Argatroban Group Research Articles

A safety comparison of heparin and argatroban anticoagulation in veno-venous extracorporeal membrane oxygenation with a focus on bleeding.

Anticoagulation during extracorporeal membrane oxygenation (ECMO) might still lead to severe bleeding complications. Heparin is the most frequently used anticoagulant, but novel drugs could be promising. Argatroban is a new alternative to heparin. To date, no robust studies have confirmed the clear superiority of argatroban (AG) over heparin, although it has some advantages and may be safer. An observational study was conducted in all adult veno-venous ECMO patients with COVID-19-associated acute respiratory distress syndrome admitted to the University Hospital Ostrava (n = 63). They were anticoagulated with heparin in the first period and with AG in the second period, targeting the same activated partial thromboplastin time (aPTT; 45-60 s). Bleeding complications requiring transfusion and life-threatening bleeding events were evaluated. The primary objective was to compare heparin and AG in terms of bleeding, transfusion requirements and mortality-related bleeding. The total time on ECMO per patient was 16 days with an in-hospital mortality of 55.6%. The red blood cell consumption in the AG group (median 2.7 transfusions/week) was significantly lower than in the heparin group (median 4.2 transfusions/week, p = 0.011). Life-threatening bleeding complications were higher in the heparin group compared to the AG group (35.7% vs. 10.2%, p = 0.035), and mortality-related bleeding complications were also higher in the heparin group (21.4% vs. 2.0%, p = 0.032). Argatroban is an interesting alternative to heparin with less bleeding, less need for red blood cell transfusions and improved safety of ECMO with less mortality-related bleeding.

The effect of argatroban on early neurological deterioration and outcomes in minor ischemic stroke: preliminary findings.

Minor ischemic stroke (MIS) is associated with early neurological deterioration (END) and poor prognosis. Here, we investigated whether argatroban administration can mitigate MIS-associated END and improve functional outcomes by monitoring activated partial thrombin time (APTT). Data were collected for patients with MIS admitted to our hospital from January 2019 to December 2022. Patients were divided into a dual antiplatelet therapy (DAPT) group (aspirin + clopidogrel) and an argatroban group (aspirin + argatroban). Those in the latter group who achieved a target APTT of 1.5-3-fold that of baseline and <100 s at 2 h after argatroban infusion were included in the argatroban subgroup. The primary outcome was the END rate of the DAPT group versus that of the argatroban group or the argatroban subgroup. Secondary outcomes included the proportion of patients with modified Rankin Scale (mRS) 0-2 at 7 and 90 days. In addition, baseline date were compared between patients with and without END in the argatroban group. 363 patients were included in the DAPT group and 270 in the argatroban group. There were no significant differences in any above outcome between them. 207 pairs were included in the DAPT group and the argatroban subgroup after 1:1 propensity score matching (PSM). Significant differences were observed in the proportion of END (OR, 2.337; 95% CI, 1.200-4.550, p = 0.011) and mRS 0-2 at 7 days (OR, 0.624; 95% CI, 0.415-0.939, p = 0.023), but not in mRS 0-2 at 90 days or the hemorrhagic events between the two groups. In the argatroban group, univariate analysis showed that the rate of diabetes (OR, 2.316; 95% CI, 1.107-4.482, p = 0.023), initial random blood glucose (OR, 1.235; 95% CI, 1.070-1.425, p = 0.004), drinking history (OR, 0.445; 95% CI, 0.210-0.940, p = 0.031) or those reaching the target APTT (OR, 0.418; 95% CI, 0.184-0.949, p = 0.033) was significantly different among patients with and without END. However, there were no statistical differences in these parameters between them following multivariate analysis. In patients with MIS, argatroban administration and reaching the target APTT can reduce the incidence of END and improve short-term functional prognosis.

Argatroban in Patients With Acute Ischemic Stroke With Early Neurological Deterioration

The effect of argatroban in patients with acute ischemic stroke (AIS) and early neurological deterioration (END) is unknown. To assess the efficacy of argatroban for END in AIS. This open-label, blinded-end point, randomized clinical trial was conducted from April 4, 2020, through July 31, 2022. The date of final follow-up was October 31, 2022. This was a multicenter trial. Eligible patients were adults with AIS who experienced END, which was defined as an increase of 2 or more points on the National Institutes of Health Stroke Scale within 48 hours from symptom onset. Patients who withdrew consent, experienced duplicate randomization, or were lost to follow-up were excluded from the study. Patients were randomly assigned to the argatroban group and control group within 48 hours of symptom onset. Both groups received standard therapy based on guidelines, including oral mono or dual antiplatelet therapy. The argatroban group received intravenous argatroban for 7 days (continuous infusion at a dose of 60 mg per day for 2 days, followed by 20 mg per day for 5 days) in addition to standard therapy. The primary end point was good functional outcome at 90 days, defined as a modified Rankin Scale score of 0 to 3. A total of 628 patients (mean [SD] age, 65 [11.9] years; 400 male [63.7%]) were included in this study (argatroban group, 314 [50%] and control group, 314 [50%]). Of these, 18 withdrew consent, 1 had duplicate randomization, and 8 were lost to follow-up. A total of 601 patients with stroke were included in the intention-to-treat analysis. Finally, 564 patients were included in the per-protocol analysis as 6 participants in the argatroban group and 31 participants in the control group did not follow the complete protocol. The number of patients with good functional outcome at 90 days was 240 (80.5%) in the argatroban group and 222 (73.3%) in the control group (risk difference, 7.2%; 95% CI, 0.6%-14.0%; risk ratio, 1.10; 95% CI, 1.01-1.20; P = .04). The proportion of symptomatic intracranial hemorrhage was 3 of 317 (0.9%) in the argatroban group and 2 of 272 (0.7%) in the control group (P = .78). Among patients with AIS with END, treatment with argatroban and antiplatelet therapy resulted in a better functional outcome at 90 days. This trial provided evidence to support the use of argatroban in reducing disability for patients with END. ClinicalTrials.gov Identifier: NCT04275180.

Membrane oxygenator longevity was higher in argatroban-treated patients undergoing vvECMO.

In severe acute respiratory distress syndrome (ARDS), venovenous extracorporeal membrane oxygenation (vvECMO) can be a lifesaver. However, anticoagulation therapy is mandatory because the nonendothelial extracorporeal surface increases the risk of thromboembolic problems. Heparin is still the most common anticoagulant, but argatroban could be an alternative. This work investigates whether argatroban offers a therapeutic advantage over heparin during vvECMO. We performed a retrospective cohort study of patients who underwent vvECMO for severe ARDS and received heparin or argatroban as anticoagulation therapy. Demographic variables, intensivecareunit(ICU) treatment and outcome parameters were evaluated. The primary outcome parameter was the operating time of the membrane oxygenator normalized to the duration of vvECMO treatment. Secondary outcome parameters were transfusion requirements normalized to the duration of vvECMO therapy. Fifty seven patients from January 2019 to February 2021 underwent vvECMO and were included in this study. Thirty three patients received heparin and 24 patients argatroban as anticoagulatory therapy. The groups did not differ in demographics, ICU scoring systems, or comorbidities. Platelet counts and partial prothrombin time did not differ between the two groups during the first 6 days of vvECMO. The argatroban group had lower requirements for red blood cells, platelets and fresh frozen plasma. The mean runtime of the individual membrane oxygenator increased from 12.3 days (heparin group) to 16.6 days in the argatroban group. Our findings suggest that argatroban can be considered as anticoagulant during vvECMO.

Application of argatroban in patients receiving extracorporeal membrane oxygenation support: a case-control study

To evaluate the safety and efficacy of argatroban applied as alternative anticoagulant in critical illness patients underwent extracorporeal membrane oxygenation (ECMO) with contraindications of unfractionated heparin (UFH), and to further explore the effective dose of argatroban. From July 1, 2013 to February 28, 2022, there were 14 patients who admitted in the respiratory intensive care unit (RICU) of Beijing Chao-Yang Hospital received ECMO and used argatroban for anticoagulation (argatroban group). Two of them received argatroban as the initial anticoagulant. The remaining 12 patients used UFH at first, and then switched to argatroban. UFH group included 28 patients who received UFH for anticoagulation after matching the demographic characteristics. Primary endpoint was the prevalence of ECMO-related thrombotic events. Secondary endpoints included the type of thrombotic events, prevalence of ECMO-related major bleeding events, bleeding sites, ICU mortality, mortality during ECMO, liver and kidney function, thrombelastogram, blood transfusion, dosage of argatroban, the dynamic changes of coagulation variables 4 days before and 7 days after argatroban treatment. In argatroban group, there were 8 patients received veno-venous ECMO (VV-ECMO), 2 patients with veno-arterial ECMO (VA-ECMO), and 4 patients with veno-arterio-venous ECMO (VAV-ECMO). In UFH group, VV-ECMO was applied in 23 patients, VA-ECMO and VAV ECMO was established in 3 patients and 2 patients, respectively. In endpoint events, the incidence of ECMO related thrombotic events in argatroban group was slightly higher than that in UFH group (28.6% vs. 21.4%). The ECMO running time in argatroban group was slightly longer than that in UFH group [days: 16 (7, 21) vs. 13 (8, 17)]. The incidence of ECMO-related bleeding events (28.6% vs. 32.1%) and mortality during ECMO (35.7% vs. 46.4%) in argatroban group were slightly lower than those in UFH group. However, the differences were not statistically significant (all P < 0.05). The platelet transfusion in argatroban group was significantly higher than that in UFH group [U: 7.7 (0, 10.0) vs. 0.8 (0, 1.0)]. The coagulation reaction time (R value) in thrombelastography in argatroban group was significantly longer than that in UFH group [minutes: 9.3 (7.2, 10.8) vs. 8.8 (6.3, 9.7)]. The maximum width value [MA value, mm: 48.4 (40.7, 57.9) vs. 52.6 (45.4, 61.5)] and blood clot generation rate [α-Angle (deg): 54.1 (45.4, 62.0) vs. 57.9 (50.2, 69.0)] in the argatroban group were significantly lower than those in the UFH group (all P < 0.05). The activated partial thromboplastin time (APTT) was prolonged after changing from UFH to argatroban in the argatroban group [seconds: 63.5 (58.4, 70.6) vs. 56.7 (53.1, 60.9)]. The PLT level showed a decreasing trend during UFH anticoagulation therapy, and gradually increased after changing to argatroban. D-dimer level was 19.1 (7.0, 28.7) mg/L after switching to argatroban, and then no longer showed an increasing trend. The level of fibrinogen (FIB) showed a decreasing trend during the anticoagulant therapy of UFH (the lowest was 23.6 g/L), and fluctuated between 16.8 and 26.2 g/L after changing to argatroban. The median initial dose of argatroban was 0.049 (0.029, 0.103) μg×kg-1×min-1, which the highest dose was in VV-ECMO patients of [0.092 (0.049, 0.165) μg×kg-1×min-1]. The initial dose of VAV-ECMO was the lowest [0.026 (0.013, 0.041) μg×kg-1×min-1], but without significant difference (P > 0.05). The maintenance dose of argatroban was 0.033 (0.014, 0.090) μg×kg-1×min-1, VV-ECMO patients was significantly higher than those in VA-ECMO and VAV-ECMO patients [μg×kg-1×min-1: 0.102 (0.059, 0.127) vs. 0.036 (0.026, 0.060), 0.013 (0.004, 0.022), both P < 0.05]. Argatroban appears to be a feasible, effective and safety alternative anticoagulant for patients with contraindications to UFH who undergoing ECMO support.

Clinical efficacy and safety analysis of argatroban and alteplase treatment regimens for acute cerebral infarction

ObjectiveThis study compared the clinical efficacy and safety of argatroban and alteplase in the treatment of acute cerebral infarction. MethodsThis study retrospectively analyzed 131 patients admitted for acute cerebral infarction within 48 h of onset from 1 December 2018 to 1 May 2021. The patients were divided according to treatment (i.e., the argatroban and alteplase groups). The National Institutes of Health Stroke Scale (NIHSS) scores (before treatment, at 24 h, and at 3, 7, and 14 days),14-day response rate, 3-month modified Rankin Scale score (mRS), activities of daily living (ADL) score, prognosis, and adverse events during treatment were compared. ResultsSixty-two and 69 patients were enrolled in the alteplase and argatroban groups, respectively, and both had comparable baseline data. The NIHSS scores of the alteplase group decreased significantly before and after treatment (24 h and at 3, 7, and 14 days), whereas those of the alteplase group decreased most rapidly after 24 h of administration. The argatroban group showed no significant changes in NIHSS score in the first 7 days after treatment until day 14, at which it significantly decreased. Statistically significant differences between the two groups were observed in four points (P < 0.05). The 14-day effectivity rate of alteplase was significantly higher than that of argatroban (83.8% vs. 65.2%; χ2 = 131; P = 0.001). The 3-month mRS, ADL and pre-treatment comparisons were statistically significant in the two groups (P < 0.05), while the inter-group comparison was not statistically significant (P > 0.05). Furthermore, the outcomes at 3 months after treatment in both groups did not vary significantly (alteplase vs. argatroban: 48/62 vs. 51/69; χ2 = 0.217; P = 0.641). Adverse events during treatment included gingival bleeding (two patients), positive fecal occult blood (two patients), and minor intracranial blood ooze (one patient) in the alteplase group, whereas no adverse events (e.g., bleeding and shock) were noted in the argatroban group. ConclusionThe short-term efficacy of argatroban in improving neurological function in patients with acute cerebral infarction was significantly lower than that of alteplase. However, the long-term efficacy at 3 months of treatment was comparably significant to that of alteplase with fewer adverse events.

Effects of wasp venom on venous thrombosis in rats.

Objective(s):This study aimed to investigate the potential effects of wasp venom (WV) from Vespa magnifica on antithrombosis in rats with inferior vena cava (IVC) thrombosis.Materials and Methods:The thrombosis rat model was established by improving the IVC stenosis, in which rats were subjected to IVC ligation for 75 min. Rats were administered argatroban (IP) or WV (s.c.) for 4 hr after IVC thrombosis. The weight, inhibition rate, and pathological morphology of the thrombosis induced by IVC ligation and the variation in four coagulation parameters, coagulation factors, and CD61+CD62P+ were simultaneously determined in IVC rats.Results:The thrombus formed as a result of IVC ligation was stable. Compared with the control group, the weight of the thrombus was significantly reduced in the argatroban group. Thrombus weight was reduced by treatment with 0.6, 0.2, and 0.05 mg/kg WV, with inhibition rates of 52.19%, 35.32%, and 28.98%, respectively. Inflammatory cells adhered to and infiltrated the vessel wall in the IVC group more than in the sham group. However, the pathological morphology and CD61+CD62P+ of the WV treatment groups tended to be normal. Conclusion:We improved the model of IVC thrombosis to be suitable for evaluation of antithrombotic drugs. Our findings demonstrated that WV could inhibit IVC thrombosis associated with reducing coagulation factors V and CD61+CD62p expression in rats.

Efficacy and safety of argatroban in treatment of acute ischemic stroke: A meta-analysis.

BACKGROUNDArgatroban is a novel direct thrombin inhibitor that has been used for treatment of acute ischemic stroke (AIS). To our knowledge, no systematic analysis has assessed the efficacy and safety of argatroban for treatment of AIS.AIMTo evaluate the efficacy and safety of argatroban for treatment of AIS.METHODSCochrane Library, Medline, PubMed, and Web of Science were searched to retrieve all studies associated with argatroban and AIS. Effective rate, adverse events rate, and 95% confidence intervals were calculated and pooled using meta-analysis methodology. RESULTSWe only found four randomized controlled studies, comprising 354 cases with 213 in the argatroban group and 141 in the control group. Great heterogeneity was found in the four studies (c2 = 11.44, I2 = 74%, P = 0.01). Subgroup analysis could not be performed because of the absence of detailed data. The two most recent studies showed acceptable heterogeneity (c2 = 1.56, I2 = 36%, P = 0.21). Our analysis showed that argatroban was not more effective than the control therapy in the acute phase of ischemic stroke (Z = 0.01, P = 0.99). Argatroban did not increase the risk of bleeding compared with the control group (c2 = 0.37, I2 = 0%, P = 0.54, Z = 0.80, P = 0.42).CONCLUSIONPatients with AIS might not benefit from argatroban and combination therapy with argatroban does not increase bleeding tendency.

Early argatroban and antiplatelet combination therapy in acute non-lacunar single subcortical infarct associated with mild intracranial atherosclerosis

BackgroundPatients with acute non-lacunar single subcortical infarct (SSI) associated with mild intracranial atherosclerosis (ICAS) have a relatively high incidence of early neurological deterioration (END), resulting in unfavorable functional outcomes. Whether the early administration of argatroban and aspirin or clopidogrel within 6–12 h after symptom onset is effective and safe in these patients is unknown.MethodsA review of the stroke database of Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University and Qingdao Center Hospital, Qingdao University Medical College in China was undertaken from May 2017 to January 2020 to identify all patients with non-lacunar SSI caused by ICAS within 6–12 h of symptom onset based on MRI screening. Patients were divided into two groups, one comprising those who received argatroban and mono antiplatelet therapy with aspirin or clopidogrel on admission (argatroban group), and the other those who received dual antiplatelet therapy (DAPT) with aspirin and clopidogrel during hospitalization (DAPT group). The primary outcome was recovery by 90 days after stroke based on a modified Rankin scale (mRS) score (0 to 1). The secondary outcome was END incidence within 120 h of admission. Safety outcomes were intracranial hemorrhage (ICH) and major extracranial bleeding. The probability of clinical benefit (mRS score 0–1 at 90 days) was estimated using multivariable logistic regression analysis.ResultsA total of 304 acute non-lacunar SSI associated with mild ICAS patients were analyzed. At 90 days, 101 (74.2%) patients in the argatroban group and 80 (47.6%) in the DAPT group had an mRS score that improved from 0 to 1 (P < 0.001). The relative risk (95% credible interval) for an mRS score improving from 0 to 1 in the argatroban group was 1.50 (1.05–2.70). END occurred in 10 (7.3%) patients in the argatroban group compared with 37 (22.0%) in the DAPT group (P < 0.001). No patients experienced symptomatic hemorrhagic transformation.ConclusionsEarly combined administration of argatroban and an antiplatelet agent (aspirin or clopidogrel) may be beneficial for patients with non-lacunar SSI associated with mild ICAS identified by MRI screening and may attenuate progressive neurological deficits.Trial registrationOur study is a retrospectively registered trial.

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

BackgroundDuring 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.MethodsWe 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).ResultsOut 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).ConclusionIn 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.

Abstract 122: Effects of Early Administration of Argatroban on CPR Quality in Porcine Model of Prolonged Out-of-Hospital Cardiac Arrest

Background: The effectiveness of CPR declines over time during prolonged cardiac arrest (CA). Intravascular thrombosis may be a contributing factor. As part of a larger study examining antithrombotic therapy in a porcine model of prolonged CA, the impact of early administration of argatroban on CPR hemodynamics is reported. Hypothesis: Early administration of argatroban during CPR improves the quality of goal-directed CPR (gdCPR). Methods: In a blinded and randomized study, 48 swine (40±5kg) underwent an 8min untreated period of ventricular fibrillation CA followed by a gdCPR protocol for 30min (total arrest time 38min). Manual and mechanical chest compressions with the use of an impedance threshold device (ITD) were introduced to maintain end-tidal CO 2 (Et-CO 2 ) &gt;20mmHg. Argatroban (350mg/kg) or placebo (20mL NSS) were administered to respective groups (n=24 per group) 12mins after initiation of CA. Et-CO 2 , coronary perfusion pressure (CPP), end-diastolic pressure (EDP), and intracranial pressure (ICP) were monitored continuously. Averages were taken over the course of gdCPR for hemodynamic parameters. Arterial blood gases (ABGs) were obtained at the end of gdCPR. Analysis between groups was performed using an unpaired t-test (significance = p &lt;0.05). Results: Average hemodynamic parameters were not statistically different between argatroban vs. placebo groups (Et-CO 2 22.6±6.7 vs. 21.5±5.9 mmHg; EDP 25.6±10.7 vs. 23.7±9.6 mmHg; ICP 25.7±2.0 vs.20.9±2.7 cmH 2 O; CPP 8.7±11.2 vs. 7.0±11.2 mmHg). Final ABG values were also not statistically different between argatroban vs. placebo groups (pH 7.23±0.1 vs. 7.23±0.2; PaO 2 187.4±146.3 vs. 132.2±187.4 mmHg; PaCO 2 38.8±16.6 vs. 43.0±26.1 mmHg; lactate 8.5±1.7 vs. 8.8±1.4 mmol/L). Conclusion: These results demonstrate that early administration of argatroban during CPR did not have a significant effect on gdCPR quality in a porcine model of prolonged CA.

Abstract 113: Effects of Anticoagulation and Thrombolytic Therapy in a Porcine Model of Prolonged Out-of-hospital Cardiac Arrest Treated with ECPR

Background: Extracorporeal cardiopulmonary resuscitation (ECPR) has been used in patients with refractory out-of-hospital cardiac arrest (OHCA). However, recovery of organ function and survival are potentially impaired due to microvascular coagulation causing a “no-reflow” phenomenon. Hypothesis: Early anticoagulant therapy (argatroban) during CPR and/or thrombolytic therapy (streptokinase) at ECPR onset improves recovery of organ function in an OHCA porcine model. Methods: In a blinded and randomized study, 48 swine (40±5kg) were subjected to 8min of ventricular fibrillation cardiac arrest (CA) followed by 30min of goal directed CPR (gdCPR), and 8h of ECPR (33°C) with heparin anticoagulation during ECPR. Animals (n=12) were randomized to one of 4 groups with 350mg/kg argatroban (Arg) or placebo (20mL NSS) given 12min after CA onset and 1.5 MU streptokinase (STK) or placebo (50mL NSS) given at ECPR initiation: Group 1 (placebo and placebo); Group 2 (Arg and placebo); Group 3 (placebo and STK); and Group 4 (Arg and STK). Recovery of cardiac function measured by a cardiac resuscitablity score (CRS), see Table. Recovery of neurologic function measured by amplitude recovery of cortical somatosensory evoked potentials (cSSEP). Data analysis: Kruskal Wallis and single factor ANOVA tests with ( p &lt;0.05 significant). Results: Average CRS and cSSEP recovery were not significantly different between groups. However, the combined average CRS of the argatroban groups (2&amp;4) was 3.2±2.1 compared to 2.0±1.6 for the groups without it (1&amp;3), p =0.03 single factor ANOVA. Furthermore, more animals in groups 2&amp;4 (n=8) achieved a robust recovery in cSSEP amplitude (≥30% amplitude return) than in groups 1&amp;3 (n=4). Discussion: These results provide evidence that argatroban given early during CPR potentially improves early recovery of cardiac and neurological function in a porcine model of OHCA. However, the impact of these therapies on long term recovery remains to be determined.

Argatroban versus heparin for the treatment of pump thrombosis in patients with ventricular assist device

Abstract Background/Introduction Pump thrombosis (PT) is a major complication from ventricular assist device (VAD) and the best therapy remains unknown. The diagnosis of PT is challenging and, based on the ISHLT (International Society of Heart and Lung Transplantation) guidelines, consists of signs of hemolysis and impaired pump function. Purpose We aimed to compare the outcomes of PT treated with continuous infusion of argatroban (ARG) versus heparin. Methods This is a retrospective cohort study including patients &amp;gt;15 years-old with VAD implanted between 2009 and 2017 and who developed PT during follow up. PT events were managed with ARG or heparin based on physician preference at our institution, and patients were grouped based on the anticoagulation treatment received. Variables of interest were survival at 1, 3 and 5 years, stroke, right heart failure (RHF), infection, laboratory data and VAD parameters before and after anticoagulation treatment, baseline characteristics and comorbidities. We used Chi-square test to analyze categorical data and the Wilcoxon signed rank test for continuous data in related samples to compare laboratory and VAD parameters pre and post anticoagulation in both groups. Kaplan Meier survival analysis was performed using the log rank statistics. Non-parametric results were reported as median and interquartile range (IQR). A 95% confidence interval (CI) was adopted. Results There were 193 VADs implanted in 170 patients. Of those, 30 patients had 47 episodes of PT, 34 treated with ARG and 13 with heparin. Of patients with PT, 73% had a HeartMate II and 27% had a HeartWare device, the median age at implantation was 48 years old (IQR 40.2, 60.2) and 90% were males; African Americans were 50%, followed by Hispanics (30%) and Caucasians (20%). The median follow-up was 2.5 years (IQR 1, 3.4). In the ARG group, there was a statistically significant reduction at the time of discharge in LDH (p&amp;lt;0.001), AST (p&amp;lt;0.001), total bilirubin (p=0.001), platelet count (p=0.046), VAD flow (p=0.011) and VAD power (p=0.004) compared with admission parameters, while no statistically significant change was present in the heparin group. ARG led to a numerically higher, but not statistically significant, survival when compared with heparin (53% vs 38%, p=0.237). One-year, 3-year and 5-year survival were not significantly different between anticoagulation strategies (p=0.23, p=0.9 and p=0.89, respectively). There was no difference in the number of VAD re-implants, RHF, stroke or infection between groups. Conclusions ARG therapy led to a statistically significant improvement in hemolysis parameters and pump function when compared to heparin therapy for PT in VAD recipients, but no survival benefit was demonstrated, which could be due to the small sample size. Other limitations were the retrospective and non-randomized data. ARG therapy must be tested in larger trials to confirm its benefits for PT. Funding Acknowledgement Type of funding source: None

Early and long-term outcomes of argatroban use in patients with acute noncardioembolic stroke

BackgroundArgatroban in acute noncardioembolic stroke ineligible for intravenous thrombolysis (IVT) or endovascular treatment (EVT) remains unclear. This study aimed to evaluate whether argatroban improved early and long-term outcomes compared with antiplatelet treatment. MethodsThis retrospective observational study, using the prospective stroke database from our hospital, included all consecutive patients who hospitalized from January 1, 2017 to December 31, 2019, with a diagnosis of acute non-cardioembolic stroke within 48 hours of stroke onset but not receiving IVT and EVT. Patients were divided into 2 groups: the argatroban group and the control group without argatroban. Outcome assessment with early neurological deterioration (END), National Institutes of Health Stroke Scale (NIHSS), the modified Rankin Scale (mRS), bleeding complications, and mortality were compared between the 2 groups in all cases and different stroke subtypes. An ordinal logistic regression analysis evaluated the association between argatroban use and mRS score at 90 days. ResultsOf 1325 patients were enrolled, 519 patients in the argatroban group and 806 in the control. Baseline characteristics, hospital bleeding complications, and 90-day mortality were similar for the 2 groups. The argatroban group showed lower END, larger improvement of 7-day NIHSS score and higher percentage of a 90-day mRS score of 02. Similar results were found in subgroup analysis with large-artery atherosclerosis, anterior circulation infarction, and moderate stroke. Also, argatroban use was significantly associated with an excellent long-term stroke outcome (mRS ≤ 2). ConclusionThe current study suggested that argatroban was safe and effective for improving short and long-term outcomes in noncardioembolic stroke patients.

Efficiency and safety evaluation of prophylaxes for venous thrombosis after gynecological surgery.

In this study, we investigate the incidence of venous thrombosis (VT), and evaluate the effectiveness and safety of 3 major thromboprophylaxes and the potential risk factors for VT in women undergoing surgery for a gynecological malignancy. We performed a randomized controlled trial of 307 patients undergoing laparoscopic surgery for gynecological malignancies at a single institution from January 2016 to October 2017. Patients were divided into 3 groups: one receiving a half dose of low-molecular-weight heparin sodium injection (FLUXUM, Alfa Wassermann, Italy) delivered by injection, one receiving a full dose of FLUXUM, and a third group receiving an Argatroban injection. None of the patients in our study developed a pulmonary embolism, bleeding, or infectious complications. There were no statistical differences in the rate of deep venous thrombosis (DVT) (0%, 0%, and 2.38%) and the superficial venous thromboembolism (SVT) (15.66%, 8.97%, and 18.6%) among the 3 groups. None of the patients developed symptomatic VT. The effect of treatment on alanine aminotransferase and aspartate aminotransferase differed between the groups, with a minimal effect in the Argatroban group, and all 3 methods resulted in minimal impairment of renal function. Decreased hemoglobin, elevated levels of D-dimer, and prothrombin time were closely related to thrombogenesis. In conclusion, the incidence of postoperative thrombosis in gynecological malignancy among these Chinese people is not as low as we had originally presumed. Argatroban is not more effective than Parnaparin as a direct thrombin inhibitor, but it has less influence on liver function, which is beneficial for patients undergoing chemotherapy. Hemoglobin, D-dimer, and prothrombin time may be used to predict or detect thrombogenesis.

A Prospective Pilot Trial to Assess the Efficacy of Argatroban (Argatra®) in Critically Ill Patients with Heparin Resistance.

The current study aims to evaluate whether prophylactic anticoagulation using argatroban or an increased dose of unfractionated heparin (UFH) is effective in achieving the targeted activated partial thromboplastin time (aPTT) of more than 45 s in critically ill heparin-resistant (HR) patients. Patients were randomized either to continue receiving an increased dose of UFH, or to be treated with argatroban. The endpoints were defined as achieving an aPTT target of more than 45 s at 7 h and 24 h. This clinical trial was registered on clinicaltrials.gov (NCT01734252) and on EudraCT (2012-000487-23). A total of 42 patients, 20 patients in the heparin and 22 in the argatroban group, were included. Of the patients with continued heparin treatment 55% achieved the target aPTT at 7 h, while only 40% of this group maintained the target aPTT after 24 h. Of the argatroban group 59% reached the target aPTT at 7 h, while at 24 h 86% of these patients maintained the targeted aPTT. Treatment success at 7 h did not differ between the groups (p = 0.1000), whereas at 24 h argatroban showed significantly greater efficacy (p = 0.0021) than did heparin. Argatroban also worked better in maintaining adequate anticoagulation in the further course of the study. There was no significant difference in the occurrence of bleeding or thromboembolic complications between the treatment groups. In the case of heparin-resistant critically ill patients, argatroban showed greater efficacy than did an increased dose of heparin in achieving adequate anticoagulation at 24 h and in maintaining the targeted aPTT goal throughout the treatment phase.

Role of argatroban in repair of spinal cord injury in rats

Objective To investigate the effect of argatroban in repair of spinal cord injury in rats. Methods A total of 54 female Wistar rats were selected and divided into three groups according to the random number table: sham group, injury group and Argatroban group, with 18 rats in each group. The sham group only took the T10lamina; the injury group used the spinal cord injury device to make the rat spinal cord injury model; the Argatroban group received Argatroban treatment after spinal cord injury. The recovery of hindlimb motor function was evaluated by BBB score and clined plate test before injury and 7, 14, 21, 28, 35 and 42 days after injury. The sensory evoked potentials (SEP) and motor evoked potentials (MEP) were detected 42 days after operation. HE staining was used to compare the size of the cavity in the local region 42 days after injury. Results At day 7 after injury, the BBB score was (3.7±0.5)points and the inclined plane test was (28.0±2.6)° in the Argatroban group, which were better than those in the injury group [(3.3±0.5)points, (24.3±1.9)°] (P<0.05). At day 42 after injury, the BBB score was (13.0±0.8)points and inclined plane test was (50.7±2.7)° in the Argatroban group, which were significantly better than those in the injury group [(9.7±1.3) points, (40.5±2.7)°] (P<0.05). But all the above values in the Argatroban group were significantly lower than those in the sham group [(21.0±0.0)points, (60.0±0.0)°](P<0.05). At day 42 after operation, the SEP latency [(25.0±0.9)ms] in the Argatroban group was significantly shorter than that in the injury group [(31.5±1.9) ms]; the amplitude [(2.1±0.1)μV] in the Argatroban group was lower than that in the injury group [(0.5±0.1)μV] (P<0.05). The MEP latency [(11.5±1.0)ms] in the Argatroban group was significantly shorter than that in the injury group [(17.5±1.1)ms], and the amplitude [(4.8±0.8)μV] in the Argatroban group was lower than that in the injury group [(2.8±0.7)μV] (P<0.05). And the SEP or MEP latency and amplitude in the Argatroban group showed significant differences compared to the sham group [(7.5±1.0)ms, (7.5±1.0)μV](P<0.05). HE staining showed that the central area of the lesion in the Argatroban group [(0.35±0.04)mm2] was significantly smaller than that in the injury group [(0.71±0.05)mm2]. Conclusion After spinal cord injury, argatroban can protect the spinal cord tissue effectively in the injured area and promote recovery of sensory and motor function in the hind limbs of rats. Key words: Spinal cord injuries; Argatroban; Inflammation; Thrombin

Safety and Feasibility of Using Argatroban Immediately After Mechanical Thrombectomy for Large Artery Occlusion

This study aims to evaluate the safety and effects of using argatroban, immediately after mechanical thrombectomy (MT) with large artery occlusion. A total of 302 patients were divided into 2 groups: the MT with post argatroban (MT+ARG) group and the MT without post argatroban (MT-ARG) group. Baseline characteristics, time interval categories, and results of MT were reviewed. Outcome assessment with the National Institutes of Health Stroke Scale, modified Rankin Scale, TICI, reocclusion, and various complications were evaluated and compared between the 2 groups. Subgroup analysis was also performed for patients using tissue plasminogen activator or tirofiban. Baseline characteristics and time intervals were similar for the 2 groups. The MT+ARG group showed significantly less occurrence of reocclusion at 24 hours and 7 days compared with the MT-ARG group (2.5% vs. 6.0%, P= 0.018; 4.2% vs. 8.2%, P= 0.020). However, there were no significant differences in incidence of complications such as brain hemorrhage between the 2 groups. In subgroup analysis with tissue plasminogen activator, the MT+ARG group showed less occurrence of reocclusion at 24 hours and 7 days compared with the MT-ARG group (P= 0.008 and P= 0.018, respectively). In subgroup analysis with tirofiban, reocclusion at 7 days occurred less in the MT+ARG group (P= 0.040). This study showed the safety and usefulness of argatroban immediately after MT, indicating that using argatroban after MT could prevent reocclusion of target artery without increasing bleeding complications.

Argatroban Increased the Basal Vein Drainage and Improved Outcomes in Acute Ischemic Stroke Patients

Background: Since venous drainage in acute arterial ischemic stroke has not been thoroughly researched, we evaluate the effect of argatroban, the selective direct thrombin inhibitor, as the therapy to increase the rate of basal vein Rosenthal (BVR) drainage and improve patients' post-stroke outcomes. Methods: In this multicenter clinical trial, 60 eligible patients at 4.5-48 hours after the stroke onset were recruited. After being randomly allocated to two groups, they were treated with standard therapy either alone or with argatroban. Results: Compared to the contralateral brain hemisphere, the mean flow velocity (MFV) in BVR drainage was significantly reduced in the stroke-afflicted ipsilateral hemisphere. After treatment with argatroban for 7 days, the MFV from BVR of the ipsilateral hemisphere was significantly increased when compared to control. At 90 days after the onset of stroke, the MFV of BVR in the ipsilateral hemisphere was similar in both groups. Compared with controls, argatroban-treated patients had smaller lesions from baseline to 7 days. Argatroban also improved NIHSS scores on day 7 after the onset of stroke. Furthermore, the argatroban group's neurological functions were superior to those of their untreated counterparts after 90 days. No difference was found in the incidence of adverse reactions between the two groups. Conclusions: These observations indicate that argatroban may improve patients' venous drainage, as well as the outcomes of acute paraventricular ischemic stroke. Trial Registration: ChiCTR-IPR-16008663. Funding Statement: This work was supported by the National Natural Science Foundation of China (Grant Nos: 81571600 and 81322018). Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: The approval of trial protocol and supportive documents was obtained from the institutional review boards of all the participating units.

Argatroban Bridging in the Immediate Post-Operative Period in Recipients of Durable Left Ventricular Assist Devices

Purpose In recipients of durable LVADs, the development of heparin induced thrombocytopenia threatens the integrity of the pump circuit and thus the life of the patient. In hospitalized HF patients, the exposure to heparin is frequent and often prolonged. We set out to change our immediate bridging protocol post-LVAD to decrease heparin exposure and evaluate the bleeding and thromboembolic consequences of these 2 different bridging strategies. Methods This is a single center retrospective study of consecutive patients implanted with a durable LVAD. Heparin (HEP) bridging was utilized in patients from Jan 2016 to June 2017 (n=30) and argatroban (ARG) bridging was utilized in patients from July 2017 through June 2018. Patients that received an RVAD at time of LVAD implantation were excluded from the analysis. Patients were started on intravenous anticoagulation the morning of POD#1 and were titrated to goal (heparin anti-factor Xa levels 0.3 to 0.5; argatroban PTT 50-70 s.) Aspirin and warfarin were also initiated on POD#1. Events were tracked 6 months post-implant. Results Device selection between the two groups was different with the following breakdown; HEP group with 27 HM2 and 3 HVADs compared to the ARG group with 11 HM2, 15 HVADs and 3 HM3. The need to return to the OR from bleeding was lower in the ARG group (6.4% vs 23.3%, p=0.27). The mean number of red blood cell transfusions was statistically lower in the ARG group (1.5 vs 2.7 units, p=0.02). There was no difference observed between the platelet counts on POD#3 or POD#7. A nonsignificant reduction in major hemolysis between the two groups was noted (HEP 20.0% vs ARG 3.2%, p=0.10). There was 1 patient with pump thrombosis in the ARG group compared to 2 patients in the HEP group. A nonsignificant increase in strokes was observed in the ARG group (overall 25.8% - 19.3% ischemic stroke; 6.5% hemorrhagic stroke) compared to the HEP group (overall 16.6% - 13.3% ischemic; 3.3 hemorrhagic stroke; p=0.58) Conclusion Argatroban bridging in the immediate post-operative period is safe in recipients of durable LVADs. There were fewer bleeding events in the ARG bridged group. Though not meeting statistical significance, there were numerically more episodes of major hemolysis and pump thrombosis in the HEP group which contrasted with more stroke events in the ARG group.