: results from Platelet IIb/IIIa Antagonist for the Reduction of Acute coronary syndrome events in a Global Organization Network B (PARAGON B)

Background Low-molecular-weight heparin (LMWH) has a more predictable anticoagulant effect than unfractionated heparin (UFH), is easier to administer, and does not require monitoring. Minimal data are available on LMWH combined with platelet glycoprotein (GP) IIb/IIIa inhibitors. Methods In the Platelet IIb/IIIa Antagonist for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network B (PARAGON B) trial, patients with an acute coronary syndrome were randomized to receive the IIb/IIIa inhibitor lamifiban or a placebo. To rigorously explore the potential benefits of LWMH and GP IIb/IIIa inhibition, we analyzed the rates of ischemic complications and safety outcomes in PARAGON B. Results Approximately one fifth of the patients received LMWH (805 vs 4395 UFH). For the overall cohort, the incidence of death/myocardial infarction (MI)/severe recurrent ischemia (SRI) was 12.2%, and this composite end point was numerically lowest in the lamifiban with LMWH group (10.2%). Similarly, the incidence of death/MI was 11.0% for the entire cohort and lowest in the lamifiban and LMWH group (9.0%). The lower event rate for patients taking LMWH in the lamifiban group was sustained at 6 months, with a lower revascularization rate (51.5% vs 42.8%) and a lower composite of death/MI (13.8% vs 11.9%). Bleeding was comparable in the 2 heparin groups (1.4% with UFH vs 0.9% with LMWH). The propensity adjusted odds ratio for 30-day revascularization was significantly lower with LMWH (odds ratio 0.67, 95% CI 0.57−0.79, P < .001). There were no significant differences in death/MI/SRI at 30 days (P = .465), death/MI at 30 days (P = .264), and stroke at 30 days with the type of heparin use (P = .201) after propensity risk adjustment. Conclusions In the PARAGON B trial, use of LMWH in conjunction with a GP IIb/IIIa inhibitor was safe and associated with a lower revascularization rate. These findings support the rationale and promise for combining GP IIb/IIIa blockers and LMWH for future management of acute coronary syndrome. (Am Heart J 2002;144:995-1002.)     

A comparative study of light transmission aggregometry and automated bedside platelet function assays in patients undergoing percutaneous coronary intervention and receiving abciximab, eptifibatide, or tirofiban.

Platelet inhibition is central to the efficacy of glycoprotein (GP) IIb-IIIa antagonist therapy, but is not routinely measured during percutaneous coronary intervention (PCI). Data directly comparing the antiplatelet effects of these agents are also limited. Therefore, we compared ex vivo platelet function by standard light transmission aggregometry (LTA) and two automated bedside platelet function assays in 36 patients undergoing PCI with GP IIb-IIIa inhibitors. At baseline and 10 min following clinically recommended bolus and infusion of abciximab (0.25 mg/kg, 0.125 microg/kg/min), eptifibatide (180 microg/kg, 2 microg/kg/min), or tirofiban (10 microg/kg, 0.1 microg/kg/min), we measured 20 microM ADP- and 1.9 mg/mL collagen-induced platelet aggregation using LTA. Platelet function was also assessed using the bedside Accumetrics Ultegra-Rapid Platelet Function Assay (RPFA) and the Xylum Clot Signature Analyzer (CSA). The degree of platelet inhibition, as assessed by LTA, varied significantly between the clinically recommended doses of these GP IIb-IIIa antagonists. RPFA measurements agreed closely with LTA for abciximab, but tended to overestimate the degree of platelet inhibition for small molecules. CSA demonstrated profoundly inhibited shear-induced platelet function, but lacked sensitivity to discriminate between agents. These findings may have implications for the results of trials comparing the efficacy of these agents in patients undergoing PCI.     

Determination of platelet aggregation inhibition during percutaneous coronary intervention with the platelet function analyzer PFA-100

Background A simple device to rapidly evaluate platelet function may aid in optimizing glycoprotein IIb/IIIa inhibition during percutaneous coronary intervention (PCI). We prospectively studied platelet function in 250 patients receiving abciximab or eptifibatide during PCI. Methods and Results The platelet function analyzer PFA-100 (Dade-Behring, Deerfield, Ill) measures platelet function by determining the time to occlusion of an aperture in a biochemically active membrane as whole blood flows under high shear conditions. Platelet aggregation causes aperture occlusion, and results are reported as a closure time (CT). All patients received either abciximab or eptifibatide, along with aspirin and heparin; patients undergoing stent implantation received aspirin and a thienopyridine postprocedure. The CT was measured at baseline and 10 minutes, 4 hours, 12 hours (abciximab-only), and 24 hours after the bolus. Profound inhibition was exhibited in most patients shortly after the platelet inhibitor bolus and during the course of therapy. We observed recovery of platelet function 12 hours after discontinuation of abciximab, with a high degree of interpatient variability, and ongoing profound platelet inhibition 4 to 6 hours after the discontinuation of eptifibatide. Among patients treated with abciximab, patients who were obese recovered from platelet inhibition sooner than patients who were not obese, whereas patients who were elderly had delayed recovery compared with patients who were not elderly. Failure to achieve maximal platelet inhibition (nonclosure) at 10 minutes indicated a possible association with adverse clinical events at the 6-month follow-up examination (60% vs 20%). Conclusions PFA-100 is a rapid simple assay used as a means of assessing inhibition of platelet aggregation during PCI performed with glycoprotein IIb/IIIa inhibition. Failure to achieve nonclosure early after the initiation of abciximab therapy warrants further investigation because there may be an association with adverse cardiac events at 6-month follow-up. (Am Heart J 2002;144:151-8.)     

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.)     

Combination Enoxaparin and Abciximab During Percutaneous Coronary Intervention: A New Standard of Care?

Evidence from randomized trials supports the administration of platelet glycoprotein (GP) IIb/IIIa blockade both to patients undergoing percutaneous coronary intervention (PCI) and those presenting with non-ST elevation acute coronary syndromes (ACSs). Similarly, the low molecular weight heparin (LMWH), enoxaparin, has demonstrated superior efficacy when compared with unfractionated heparin (UFH) in the treatment of patients with non-ST elevation ACS. Algorithms for seamless integration of pharmacotherpy through the course of hospitalization for patients who present with ACS and who require PCI will likely combine therapy with enoxaparin and platelet GP IIb/IIIa blockade (abciximab). Our preliminary experience with combination enoxaparin and abciximab as adjunctive pharmacotherapy for PCI suggests that this strategy is safe and effective and may offer advantages over a conventional strategy, which employs UFH.     

Randomized comparison of enoxaparin with unfractionated heparin for the prevention of venous thromboembolism in medical patients with heart failure or severe respiratory disease

Background We compared the efficacy and safety of the low-molecular weight heparin enoxaparin with unfractionated heparin (UFH) for the prevention of venous thromboembolic disease in patients with heart failure or severe respiratory disease. Methods This was a multicenter, controlled, randomized, open study in which patients received either enoxaparin (40 mg once daily) or UFH (5000 IU 3 times daily) for 10 ± 2 days in 64 medical departments in Germany. Patients were stratified and enrolled according to their underlying disease: severe respiratory disease or heart failure. The primary efficacy parameter was a thromboembolic event up to 1 day after the treatment period. Results Of the 665 patients enrolled, 451 patients were able to be evaluated in the primary efficacy analysis. The incidence of thromboembolic events was 8.4% with enoxaparin and 10.4% with UFH. Enoxaparin was at least as effective as UFH, with a 1-sided equivalence region of −4% (90% CI −2.5-6.5, P = .015). Enoxaparin was associated with fewer deaths, less bleeding, and significantly fewer adverse events (45.8% vs 53.8%, P = .044). Conclusions Enoxaparin is at least as effective as UFH in the prevention of thromboembolic events in patients with heart failure or severe respiratory disease. Its beneficial safety profile and once-daily administration is advantageous for inpatient and outpatient use. (Am Heart J 2003;145:614-21.)     

Persistence of the prothrombotic state after acute coronary syndromes: implications for treatment

Background and Purpose Acute coronary syndromes (unstable angina and acute myocardial infarction) are generally caused by thrombosis over a disrupted atherosclerotic plaque. During the acute phase, antithrombotic therapy (including aspirin and heparin) has been shown to reduce the risk of death or myocardial infarction (MI). The purpose of this review is to examine the high-risk period for clinical thrombotic events that extends for several weeks after presentation and to review the treatments aimed at reducing these events. Results More than half of clinical events reported during the first month occur after the first 3 to 5 days that comprise the standard in-hospital treatment period. Several different antithrombotic approaches have been tested, including longer duration of antiplatelet therapy, anticoagulant treatment, and oral glycoprotein (GP) IIb/IIIa inhibitors. Aspirin is effective at reducing risk, and clopidogrel provides additional benefit, as does dalteparin for at least the first month. Warfarin in addition to aspirin, while generally disappointing, has not been adequately tested at higher doses. Oral GP IIb/IIIa inhibitors cause a paradoxic increased risk of death for unclear reasons. Conclusion Further reduction of risk during the weeks after presentation with acute coronary syndromes remains an important therapeutic goal. (Am Heart J 2002;143:205-16.)     

Distinct yet complementary mechanisms of heparin and glycoprotein IIb/IIIa inhibitors on platelet activation and aggregation: implications for restenosis during percutaneous coronary intervention

Objective: To study the effect of unfractionated heparin (UFH) versus low molecular weight heparin (LMWH) in combination with glycoprotein (Gp) IIb/IIIa blockers on platelet activation and aggregation.

Methods: Washed platelets were stimulated with thrombin in the presence or absence of UFH (monoparin), LMWH (enoxaparin), and a Gp IIb/IIIa blocker (abciximab, eptifibatide, or tirofiban).

Results: Although Gp IIb/IIIa antagonists blocked the final common pathway of thrombin induced platelet aggregation, UFH and LMWH were better at blocking upstream platelet activation. UFH was significantly more effective than LMWH at inhibiting P selectin expression (p = 0.001) and platelet derived growth factor release from thrombin activated platelets (p = 0.012).

Conclusions: UFH and LMWH exert complementary effects to Gp IIb/IIIa blockers by inhibiting afferent pathways of platelet activation. Coadministration of heparin with Gp IIb/IIIa blockers provides improved protection against persistent platelet activation, thereby improving outcome after percutaneous coronary intervention. Judging from these data, UFH may be more effective in this regard than LMWH, at least in vitro. The use of LMWH in preference to UFH during percutaneous coronary intervention, although initially attractive, may inadequately protect against platelet activation despite the presence of Gp IIb/IIIa blockers.

     

Bivalirudin with planned or provisional abciximab versus low-dose heparin and abciximab during percutaneous coronary revascularization: results of the Comparison of Abciximab Complications with Hirulog for Ischemic Events Trial (CACHET)

Background The direct thrombin inhibitor bivalirudin has previously been associated with better efficacy and lower hemorrhage risk than heparin during balloon angioplasty. This agent has not yet been tested with stenting or in combination with platelet glycoprotein IIb/IIIa antagonists. Methods and Results In a pilot trial, 268 patients who underwent coronary intervention were randomized in 3 sequential phases to treatment with bivalirudin (with or without abciximab) or the control regimen of low-dose weight-adjusted heparin with abciximab. Patients in the bivalirudin arms received bivalirudin (1.0 mg/kg bolus, infusion of 2.5 mg/kg/h for 4 hours) plus abciximab in phase A, bivalirudin (0.5 mg/kg bolus, infusion of 1.75 mg/kg/h for the procedure duration) plus provisional (“rescue”) abciximab in phase B, or bivalirudin (0.75 mg/kg bolus, infusion of 1.75 mg/kg/h for the procedure duration) plus provisional abciximab in phase C. Abciximab was necessitated on a provisional basis in 24% of the patients in the bivalirudin arms of phases B and C. A composite clinical endpoint of death, myocardial infarction, repeat revascularization, or major bleeding by 7 days occurred in 3.3%, 5.9%, 0, and 10.6% of the patients in the bivalirudin phase A, bivalirudin phase B, bivalirudin phase C, and heparin plus planned abciximab arms, respectively (P = .018 for the pooled bivalirudin groups versus the heparin group). Conclusion Bivalirudin with planned or provisional abciximab may be at least as safe and effective as low-dose heparin plus abciximab during percutaneous coronary intervention. (Am Heart J 2002;143:847-53.)     

A safety and feasibility report of combined direct thrombin and GP IIb/IIIa inhibition with bivalirudin and tirofiban in peripheral vascular disease intervention: treating critical limb ischemia like acute coronary syndrome

BACKGROUND: The combination of glycoprotein (GP) IIb-IIIa inhibition and direct thrombin inhibition (DTI) with bivalirudin (Angiomax, The Medicines Company, Cambridge, Massachusetts) have shown ischemic and hemorrhagic outcomes benefit in coronary interventions and may have similar benefits in percutaneous peripheral interventions (PPI). The high incidence of diabetes, chronic renal disease, platelet dysfunction, hypercoagulability, inflammation and a thrombus-rich environment make a GP IIb-IIIa and DTI combination with tirofiban (Aggrastat Merck and Company, Inc., Whitehouse Station, New Jersey) an attractive anticoagulation strategy in the PPI treatment of critical limb ischemia (CLI). METHODS: Between May 1, 2001 and January 31, 2003, a CLI treatment group of 149 patients received PPI with bivalirudin (0.75 mg per kg bolus with 1.75 mg per kg per hour periprocedural infusion) and tirofiban (10 mcg per kg per minute bolus with 12-hour 0.1 mcg per kg per minute infusion) as an anticoagulation and antiplatelet strategy, and were compared to a matched unfractionated heparin (UFH) control group without GP IIb-IIIa inhibitors. Clinical and hemostasis outcomes were analyzed, including distal embolization (DE). RESULTS: Procedural success was 95.9% and 97.3% in the UFH control group and DTI-GP IIb-IIIa group, respectively. Significant differences were observed in the sheath removal time < 2 hours (60.5% UFH group versus 19.4% DTI-GP IIb-IIIa group; p = < 0.0001). Vascular closure devices were used equally in both groups. No statistical significance was observed in major and minor complications, femoral access complications, acute (< 48 hours) or subacute (30 days) vessel thrombosis, and 6-month duplex ultrasound restenosis rate between the DTI-GP IIb-IIIa versus the UFH group. A trend towards statistical significance was observed in the 6-month secondary re-intervention and limb salvage rates (10.7% versus 18.8%; p = 0.0501 and 93.9% versus 88.5%; p = 0.053) in the DTI-GP IIb-IIIa versus the UFH group, respectively. Angiographically relevant DE occurred in 4 of 149 (1.3%) and 8 of 149 (5.4%) of the bivalirudin-tirofiban and UFH groups, respectively. CONCLUSION: The combination of DTI with bivalirudin and GP IIb-IIIa inhibition with tirofiban is a safe and feasible alternative anticoagulation and antiplatelet strategy in PPI, and may offer improved clinical and hemostasis outcomes in treating CLI. A larger, prospective randomized trial is warranted.     

Heparin dosing and outcome in acute coronary syndromes: the GUSTO-IIb experience. Global Use of Strategies to Open Occluded Coronary Arteries

Background This study analyzed relationships among heparin dosage, patient characteristics, and 30-day outcome because optimal unfractionated-heparin dosing in acute coronary syndromes remains uncertain. Methods Patients (n = 5335) randomized to heparin therapy in the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb trial were studied. The heparin dose was adjusted to a target activated partial thromboplastin time (aPTT) and normalized for the patient's weight. Mortality and cardiac (re)infarction within 30 days and their association with patient characteristics and heparin dosing were evaluated. Results The lowest mortality rate appeared with a heparin dose of approximately 14 U/kg/h or an aPTT of approximately 70 seconds. Heparin dosing was a significant predictor of outcome after adjusting for presenting coronary syndrome; a trend remained after adjusting for other baseline differences. This association was lost when adjusted for the aPTT result. Patients who died early appeared to have lower heparin dosing than those with later mortality (P = .012). Heparin “resistance” with relatively high heparin dosages and low aPTT values did not increase the risk for adverse outcome. Conclusions There is a defined, dose-associated benefit of unfractionated heparin in acute coronary syndromes similar to that seen previously in thrombolytic-treated infarctions. Heparin therapy is complicated by its complex biologic interactions and relatively crude measures of its effect. Better measures of heparin effectiveness and strategies need to be developed with either better antithrombin agents or adjunctive therapies such as antiplatelet regimens to treat patients who require benefits beyond that supplied by unfractionated heparin. (Am Heart J 2002;144:73-80.)     

Safety and efficacy of abciximab combined with dalteparin in treatment of acute coronary syndromes.

AIMS: The safety and efficacy of abciximab in addition to low-molecular-weight-heparin as the primary medical treatment of acute coronary syndromes has not previously been investigated. METHODS AND RESULTS: The GUSTO IV-ACS trial included 7800 patients with chest pain and either ST-segment depression or a positive troponin test. They were randomized to abciximab for 24 h, 48 h or placebo. In the dalteparin substudy, 974 patients received 5 days of s.c. dalteparin, instead of a 48 h infusion of unfractionated heparin (UFH). Major and minor bleedings were more frequent for abciximab (24 and 48 h combined) than placebo both in the dalteparin (abciximab 5.0% vs placebo 1.8% P<0.05) and in the UFH cohort (3.8% vs 1.8% P<0.001). However, stroke rates were low, < or = 0.6%. At 30 days there were no significant differences in the rate of death or MI, either in the dalteparin (abciximab 9.6% vs placebo 11.3%: O.R. 0.85; 95% C.I. 0.58-1.25) or in the UFH cohort (8.5% vs 7.6%: O.R.; 1.12: 0.95-1.34). CONCLUSION: Treatment with abciximab, aspirin and s.c. dalteparin is associated with a low risk of major side effects and is as safe as the combination of abciximab and UFH. Without early coronary intervention there is no indication for abciximab treatment.     

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.)     

Perspectives on the Long Term Management of Heparin-Induced Thrombocytopenia

The glycoprotein (GP) IIb/IIIa receptor antagonists used widely in the medical treatment of acute coronary syndromes and during percutaneous coronary interventions, prevent fibrinogen cross-linking and platelet aggregation, critical initiating steps in arterial thrombosis. Their anticoagulant properties, particularly when administered conjunctively with heparin preparations, are less well-characterized. In a series of in vitro studies, increasing concentrations of abciximab, tirofiban, and eptifibatide either alone or in combination with unfractionated heparin (UFH) or fractionated heparin (enoxaparin) were added to washed platelets suspended in Tyrode's buffer. Following platelet activation and prothrombinase assembly, thrombin generation was determined by enzyme-linked immunosorbent assay (ELISA). There was a concentration-dependent reduction in platelet-dependent thrombin generation with each of the GPIIb/IIIa receptor antagonists. The combination of tirofiban and UFH yielded percent, absolute and relative reductions (compared with tirofiban alone) of 48.0%, 16.9%, and 35.2%, respectively. The corresponding values for eptifibatide and abciximab were 38.0%, 13.5%, 35.5%, and 55.1%, 3.8%, 8.4%, respectively. Thrombin generation was decreased by an additional 2 to 3% (absolute reduction) with high concentrations of enoxaparin in combination with either eptifibatide or abciximab. Platelet GPIIb/IIIa receptor antagonists, beyond their ability to prevent fibrinogen-mediated aggregation, inhibit platelet-dependent prothrombinase activity and thrombin generation in a concentration-dependent manner. Heparin facilitates the existing anticoagulant properties, supporting combination therapy in clinical practice. The potential added benefit of fractionated heparin over UFH will require further investigation.     

The SYNERGY trial: study design and rationale

Background Enoxaparin was shown to be superior to unfractionated heparin in the patients with non-ST-segment elevation acute coronary syndromes (ACS) in the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events study and the Thrombolysis In Myocardial Infarction (TIMI) 11B trial. However, enoxaparin has had limited acceptance in clinical practice, in part because of the contemporary management of these patients, which includes glycoprotein IIb/IIIa inhibition and the use of early invasive management strategies. Study Design The Superior Yield of the New strategy of Enoxaparin, Revascularization and GlYcoprotein IIb/IIIa inhibitors (SYNERGY) trial is an 8000-patient, prospective, randomized, open-label, multicenter investigation of enoxaparin compared with unfractionated heparin in patients at high risk with non-ST-segment elevation ACS treated with an early invasive strategy. The primary efficacy end point is death or nonfatal myocardial infarction 30 days after enrollment. Implications The SYNERGY trial is the largest study currently planned for the acute therapy of patients with non-ST-segment elevation ACS and the first large trial since the publication of the revised American College of Cardiology/American Heart Association guidelines for the management of these patients. In addition to evaluating the potential superiority of enoxaparin over unfractionated heparin, this investigation will provide important observations of current treatment strategies in patients with ACS. (Am Heart J 2002;143:952-60.)     

Treatment with Dalteparin is Associated with a Lower Risk of Bleeding Compared to Treatment with Unfractionated Heparin in Patients with Renal Insufficiency

BACKGROUND

Low molecular weight heparins (LMWHs) have been cautiously used in patients with chronic kidney disease (CKD) due to fear of accumulation. Dalteparin, however, has shown minimal tendency to accumulate in patients with CKD and may be safe to use in this patient population.

OBJECTIVE

We compared the incidence of clinically significant bleeding in patients with CKD receiving therapeutic doses of dalteparin to that of patients with CKD receiving therapeutic doses of UFH.

DESIGN

This was a retrospective cohort study.

SUBJECTS

Inpatients with CKD (GFR?<?60 ml/min) who were treated with therapeutic dalteparin or UFH were included in the study

MAIN MEASURES

Primary outcome was major bleeding within 10 days of anticoagulation, identified by ICD-9 code and confirmed by chart review. Demographic characteristics, laboratory values, comorbidities, prior bleeding history and inpatient medications were extracted for each admission from the electronic medical record. Logistic regression models were created to examine the association between choice of anticoagulant and bleeding rates, after adjustment for demographic and clinical characteristics.

KEY RESULTS

Dalteparin-treated patients were significantly less likely to experience a major bleed than patients treated with UFH (1.14 % vs. 3.49 %, p?<?0.001). The reduced likelihood of bleeding associated with dalteparin treatment remained significant after adjustment for patient characteristics (HR 0.39, 95 % CI: 0.21–0.70, p?<?0.0001). A stratified analysis for subgroups with GFR< 30 mL/min and with GFR between 30 and 60 mL/min showed that dalteparin was still associated with lower odds of bleeding compared to treatment with unfractionated heparin, but the difference was nonsignificant for GFR< 30 (HR 0.35, 95 % CI: 0.11–1.15), even after adjustment (OR 0.37, 95 % CI: 0.11–1.22).

CONCLUSION

In patients with CKD, treatment with therapeutic dose dalteparin was associated with lower rates of bleeding than treatment with unfractionated heparin. For patients with severe CKD (GFR< 30), dalteparin was shown to be at least as safe as unfractionated heparin.

     

Glycoprotein IIb-IIIa inhibition with abciximab and postprocedural risk assessment: lessons from the evaluation of platelet IIb/IIIa inhibitor for stenting trial and implication for ad hoc use of glycoprotein IIb-IIIa antagonists

Background Angiographic features of vessels in which stents have been deployed can be used to predict the risk of postprocedural ischemic events. The purpose of this study was to compare the effects of abciximab in patients with and without high-risk postprocedure features. Methods and Results Protocol-mandated stent implantation was performed in 1586 patients in the Evaluation of Platelet IIb/IIIa Inhibitor for Stenting trial, 783 of whom received abciximab, and was successful in 97% of the patients. High-risk features were defined as the presence of Thrombolysis In Myocardial Infarction (TIMI) flow <3, presence of thrombus or major dissection, or residual stenosis >10%. The primary endpoint was a composite of death, myocardial infarction, and urgent target vessel revascularization at 30 days. High-risk features were present in 21% of the patients. In patients without high-risk features after stent placement, abciximab reduced the primary endpoint from 9.0% to 3.9% (P <.001) compared with 16.2% to 8.6% (P = .046) in patients in whom high-risk features were present. There was no statistical evidence of interaction between abciximab treatment and the presence or absence of high-risk features. Conclusion Glycoprotein IIb-IIIa antagonism with abciximab is equally effective in prevention of a composite of ischemic events in patients with and without high-risk features after stent placement. However, patients in whom high-risk features are present after stent placement are at increased risk of ischemic cardiac events even with abciximab treatment. (Am Heart J 2002;143:594-601.)