In vitro comparison of the novel,dual-acting FIIa/FXa-inhibitor EP217609C101, unfractionated heparin,enoxaparin, and fondaparinux in preventing cardiac catheter thrombosis

Efficient and safe anticoagulation is crucial in patients requiring percutaneous coronary intervention (PCI) or extracorporeal circulation during cardiac surgery. Although new anticoagulant strategies have emerged for PCI as alternatives to the established treatment with heparins, the development of new anticoagulants with an improved efficacy/safety ratio is still necessary. Our study compared the efficacy of the novel, dual-acting, neutralizable FIIa/FXa-inhibitor EP217609C101 (EP) at 2, 1.2, 0.9, and 0.6 μg/ml to unfractionated heparin (UFH), enoxaparin, and fondaparinux in preventing cardiac catheter thrombosis under in vitro conditions. Blood drawn by venepunction from healthy male volunteers (n = 10) pretreated with 500 mg aspirin orally was treated with the anticoagulant to test and continuously circulated through a cardiac catheter for 60 min or until the catheter became blocked by thrombotic debris. Anticoagulant efficacy was assessed by thrombus weight, electron microscopic features of the developing thrombi, and laboratory parameters. Whereas UFH, enoxaparin, EP 2, and EP 1.2 μg/ml secured maximum circulation times, statistically significant premature catheter occlusions were observed for EP 0.9, EP 0.6 μg/ml, and fondaparinux. The UFH group and both high-dose concentrations of EP showed significantly lower thrombus weights than the low-dose concentrations of EP and fondaparinux, (p ≤ 0.05). On electron microscopic analysis of the thrombotic debris no differences were observed in erythrocyte deposition between UFH, enoxaparin, and all EP concentrations tested. A significant reduction in fibrin deposition was achieved by UFH and EP 2 μg/ml but no significant differences in platelet deposition were found, except for a significant reduction for EP 0.6 μg/ml. Our in vitro study showed that EP217609C101 is a promising new drug that is dose-dependently superior to classical (UFH, enoxaparin) and newer (fondaparinux) drugs in preventing heart catheter thrombosis.     

Low-molecular-weight heparin use in acute coronary syndromes and percutaneous coronary interventions: An update

Based on important studies published in the past year, the role of low-molecular-weight heparin in acute coronary syndromes and percutaneous coronary interventions has continued to evolve. For patients with non-ST-elevation acute coronary syndromes, several alternatives to enoxaparin have been introduced, including fondaparinux and bivalirudin. In patients with ST-elevation myocardial infarction, recent studies have demonstrated a clear mortality benefit from adjunctive antithrombin therapy and the superiority of a prolonged course of enoxaparin over a standard duration of unfractionated heparin. Furthermore, recent data have demonstrated the safety of enoxaparin as an alternative to unfractionated heparin among patients undergoing percutaneous coronary interventions.     

Usefulness of intravenous enoxaparin for percutaneous coronary intervention in stable angina pectoris

This pilot study was designed to determine whether the low molecular weight heparin, enoxaparin, could be used for elective percutaneous coronary intervention (PCI) to provide antithrombotic effects without the full systemic anticoagulation that occurs with the use of unfractionated heparin. Sixty patients were randomized to receive intravenous enoxaparin (1 mg/kg bolus dose) or unfractionated heparin at the time of coronary intervention. Laboratory testing was performed at baseline, 5 minutes, and 4 hours after study drug to test if a single bolus dose of intravenous enoxaparin can consistently achieve therapeutic antithrombotic effect, thus eliminating the need for multiple doses of heparin and closely monitoring levels of anticoagulation during PCI. Thirty percent of patients who received unfractionated heparin required a second bolus of intravenous heparin to achieve the target-activated clotting time of 300 seconds before PCI. Enoxaparin showed antithrombotic properties comparable to that of unfractionated heparin as measured by anti-Xa levels, with less inhibition of thrombin (factor IIa) at the time points measured (p <0.0001). Angioplasty success rates, in-hospital ischemia, bleeding, and vascular complications were similar in both groups. Thus, intravenous enoxaparin has predictable and effective antithrombotic effects during elective PCI. Although the level of anticoagulation attained with enoxaparin is significantly lower than that after unfractionated heparin, no increase in ischemic complications were noted. The use of a single bolus of intravenous enoxaparin, without the need for measuring the activated clotting time or titrating heparin anticoagulation, has the potential for simplifying the performance and perhaps enhancing the safety of PCI.     

Usefulness of intravenous enoxaparin for percutaneous coronary intervention in stable angina pectoris

This pilot study was designed to determine whether the low molecular weight heparin, enoxaparin, could be used for elective percutaneous coronary intervention (PCI) to provide antithrombotic effects without the full systemic anticoagulation that occurs with the use of unfractionated heparin. Sixty patients were randomized to receive intravenous enoxaparin (1 mg/kg bolus dose) or unfractionated heparin at the time of coronary intervention. Laboratory testing was performed at baseline, 5 minutes, and 4 hours after study drug to test if a single bolus dose of intravenous enoxaparin can consistently achieve therapeutic antithrombotic effect, thus eliminating the need for multiple doses of heparin and closely monitoring levels of anticoagulation during PCI. Thirty percent of patients who received unfractionated heparin required a second bolus of intravenous heparin to achieve the target-activated clotting time of 300 seconds before PCI. Enoxaparin showed antithrombotic properties comparable to that of unfractionated heparin as measured by anti-Xa levels, with less inhibition of thrombin (factor IIa) at the time points measured (p <0.0001). Angioplasty success rates, in-hospital ischemia, bleeding, and vascular complications were similar in both groups. Thus, intravenous enoxaparin has predictable and effective antithrombotic effects during elective PCI. Although the level of anticoagulation attained with enoxaparin is significantly lower than that after unfractionated heparin, no increase in ischemic complications were noted. The use of a single bolus of intravenous enoxaparin, without the need for measuring the activated clotting time or titrating heparin anticoagulation, has the potential for simplifying the performance and perhaps enhancing the safety of PCI.     

Anticoagulation after subcutaneous enoxaparin is time sensitive in STEMI patients treated with tenecteplase

The adequacy of anticoagulation with enoxaparin as an adjuvant to fibrinolytic therapy for STEMI is unclear and has implications for both efficacy and safety; especially in patients undergoing a pharmacoinvasive reperfusion strategy. A subset of fibrinolytic-treated patients in the WEST study was enrolled in a systematic anti-Xa substudy. All received ASA and subcutaneous (SQ) enoxaparin 1 mg/kg followed by TNK-tPA. Incremental IV dosing of enoxaparin (0.3-0.5 mg/kg) was allowed prior to percutaneous coronary intervention (PCI). Anti-Xa blood samples were drawn prior and after angiography. Data are presented as percentages, medians and IQRs. Forty-five patients underwent angiography 2.8 h (2.5-14.6) after fibrinolytic. The pre-angiography median anti-Xa acquired 179 min (153-875) after SQ enoxaparin was 0.48 U/ml (0.42-0.65); a relationship between anti-Xa activity and time from administration was evident (r = 0.418, p < 0.007). Without supplemental IV enoxaparin the 2nd anti-Xa acquired 218 min (195-930) after SQ enoxaparin was 0.48 U/ml (0.41-0.80, n = 29). After supplemental IV enoxaparin, the 2nd anti-Xa was 0.92 U/ml (0.72-1.10, n = 16). An incremental IV enoxaparin dose and anti-Xa relationship was demonstrated (r = 0.59, p = 0.001) i.e. no IV 0.48 U/ml (0.41-0.80, n = 29), 0.3 mg/kg IV 0.81 U/ml (0.63-1.00, n = 12), and 0.5 mg/kg IV 1.34 U/ml (1.16-1.54, n = 4). Most fibrinolytic treated STEMI patients receiving weight-adjusted SQ enoxaparin (1 mg/kg) had subtherapeutic anti-Xa levels (<0.5 U/ml) after ~3 h. A strategy of supplemental 0.3 mg/kg IV enoxaparin at time of PCI reliably achieved anti-Xa ≥ 0.5 U/ml. Our findings provide a rational novel strategy for anti-thrombotic management in STEMI patients undergoing a pharmacoinvasive reperfusion strategy.     

Antithrombotische Therapie bei akutem Myokardinfarkt

Inhibition of blood coagulation is an essential cornerstone of the therapy of acute myocardial infarction. Risk stratification represents a valuable tool to adjust the intensity of anticoagulation and timing of invasive therapy according to patient risk. All patients presenting with myocardial infarction should be treated with aspirin and clopidogrel. Patients with ST-segment elevation myocardial infarction and high-risk patients with myocardial infarction without ST-segment elevation who undergo invasive therapy should be treated immediately with unfractionated heparin (alternatively enoxaparin) and a glycoprotein (GP) IIb/IIIa antagonist in the catheter laboratory. The direct thrombin antagonist bivalirudin may emerge as an attractive alternative in these patients. In low-risk patients who undergo delayed urgent elective interventional therapy the factor Xa antagonist fondaparinux may be advantageous because of its low bleeding rate. In these patients administration of unfractionated heparin is necessary for percutaneous coronary intervention.     

Differential effects of direct thrombin inhibitors and antithrombin-dependent anticoagulants on the dynamics of clot formation.

New anticoagulants, including the direct thrombin inhibitors (DTIs) and fondaparinux, are increasingly replacing unfractionated heparin and enoxaparin. We examined the effects of argatroban (n = 60), bivalirudin (n = 44), heparin (n = 14), enoxaparin (n = 22), and fondaparinux (n = 24) on clot formation utilizing thromboelastography. Blood samples containing anticoagulants at clinically relevant concentrations were prepared ex vivo and analyzed using kaolin or tissue factor activation. Thromboelastography parameters of clot initiation (R), clot propagation (K and angle), clot rigidity (maximum amplitude) and clot elasticity (G) were compared between anticoagulants. Thromboelastography was also performed on blood from eight patients receiving anticoagulants. Each anticoagulant exerted significant concentration-dependent effects on R, K and angle. Only heparin, enoxaparin, and fondaparinux significantly affected maximum amplitude and G. Significant differences existed for all parameters between heparin and each anticoagulant and between fondaparinux and each DTI (P < 0.001), and for angle, maximum amplitude, and G between enoxaparin and each DTI (P < 0.008). Thromboelastography responses in ex-vivo samples and patient samples were comparable. In conclusion, whereas argatroban, bivalirudin, heparin, enoxaparin and fondaparinux each delay clot formation, the DTIs do not alter clot rigidity or elasticity. The reduced bleeding reported with DTIs versus heparin may relate to the fact that clots form with normal rigidity and elasticity.     

M118, a novel low-molecular weight heparin with decreased polydispersity leads to enhanced anticoagulant activity and thrombotic occlusion in ApoE knockout mice

Heparin and low-molecular weight heparin (LMWH) are complex, heterogeneous polysaccharides used in the treatment of arterial and venous thrombosis. M118 is a novel LMWH with low polydispersity and pronounced anti-Xa and anti-thrombin (IIa) activity as compared to current LMWHs. To determine if M118 is effective in preventing thrombosis in the setting of a vascular plaque, apolipoprotein E knockout mice fed a high fat diet were injected with M118, enoxaparin, unfractionated heparin, or saline control and examined for arterial thrombosis using a rose bengal laser induced carotid artery injury model. M118 significantly increased the time to occlusion as compared to control and unfractionated heparin but not compared to enoxaparin although fewer M118 treated animals had any vascular occlusion present at the time of protocol completion. Platelet-neutrophil aggregates were studied by flow cytometry and were found to be decreased with M118 as compared to enoxaparin. This is the first published report examining M118, a novel LMWH designed to have low polydispersity and enhanced anticoagulant activity. In an animal model of vascular plaque, M118 is a potent inhibitor of arterial thrombosis and, despite lower in vivo anti-Xa and anti-IIa activity levels, M118 was superior to UFH in the prevention of arterial thrombosis.     

Effects of Intravenous Enoxaparin and Intravenous Inogatran in an Electrolytic Injury Model of Venous Thrombosis in the Dog

The objective of this study was to compare the effectiveness of the low molecular weight heparin, enoxaparin (Lovenox®), and inogatran (a direct thrombin inhibitor) in a canine electrolytic injury model of venous thrombosis. Effectiveness was defined as the ability of either drug to prolong the following parameters: activated partial thromboplastin time (aPTT), thrombin time (TT), prothrombin time (PT), and time to formation of an occlusive thrombus in the vein. There were 5 dogs and 10 vessels for each group (the right and left femoral veins were used in each dog to measure time to occlusion). Dogs were randomly assigned to one of six groups: (1) saline controls; (2) low-dose inogatran (0.075 mg/kg IV bolus followed by a 5 g/kg/min infusion); (3) mid-dose inogatran (0.25 mg/kg IV bolus followed by a 20 g/kg/min infusion); (4) high-dose inogatran (0.75 mg/kg IV bolus followed by a 50 g/kg/min infusion); (5) low-dose enoxaparin (100 units/kg IV bolus followed by a 50 U/kg/h infusion); and (6) high-dose enoxaparin (200 U/kg IV bolus followed by a 100 U/kg/h infusion). Administration of inogatran resulted in dose-dependent increases in aPTT, TT, and PT, and administration of enoxaparin resulted in dose-dependent increases in aPTT and TT. There were no changes in hemodynamics. The time to occlusion in the control group averaged 81.7 ± 9.9 minutes compared with 141.8 ± 12.7, 185.8 ± 17.6, and 226.9 ± 8.8 minutes with the low, mid, and high doses of inogatran, and 131 ± 20.3, and 183.0 ± 19.0 minutes with the low and high doses of enoxaparin. Bleeding times were elevated by inogatran and enoxaparin, but no appreciable differences were detected between the two compounds. In summary, the direct thrombin inhibitor inogatran, administered intravenously, was as effective as the low molecular weight heparin enoxaparin in a canine model of venous thrombosis induced by electrolytic injury, supporting the conclusion that direct antithrombins may prove useful for prevention and treatment of deep venous thrombosis.     

Comparison of enoxaparin versus heparin during elective percutaneous coronary intervention performed with either eptifibatide or tirofiban (the ACTION Trial)

Limited data are available with regard to the pharmacodynamics and safety of combining enoxaparin with glycoprotein IIb/IIIa inhibition during elective percutaneous coronary interventions (PCIs). We randomized 200 patients to receive open-label enoxaparin (0.75 mg/kg intravenous bolus) or unfractionated heparin (60 U/kg intravenous bolus) and eptifibatide or tirofiban during PCI. This yielded 4 groups of combination therapy (50 patients/group). The first 10 patients per group had anti-Xa activity and inhibition of platelet aggregation measured at baseline, and at 5 minutes, 10 minutes, 4 hours, and 24 hours. All patients received aspirin and clopidogrel therapy before PCI. Patients who received enoxaparin and heparin achieved therapeutic peak anti-Xa activity observed shortly after drug administration. At 4 hours, a differential anticoagulant effect was observed, with patients who received enoxaparin having a more gradual decrease in anti-Xa activity. Patients who received eptifibatide achieved >80% inhibition of platelet aggregation soon after initiation of therapy more often than did those who received tirofiban. Type of heparin did not affect inhibition of platelet aggregation. Compared with patients who received heparin, periprocedural myocardial infarction and bleeding events occurred less frequently among those who received enoxaparin (14% vs 8% and 10% vs 5%); however, these differences were not statistically significant. Three cases of intraprocedural thrombus occurred among patients who received enoxaparin. Two patients received concomitant tirofiban therapy. Compared with unfractionated heparin, similar levels of anticoagulation and platelet inhibition are achieved with enoxaparin when concomitant therapy with eptifibatide or tirofiban is used during elective PCI, without an observed increase in early bleeding events or periprocedural ischemic complications.     

The activated clotting time (ACT) can be used to monitor enoxaparin and dalteparin after intravenous administration

BACKGROUND: The use of low-molecular weight heparin (LMWH) during percutaneous coronary intervention (PCI) has been limited by the presumed inability to monitor its anticoagulant effect using bedside assays. OBJECTIVES: This study was designed to compare the dose-response of enoxaparin, dalteparin and unfractionated heparin (UFH) on the activated clotting time (ACT), and to determine whether the ACT or aPTT can be used to monitor intravenous (IV) low molecular weight heparin (LMWH). METHODS: A total of 130 patients undergoing cardiac catheterization were assigned to intravenous enoxaparin 0.5 mg/kg, dalteparin 50 international units/kg or UFH 50 units/kg. Of the 130 patients, 46 (35%) underwent PCI, all of whom received a glycoprotein (GP) IIb/IIIa inhibitor. We measured ACT, activated partial thromboplastin time (aPTT) and plasma anti-Xa levels after serial sampling. RESULTS: Both enoxaparin and dalteparin induced a significant rise in the ACT and aPTT, with an ACT dose-response approximately one-half the magnitude of that obtained using UFH. The time course of changes in the ACT and aPTT after administration of enoxaparin and dalteparin was virtually identical, with a return to baseline at approximately 2 hours. The enoxaparin and dalteparin-treated patients successfully underwent PCI with no major hemorrhagic complications. CONCLUSIONS: The ACT is equally sensitive to IV enoxaparin and dalteparin. These data support an ACT-guided strategy for intravenously administered LMWH during PCI. Additional studies with larger patient populations may be indicated to determine the ideal target ACT for LMWH in PCI.     

Low-dose fondaparinux in suspected heparin-induced thrombocytopenia in the critically ill

BACKGROUND: In critically ill patients, heparin-induced thrombocytopenia (HIT) is estimated to account for approximately 1 to 10% of all causes of thrombocytopenia. HIT exerts a strong procoagulant state. In case of suspected HIT, it is an important clinical decision to stop heparin and start treatment with alternative nonheparin anticoagulation, awaiting the results of laboratory testing for the final diagnosis of HIT (bridging therapy). Fondaparinux acts by factor Xa inhibition and expresses no cross-reactivity with HIT antibodies. Excretion of fondaparinux is mainly renal. We describe our early experience with fixed low-dose fondaparinux bridging therapy and monitoring of anticoagulant activity for safety reasons. METHODS: This retrospective cohort study was conducted in a closed format general intensive care unit in a teaching hospital. Consecutive critically ill patients suspected of HIT were treated with fondaparinux after discontinuation of unfractionated heparin or nadroparin. Anti-Xa levels were determined afterwards. RESULTS: Seven patients were treated with fondaparinux 2.5 mg/day for 1.8 to 6.5 days. Anti-Xa levels varied from 0.1 to 0.6 U/ml. A negative correlation was found between creatinine clearance and mean and maximum anti-Xa levels. No thromboembolic complications occurred. Bleeding complications were only minor during fondaparinux treatment. Transfusion requirements did not differ significantly between treatment episodes with fondaparinux or with heparin anticoagulants. CONCLUSION: In this small sample of critically ill patients suspected of HIT, bridging therapy with fixed low-dose fondaparinux resulted in prophylactic and therapeutic anti-Xa levels. Monitoring of anticoagulant activity is advised in patients with renal insufficiency.     

The combination of enoxaparin, glycoprotein IIb/IIIa inhibitors and an early invasive approach among acute coronary syndrome patients

OBJECTIVES: This study was designed to assess the feasibility and safety of enoxaparin in combination with glycoprotein (GP) IIb/IIIa inhibitors during percutaneous coronary intervention (PCI) as part of an early invasive strategy in patients presenting with acute coronary syndromes (ACS). BACKGROUND: Trials in patients with ACS have evaluated the utility of enoxaparin, adjuvant GP IIb/IIIa inhibitors with PCI, and an early invasive approach. Information about the combination of all three of these approaches, however, is limited. METHODS: Forty-nine patients with ACS underwent cardiac catheterization, of whom 23 underwent PCI with enoxaparin and GP IIb/IIIa inhibitors. RESULTS: The primary endpoint of the study, a composite of death, myocardial infarction or urgent revascularization at 30 days, occurred in 8% of patients undergoing PCI. There were no deaths. One patient received a blood transfusion. No other adverse events occurred. These event rates were comparable to those from the pooled EPILOG/EPISTENT database, in which intravenous unfractionated heparin was used in conjunction with GP IIb/IIIa receptor blockade. The mean anti-Xa level in patients undergoing PCI was 0.74 0.48 U/ml. The majority of patients who underwent PCI within eight hours of their last dose of enoxaparin had therapeutic anti-Xa levels. CONCLUSION: In patients with ACS, enoxaparin in combination with GP IIb/IIIa inhibitors and an early invasive approach resulted in comparable clinical complication and bleeding rates versus historical references utilizing unfractionated heparin.     

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.     

The utility of thromboelastography in monitoring low molecular weight heparin therapy in the coronary care unit

Low molecular weight heparins (LMWHs) are used for prevention and management of vascular thrombosis. In general, monitoring of anticoagulant activity is not required, however, certain populations may be susceptible to overdosing or underdosing. As anti-activated factor X(anti-Xa) activity testing is not readily available, it was our aim to investigate the usefulness of thromboelastography (TEG; Haemoscope Corporation, Skokie, Illinois, USA) for the assessment of coagulation in patients on LMWH. All patients admitted to the coronary care unit on therapeutic dose of enoxaparin were included (1 mg/kg twice daily). Blood samples were collected 4 h after the morning dose of enoxaparin once the participant had received at least three doses. When anti-Xa activity was classified as low (0-0.5), correct (0.5-1.0) or high (>1.0), the distribution of reaction time (R) and dose per kg showed little association with anti-Xa activity. The difference between mean R for the high anti-Xa group and the correct anti-Xa group was statistically nonsignificant using two-sample t-test (P = 0.26). A linear regression model showed no evidence of association between dose per kg and anti-Xa (P = 0.95). However, there was evidence of positive association between dose per kg and R (P = 0.011) wherein a 10% increase in dose per kg was associated with an increase in R of 2.7 (95% confidence interval 0.6-4.7). There was no evidence of association between R and anti-Xa (P = 0.38). TEG was unable to be used to predict anti-Xa activity. However, TEG R was prolonged in more than 90% patients and correlated with dose of enoxaparin. As enoxaparin dose correlated poorly with anti-Xa activity, a more global test might be necessary to adjust dosing of LMWH in sick, hospitalized patients.     

Stable and optimal anticoagulation is achieved with a single dose of intravenous enoxaparin in patients undergoing percutaneous coronary intervention

This study assessed the pharmacokinetics, safety and efficacy of intravenous enoxaparin in patients undergoing percutaneous coronary intervention (PCI). Sixty consecutive patients [(age, 62 11 years; female, 16%; diabetes, 18%; hypertension, 53%; prior myocardial infarction (MI), 43%] undergoing PCI (stable angina, 89%; stent, 92%; two-vessel disease, 23%; B2/C lesions, 45%) were administered intravenous enoxaparin 1 mg/kg for procedural anticoagulation. Blood samples for anti-Xa level and activated partial thromboplastin time (aPTT) were assayed from the first 20 patients before and after enoxaparin administration at the following intervals: 5, 30, 60, 90, 120, 150, 180, 210, 240, 360 and 480 minutes. Activated clotting time was assessed 5 minutes after enoxaparin administration. Bleeding complications were classified according to Thrombolysis In Myocardial Infarction (TIMI) criteria. All patients were monitored for adverse clinical events at clinic visit 4 8 weeks after hospital discharge. No TIMI major or minor bleedings occurred during hospitalization for the PCI (median stay post-PCI = 1 day). One patient (2%) developed a non-Q wave MI after the PCI and before hospital discharge. There was no death or urgent revascularization up to clinical follow-up. The peak anti-Xa level was 1.30 0.18 IU/ml (range, 1.03 1.69 IU/ml). The minimum anti-Xa level was 0.55 IU/ml 4 hours after enoxaparin. Thus, the use of intravenous enoxaparin in patients undergoing PCI is associated with a low incidence of ischemic and bleeding complications. A stable therapeutic anticoagulant effect is provided without the need for monitoring within 4 hours of enoxaparin administration.     

Degree of Anticoagulation after One Subcutaneous and One Subsequent Intravenous Booster Dose of Enoxaparin: Implications for Patients with Acute Coronary Syndromes Undergoing Early Percutaneous Coronary Intervention

BACKGROUND: Many cardiologists continue to be reluctant to utilize low-molecular-weight heparin in the treatment of patients with non-ST-segment-elevation acute coronary syndrome because they are concerned about how to manage such patients if they have received only one dose of subcutaneous enoxaparin and are then taken within hours of such treatment to the cardiac catheterization laboratory for percutaneous coronary intervention (PCI). Although we and others have recommended that such patients who have received only one subcutaneous enoxaparin dose receive an intravenous 0.3 mg/kg enoxaparin "booster" dose immediately prior to PCI, there are little actual data to support this recommendation. METHODS: 20 middle-aged subjects were treated with 1 mg/kg subcutaneously-administered enoxaparin and then 6 hours later with a "booster" dose of 0.3 mg/kg intravenously-administered enoxaparin. Anti-Xa levels, as well as ENOX Times, were assessed at baseline, at 2, 4 and 6 hours after the initial SC dose, and at 5 min, 1 and 2 hours after the IV booster dose. RESULTS: At 2 and 6 hours after the initial subcutaneous enoxaparin dose, thirty-five percent of patients had anti-Xa levels below 0.6 IU/mL; twenty percent and ten percent had anti-Xa levels below 0.5 IU/mL at 2 and 6 hours after the initial subcutaneous dose, respectively. After the IV booster dose, all patients had anti-Xa levels in the therapeutic range during the 5 minutes to 2 hours during which blood samples were obtained. There was no significant "overshoot" with this booster dose above what is considered to be the upper therapeutic range. ENOX times showed an overall moderate correlation with anti-Xa levels. CONCLUSIONS: A strategy of administering a 0.3 mg/kg IV booster dose to patients who have received only one subcutaneous dose of enoxaparin and then undergo PCI within the first 2-6 hours of such treatment reliably leads to anti-Xa levels in the therapeutic range.     

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.)     

Recombinant activated factor VII effectively reverses the anticoagulant effects of heparin, enoxaparin, fondaparinux, argatroban, and bivalirudin ex vivo as measured using thromboelastography.

Bleeding is the major adverse reaction to anticoagulants, leading to significant morbidity and even mortality. Protamine is a specific antidote for heparin yet is only partially effective for enoxaparin, and the activated factor X inhibitor fondaparinux and the direct thrombin inhibitors argatroban and bivalirudin lack specific antidotes. We evaluated the ability of recombinant activated factor VII (rFVIIa), a general hemostatic agent, to reverse the anticoagulant effects of heparin, enoxaparin, fondaparinux, argatroban, and bivalirudin, as measured by thromboelastography. Whole-blood samples containing each test anticoagulant, with or without rFVIIa 1.5-4.5 microg/ml, were prepared ex vivo (n >or= 48, each anticoagulant) and analyzed by thromboelastography. The thromboelastography parameters of clot initiation, propagation, rigidity and elasticity were compared for the ex-vivo samples for each anticoagulant. The reversal ability of rFVIIa was also assessed using the standard clinical assay used to monitor each anticoagulant. Thromboelastography was performed on blood from eight stably anticoagulated patients, with and without exogenous rFVIIa. For each anticoagulant, rFVIIa significantly improved and, in some cases, completely normalized all thromboelastography parameters (P < 0.001). rFVIIa significantly (P < 0.01) decreased the activated partial thromboplastin time for argatroban-containing, bivalirudin-containing, or heparin-containing blood yet did not affect the anti-activated factor X levels for enoxaparin-containing or fondaparinux-containing blood. By thromboelastography, rFVIIa exerted generally similar reversal effects on the anticoagulated patient samples as on the ex-vivo samples. In conclusion, rFVIIa effectively reverses the anticoagulant effects of heparin, enoxaparin, fondaparinux, argatroban, and bivalirudin, and should be considered for patients with excessive bleeding associated with these anticoagulants.     

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.