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Emicizumab is a bi-specific humanized monoclonal antibody mimicking the factor (F) VIII cofactor activity in mediating the activation of FX by FIXa. Recent observations showed that emicizumab when added to pooled normal plasma (PNP), hemophilic plasma or PNP added with unfractionated heparin is able to interfere with coagulation assays. To further explore the mechanisms of assay interference we investigated the effect of emicizumab on global coagulation assays for the PNP added with two direct oral anticoagulants, apixaban or argatroban. Aliquots of PNP were added with purified apixaban or argatroban at a concentration of 500 ng/mL and emicizumab at concentrations ranging from 0 to 100 µg/mL. Plasma samples were then tested for the activated partial thromboplastin time (APTT) and for thrombin generation (the latter for the apixaban plasma only). Emicizumab at a 25–50 µg/mL shortened the APTT of the PNP with or without apixaban or argatroban. The extent of correction was greater for the apixaban or argatroban plasma and amounted to 35% or 42%, respectively. The parameters of thrombin generation (lag-time and time-to-peak) for the PNP supplemented with apixaban were shortened by 30% or 25%, respectively and the endogenous thrombin potential and the peak-thrombin were marginally affected. Emicizumab attenuates in vitro the anticoagulant activity of the PNP induced by apixaban or argatroban as documented by the correction of prolonged APTT and velocity of thrombin generation (i.e., lag-time and time-to-peak). Whether the above effects have any relevance in vivo is unknown.

A prospective comparison of three argatroban treatment regimens during hemodialysis in end-stage renal disease. We prospectively evaluated 3 treatment regimens of argatroban, a direct thrombin inhibitor, for providing adequate, safe anticoagulation in patients with end-stage renal disease (ESRD) during hemodialysis. In this randomized, 3-way crossover study, ESRD patients underwent hemodialysis sessions of 3- or 4-hour duration using high-flux membranes and each of 3 argatroban treatment regimens (A: 250-μg/kg bolus, with an additional 250-μg/kg bolus allowed; B: 250-μg/kg bolus followed by 2-μg/kg/min infusion; C: steady-state, 2-μg/kg/min infusion initiated 4 hours before dialysis). Pharmacodynamic effects including activated clotting times (ACTs); hemodialysis efficacy including single-pool Kt/V, urea reduction ratio (URR), and circuit flow; and safety through a 3-day follow-up were monitored. Argatroban pharmacokinetic parameters including dialytic clearance were evaluated during regimen C. Thirteen patients completed 38 hemodialysis sessions (1 patient withdrew consent after 2 sessions). Mean ± SD ACTs increased from 131 ± 14 seconds at baseline to 153 ± 24, 200 ± 30, and 197 ± 33 seconds, respectively, after 60 minutes of hemodialysis using regimens A, B, and C. Across regimens, mean Kt/Vs (1.5–1.6) and URRs (70%-73%) were comparable. No dialyzer was changed; 1 session was shortened 15 minutes because of circuit clot formation. Systemic argatroban clearance increased ∼20% during hemodialysis, without clinically significantly affecting ACTs. Upon argatroban discontinuation, ACTs and plasma argatroban decreased concurrently (elimination half-life, 35 ± 6 min). No thrombosis, bleeding, serious adverse events, or clinically significant changes in vital signs or routine laboratory measures occurred. Argatroban, administered by each treatment regimen, provides safe, adequate anticoagulation to enable successful hemodialysis in ESRD patients. Argatroban dialytic clearance by high-flux membranes is clinically insignificant.

Background Blood salvage systems help to minimize intraoperative transfusion of allogenic blood. So far no data is available on the use of argatroban for anticoagulation of such systems. We conducted an ex-vivo trial to evaluate the effectiveness of three different argatroban doses as compared to heparin and to assess potential residual anticoagulant in the red cell concentrates. Methods With ethical approval and individual informed consent, blood of 23 patients with contraindications for use of blood salvage systems during surgery was processed by the Continuous-Auto-Transfusion-System (C.A.T.S. ® Cell Saver System, Fresenius Kabi, Bad Homburg, Germany) using 5,50 or 250 mg of argatroban or 25.000 U of heparin in 1000 ml saline for anticoagulation of the system. Emergency and high-quality washing modes were applied in random order. Patency of the system and residual amount of anticoagulants in the re-transfusion bag were measured. The collected blood was not re-infused, but only used for analysis of hematocrit, heparin and argatroban concentrations. Results Patency of the system was provided by all anticoagulants except for 3/8 cases with 5 mg of argatroban. Residual anticoagulant was found in 2/10 (20 %) heparin samples in two different patients (1 emergency and 1 high-quality washing) and in all argatroban samples. High quality washing eliminated 89–95 % and emergency washing 60–90 % of the initial argatroban concentration. Residual argatroban concentrations ranged from 55 ng ml −1 to 6810 ng ml −1 , with initial argatroban concentrations of 5 and 250 mg, respectively. Conclusion The C.A.T.S. does not reliably remove heparin and should therefore not be used in HIT patients. Anticoagulation with 50 and 250 mg argatroban, maintains the systems patency and is significantly removed during washing. In this ex-vivo study a concentration of 50 μg ml −1 argatroban provided the best ratio of system patency and residual argatroban concentration. Additional dose-finding studies with different blood salvage systems are needed to evaluate the optimal argatroban concentration.

Monitoring of direct inhibitors of thrombin (DTI) is critical for their safe and effective use as anticoagulants. We examined samples containing several concentrations of argatroban or lepirudin in reconstituted standard human plasma and plasma from medical outpatients and intensive care patients. Prothrombin time (PT), activated partial thromboplastin time (aPTT), and thrombin time (TT) were determined using automated analyzers. Ecarin clotting time (ECT) was measured using a 10 IU/mL dilution of ecarin in 0.05 mol/L CaCl2. Calibration curves were approximately linear for TT and ECT in samples containing argatroban and lepirudin, respectively. Activated partial thromboplastin curves reached a plateau at DTI concentrations ≥2 µg/mL, suggesting that the aPTT may not reliably detect overdosing. Prothrombin time increased exponentially. A broad range of clotting times was seen in patient samples with all tests suggesting that individual morbidity and therapies may strongly influence test results and may lead to underestimation of DTI doses.

Antithrombin agent, argatroban, is currently undergoing several clinical trials for cardiovascular indications. Because of its solubility, this drug is usually administered via an intravenous bolus followed by infusion. The purpose of this study was to determine the pharmacokinetics of argatroban after intravenous bolus injection in primates. Parallel in vitro studies in primate whole blood were carried out to simulate a one-compartment system. Argatroban (range 1.0-7.5 mg/kg) was administered to four groups of primates and blood samples were drawn at various time periods. Argatroban measurements were made in plasma using functional (aPTT, Heptest, TT) and HPLC methods. In vitro, argatroban primarily distributed in the plasma in proportionate amounts. Relative uptake of argatroban to the blood cells (leukocytes and erythrocytes) was minimum. However, in vivo, argatroban followed a complex pharmacokinetics. Within 5 min after the bolus administration, only <20% of argatroban was recovered. The recovered amount was proportionate to the dosage and followed the expected kinetics with a half-life of <20 min. Simultaneous quantitation of M1-metabolite of argatroban revealed only a fraction of recovered argatroban (approximately 25%) converted into M1 in these experimental settings. Results obtained from the functional and absolute methods correlated well. HPLC profile did not reveal the presence of any other metabolite(s). These observations suggest that argatroban may be endogenously taken up by the vascular or other sites and may exhibit a complex kinetics. In acute settings, the metabolic transformation of argatroban to M1 is relatively low. To further clarify the pharmacokinetics/pharmacodynamics of this drug, additional studies are warranted.

Argatroban is considered to be an alternative anticoagulant of choice in patients with heparin-induced thrombocytopenia (HIT) and renal impairment. The recommended initial dose in HIT is 2 microg/kg/min (0.5 microg/kg/min in hepatic impairment), adjusted to achieve activated partial thromboplastin times (aPTTs) 1.5-3 times baseline. Although argatroban is predominantly hepatically metabolized with minimal renal clearance, recent limited data have suggested that a patient's renal function should also be considered when initiating argatroban therapy for HIT. We retrospectively evaluated the effect of renal function on argatroban therapy in HIT patients with normal hepatic function, with the goal of refining dosing guidance, if needed. From case records of previous prospective studies of argatroban in clinically diagnosed HIT, we identified patients who had baseline laboratory data on liver and renal function. Individuals with abnormal hepatic function (serum total bilirubin > 1.5 mg/dl or ALT or AST > 100 U/l) were excluded. Patients were stratified according to their estimated creatinine clearance (CL(cr)): normal or mild impairment (CL(cr) > 60 ml/min), moderate impairment (CL(cr) 30-60 ml/min), or severe impairment (CL(cr) < 30 ml/min). Argatroban doses, aPTTs, and clinical outcomes were summarized overall and by group. By-patient relationships between CL(cr) and dose or aPTT during therapy were explored using regression analyses. The analysis population included 260 patients with normal to mild (n = 144), moderate (n = 80), or severe (n = 36) renal impairment. Argatroban was initiated at a mean infusion dose of 1.8 +/- 0.7 microg/kg/min (overall), titrated to achieve aPTTs 1.5-3 times baseline. Among renal function groups, no significant differences occurred in argatroban dose during therapy (overall value, 1.9 +/- 1.1 microg/kg/min), duration of therapy (7 +/- 6 days), or aPTTs (63 +/- 17 s). Regression analyses showed a 0.1 microg/kg/min increase in dose (r2 = 0.02) for each 30 ml/min increase in CL(cr). Within a 37 day follow-up, 46 (17.7%) patients died, most often when severe renal impairment was present. New thrombosis (11.5% overall) and major bleeding (5.0%) did not differ among groups. In this large cohort of HIT patients with normal hepatic function and varying levels of renal function, argatroban administered in accordance with current recommendations provided adequate levels of anticoagulation and was well tolerated. Altered renal function did not clinically significantly affect argatroban doses, aPTT responses, or rates of thrombosis or bleeding. These findings further support argatroban as an alternative anticoagulant of choice, without need for initial dose adjustment, in most patients with HIT and renal impairment. We retrospectively evaluated the effect of renal function on argatroban therapy in HIT patients with normal hepatic function, with the goal of refining current dosing guidance, if needed. From previous prospective studies of argatroban in HIT, we identified 260 patients with clinically diagnosed HIT, normal hepatic function, and varying degrees of renal function. Among patients whose renal function was normal or mildly impaired (estimated creatinine clearance, CL(cr) > 60 ml/min); moderately impaired (CL(cr) 30-60 ml/min), or severely impaired (CL(cr) < 30 ml/min), no significant differences occurred in the argatroban dose, aPTT response, duration of therapy, or rates of thrombosis or major bleeding. By regression analysis, there was a clinically insignificant 0.1 microg/kg/min increase in dose for each 30 ml/min increase in CL(cr). Overall, argatroban administered in accordance with current recommendations provided adequate levels of anticoagulation and was well tolerated, supporting its use as an alternative anticoagulant of choice, without need for initial dose adjustment, in most patients with HIT and renal impairment.

Argatroban, a hepatically metabolized direct thrombin inhibitor, is approved for anticoagulation in patients with or at risk of heparin-induced thrombocytopenia (HIT) undergoing percutaneous coronary intervention (PCI). We investigated the effect of renal function on argatroban therapy during PCI. From previous argatroban studies in PCI, we evaluated relationships between estimated creatinine clearance (CrCl) and activated clotting times (ACTs), dosage, and outcomes in 219 patients with or at risk of HIT (HIT group, n  = 67) or administered glycoprotein IIb/IIIa inhibition (non-HIT group, n  = 152). Patients received an argatroban bolus (350 mcg/kg, HIT group; 250 or 300 mcg/kg, non-HIT group) then 25–30 mcg/kg/min (adjusted to achieve ACTs 300–450 s, HIT group) or 15 mcg/kg/min (target ACTs 275–325 s, non-HIT group), with additional 150-mcg/kg boluses if needed. Of 219 patients, 55 (25%) had CrCl ≤ 60 ml/min (8 with CrCl ≤ 30 ml/min). Regression analyses detected no association between CrCl (range 7–231 ml/min) and initial ACT (by bolus) or mean infusion dose. Multi-bolus usage was similar in patients with, versus without, CrCl ≤ 60 ml/min. In the non-HIT group, CrCl was associated ( P  = 0.01) with the time to ACT ≤ 160 s after argatroban cessation (~17 min slower per 30-ml/min CrCl decrease). Eight patients (none with CrCl ≤ 60 ml/min) had ischemic complications. Three patients (1 with CrCl 40 ml/min) experienced major bleeding. Argatroban dose adjustment for renal function appears unnecessary during PCI. Renal dysfunction may be associated with slower (by minutes) ACT effect decay after argatroban cessation. Argatroban is well tolerated in PCI patients with renal impairment.

ARGAMI was designed to assess safety and efficacy of argatroban compared with heparin as adjunctive treatment to alteplase in the treatment of patients with acute myocardial infarction. ARGAMI consisted of an open-dose finding study (35 patients) followed by a placebo-controlled study with double dummy technique and 2:1 (argatroban:heparin) randomization. An argatroban dosage of 100 microg/kg bolus plus 3 microg/kg/min infusion for 72 hours was selected for the randomized study in which 82 patients were allocated to argatroban and 45 to heparin (5000 U intravenous bolus, 1000 U/h infusion). Patency of the infarct-related artery (Thrombolysis in Myocardial Infarction [TIMI] grade 2 or 3 flow) after 90 minutes was obtained in 62 patients (76%) allocated to argatroban versus 37 patients (82%) allocated to heparin (p=ns). Angiograms after 24 hours and 5 to 10 days showed low reocclusion rates in both groups. Bleeding complications were observed in 16 patients allocated to argatroban (19.5%) and in 9 patients allocated to heparin (20.0%). One patient allocated to heparin suffered from hemorrhage stroke. Argatroban, given as adjunctive treatment to alteplase, is tolerated well in patients with acute myocardial infarction. Safety and efficacy of the combination alteplase and argatroban (with this dose regimen) are similar to those of alteplase and heparin.

Antithrombotic and antiplatelet therapies are the cornerstones of management of cardiovascular disorders today. Due to the safety and efficacy limitations of the classic antithrombotic, unfractionated heparin, considerable effort has been directed at developing novel anticoagulants. Direct thrombin inhibitors as a class of drugs offer inhibition of clot-bound as well as fluid-phase thrombin and a more predictable anticoagulant response. Specifically, argatroban, a synthetic small molecule direct thrombin inhibitor, selectively inhibits the catalytic site of thrombin in a reversible manner. Overall, argatroban's short half-life, ease of monitoring with an activated partial thromboplastin time, and safety in renal failure patients make this drug the preferable mode therapy for prevention of thrombosis in heparin-induced thrombocytopenia. The role of adjunctive argatroban therapy in acute coronary syndromes and during percutaneous coronary intervention is currently being studied.