Argatroban versus heparin in patients without heparin-induced thrombocytopenia during venovenous extracorporeal membrane oxygenation: a propensity-score matched study.

BACKGROUND: During venovenous extracorporeal membrane oxygenation (vvECMO), direct thrombin inhibitors are considered by some potentially advantageous over unfractionated heparin (UFH). We tested the hypothesis that Argatroban is non-inferior to UFH regarding thrombosis and bleeding during vvECMO. METHODS: We conducted a propensity-score matched observational non-inferiority study of consecutive patients without heparin-induced-thrombocytopenia (HIT) on vvECMO, treated between January 2006 and March 2019 in the medical intensive care unit at the University Hospital Regensburg. Anticoagulation was realized with UFH until August 2017 and with Argatroban from September 2017 onwards. Target activated partial thromboplastin time was 50 ± 5seconds in both groups. Primary composite endpoint was major thrombosis and/or major bleeding. Major bleeding was defined as a drop in hemoglobin of ≥ 2 g/dl/day or in transfusion of ≥ 2 packed red cells/24 h, or retroperitoneal, cerebral, or pulmonary bleeding. Major thrombosis was defined as obstruction of > 50% of the vessel lumen diameter by means of duplex sonography. We also assessed technical complications such as oxygenator defects or pump head thrombosis, the time-course of platelets, and the cost of anticoagulation (including HIT-testing). RESULTS: Out of 465 patients receiving UFH, 78 were matched to 39 patients receiving Argatroban. The primary endpoint occurred in 79% of patients in the Argatroban group and in 83% in the UFH group (non-inferiority for Argatroban, p = 0.026). The occurrence of technical complications was equally distributed (Argatroban 49% vs. UFH 42%, p = 0.511). The number of platelets was similar in both groups before ECMO therapy but lower in the UFH group after end of ECMO support (median [IQR]: 141 [104;198]/nl vs. 107 [54;171]/nl, p = 0.010). Anticoagulation costs per day of ECMO were higher in the Argatroban group (€26 [13.8;53.0] vs. €0.9 [0.5;1.5], p < 0.001) but not after accounting for blood products and HIT-testing (€63 [42;171) vs. €40 [17;158], p = 0.074). CONCLUSION: In patients without HIT on vvECMO, Argatroban was non-inferior to UFH regarding bleeding and thrombosis. The occurrence of technical complications was similarly distributed. Argatroban may have less impact on platelet decrease during ECMO, but this finding needs further evaluation. Direct drug costs were higher for Argatroban but comparable to UFH after accounting for HIT-testing and transfusions.

Clinical controversies in anticoagulation monitoring and antithrombin supplementation for ECMO.

During extracorporeal membrane oxygenation (ECMO), a delicate balance is required to titrate systemic anticoagulation to prevent thrombotic complications within the circuit and prevent bleeding in the patient. Despite focused efforts to achieve this balance, the frequency of both thrombotic and bleeding events remains high. Anticoagulation is complicated to manage in this population due to the complexities of the hemostatic system that are compounded by age-related developmental hemostatic changes, variable effects of the etiology of critical illness on hemostasis, and blood-circuit interaction. Lack of high-quality data to guide anticoagulation management in ECMO patients results in marked practice variability among centers. One aspect of anticoagulation therapy that is particularly challenging is the use of antithrombin (AT) supplementation for heparin resistance. This is especially controversial in the neonatal and pediatric population due to the baseline higher risk of bleeding in this cohort. The indication for AT supplementation is further compounded by the potential inaccuracy of the diagnosis of heparin resistance based on the standard laboratory parameters used to assess heparin effect. With concerns regarding the adverse impact of bleeding and thrombosis, clinicians and institutions are faced with making difficult, real-time decisions aimed at optimizing anticoagulation in this setting. In this clinically focused review, the authors discuss the complexities of anticoagulation monitoring and therapeutic intervention for patients on ECMO and examine the challenges surrounding AT supplementation given both the historical and current perspectives summarized in the literature on these topics.

Storage Stability of Bivalirudin: Hydrophilic Versus Lipophilic Solutions.

It was the aim of this study to incorporate a model peptide bivalirudin in self-emulsifying drug delivery system (SEDDS) and compare its storage stability with conventional aqueous solutions. Firstly, bivalirudin lipophilicity was increased via hydrophobic ion pairing using anionic or cationic surfactants. The chosen bivalirudin docusate complex (BIV/AOT) was incorporated into SEDDS composed of 40% (w/w) Cremophor EL, 20% (w/w) Capmul PG-8, and 40% (w/w) propylene glycol with a drug payload of 0.20% (w/w). SEDDS were stable over a wide pH range for at least 7 days at 37°C and showed an immediate bivalirudin release profile. Moreover, aqueous bivalirudin solutions were shown to be most stable between apparent pH 3 and 4. Furthermore, 94.39% and 72.66% of bivalirudin in SEDDS and 10% propylene glycol, respectively, remained intact after 90 days of storage at 25°C ± 2°C, whereas 99.12% and 80.54% were still intact in SEDDS and 10% propylene glycol at 5°C ± 3°C, respectively. Bivalirudin in reconstituted commercially available product Angiomax® was, however, long-term unstable. According to these findings, SEDDS could be considered as a potential bivalirudin stabilization medium against chemical degradation.

A collaborative study to establish a Korea national biological standard for antithrombin concentrate.

BACKGROUND AND OBJECTIVES: Six laboratories consisting of three manufacturers and three national control laboratories participated in a collaborative study to evaluate the suitability of a candidate material to serve as the first Korean National Standard for Antithrombin (AT) concentrate. MATERIALS AND METHODS: The potency of this candidate preparation was determined using the heparin cofactor chromogenic method. The method is described in the Minimum Requirements for Biological Products in Korea and in the European Pharmacopoeia. The candidate was calibrated against the second International Standard for AT concentrate, coded as 96/520. RESULTS: The participants contributed data from a total of 90 independent assays and the results were accepted as statistically valid when the outcome of the analysis exhibited linear dose-response relationships and intersected at a common point at zero dose in the slope-ratio model. The combined potency estimates were obtained by taking the geometric means of results from all assays at each laboratory, and overall potency estimates were calculated as unweighted geometric means of results from all laboratories. The results were expressed in the form of histograms with 95% confidence intervals. CONCLUSIONS: According to the results of the collaborative study, the candidate preparation showed excellent intra- and inter-laboratory correlations and is judged to be suitable to serve as the Korean National Standard for AT concentrate with the following potency: 51.9 IU/vial (95% confidence intervals=48.24 approximately 55.98 IU/vial).

[Future potential indications for an oral thrombin inhibitor]. / Zukünftiges Indikationspotenzial eines oralen Thrombininhibitors.

By the use of conventional anticoagulants, significant improvements were achieved in all fields of medicine. Although efficacious and widely used, their use is limited in several respects. In particular, the use of vitamin K antagonists is restricted in the clinical routine setting. The main reasons are the delayed on- and off-set of action, the narrow therapeutic window, the necessity of individual laboratory-controlled dosing, and interactions with food ingredients and drugs. The search for new antithrombotics with an improved safety/efficacy profile led to the development of the direct oral thrombin-inhibitor ximelagatran. It can be administered without routine monitoring of coagulation parameters and does not possess any of the previously mentioned limitations. The results from clinical phase II studies obtained so far are very encouraging. After completion of the clinical development program focussing on prevention and treatment of venous thromboembolism, on stroke prevention in atrial fibrillation and on acute coronary syndromes, it is desirable to continue with investigations with regard to long-term prophylaxis in high risk surgery, in chronic peripheral artery disease, in patients with left ventricular thrombi, artificial heart valves, or thrombophilia, as an alternative anticoagulant in heparin induced thrombocytopenia and for prevention of thromboembolic complications in oncology. Because of the mitogenic effects of thrombin on the proliferation of tumour cells, additional experimental studies aiming at a potential inhibition of thrombin-triggered oncogenesis is of uttermost interest.

Combination of a direct thrombin inhibitor and a platelet glycoprotein IIb/IIIa blocking peptide facilitates and maintains reperfusion of platelet-rich thrombus with alteplase.

We sought to determine the efficacy of the combination of argatroban, a direct thrombin inhibitor, and G4120, a platelet glycoprotein (GP) IIb/IIIa blocker, to enhance thrombolysis with alteplase. Platelet-rich thrombus in the rabbit arterial thrombosis model is relatively resistant to alteplase despite the addition of aspirin and heparin. The adjunctive use of either direct thrombin inhibitors or GP IIb/IIIa inhibitors in thrombolysis has been investigated with encouraging, but limited, success. The usefulness of combining both agents as adjunctive therapy to thrombolysis has not been fully explored. Following platelet-rich thrombus formation in the rabbit, argatroban (3 mg/kg), G4120 (0.5 mg/kg), G4120 plus heparin (200 U/kg), or G4120 plus argatroban were intravenously infused over 60 minutes. Alteplase was given as intravenous boluses (0.45 mg/kg) at 15-minute intervals up to 4 doses or until reperfusion. Blood flow and bleeding time were monitored for 2 hours. The combination of G4120 plus argatroban resulted in a persistent patency in 5 of 7 animals compared with 0 of 6 for argatroban alone (p=0.02), 1 of 6 for G4120 alone (p=0.08), and 2 of 6 for G4120 plus heparin (p=0.2). Although during the infusion the bleeding times were longer in the groups that received G4120 (26+/-7.7 minutes vs. 14+/-10 minutes, p<0.05), by the end of the experiment there were no statistically significant differences. Similarly, during the infusion the activated partial thromboplastin times (aPTT) was higher in groups that received heparin or argatroban (99+/-51 seconds vs. 32+/-7.6 seconds, p<0.001), but by the end of the experiment the aPTTs had returned to close to baseline in all groups except the G4120 plus heparin group. These results suggest that lysis of platelet-rich thrombus with alteplase requires the addition of both potent platelet and thrombin inhibitors. Specifically designed agents, G4120 and argatroban, are effective without additional increased risk for bleeding.