Intravenous Argatroban Research Articles

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.

Effect of Argatroban Plus Intravenous Alteplase vs Intravenous Alteplase Alone on Neurologic Function in Patients With Acute Ischemic Stroke

Previous studies suggested a benefit of argatroban plus alteplase (recombinant tissue-type plasminogen activator) in patients with acute ischemic stroke (AIS). However, robust evidence in trials with large sample sizes is lacking. To assess the efficacy of argatroban plus alteplase for AIS. This multicenter, open-label, blinded end point randomized clinical trial including 808 patients with AIS was conducted at 50 hospitals in China with enrollment from January 18, 2019, through October 30, 2021, and final follow-up on January 24, 2022. Eligible patients were randomly assigned within 4.5 hours of symptom onset to the argatroban plus alteplase group (n = 402), which received intravenous argatroban (100 μg/kg bolus over 3-5 minutes followed by an infusion of 1.0 μg/kg per minute for 48 hours) within 1 hour after alteplase (0.9 mg/kg; maximum dose, 90 mg; 10% administered as 1-minute bolus, remaining infused over 1 hour), or alteplase alone group (n = 415), which received intravenous alteplase alone. Both groups received guideline-based treatments. The primary end point was excellent functional outcome, defined as a modified Rankin Scale score (range, 0 [no symptoms] to 6 [death]) of 0 to 1 at 90 days. All end points had blinded assessment and were analyzed on a full analysis set. Among 817 eligible patients with AIS who were randomized (median [IQR] age, 65 [57-71] years; 238 [29.1%] women; median [IQR] National Institutes of Health Stroke Scale score, 9 [7-12]), 760 (93.0%) completed the trial. At 90 days, 210 of 329 participants (63.8%) in the argatroban plus alteplase group vs 238 of 367 (64.9%) in the alteplase alone group had an excellent functional outcome (risk difference, -1.0% [95% CI, -8.1% to 6.1%]; risk ratio, 0.98 [95% CI, 0.88-1.10]; P = .78). The percentages of participants with symptomatic intracranial hemorrhage, parenchymal hematoma type 2, and major systemic bleeding were 2.1% (8/383), 2.3% (9/383), and 0.3% (1/383), respectively, in the argatroban plus alteplase group and 1.8% (7/397), 2.5% (10/397), and 0.5% (2/397), respectively, in the alteplase alone group. Among patients with acute ischemic stroke, treatment with argatroban plus intravenous alteplase compared with alteplase alone did not result in a significantly greater likelihood of excellent functional outcome at 90 days. ClinicalTrials.gov Identifier: NCT03740958.

Using Thrombin Time to Evaluate the Efficacy of Anticoagulant Therapy for Acute Cerebral Infarction

Background: Although intravenous thrombolysis therapy considered as a significant progress in the treatment of acute ischemic stroke, there are limited effective treatments for patients with onset ischemic symptom that beyond six hours during acute ischemic stroke. In this study, we investigated the effectiveness of the intravenous argatroban therapy in acute ischemic stroke patients who cannot be treat with intravenous thrombolysis due to the limited time window. Methods: One hundred and eighty patients with acute ischemic stroke that had beyond six hours ischemic symptom were admit to our hospital and analyzed retrospectively. ELISA measured levels of activated partial thromboplastin time (aPTT), prothrombin time (PT) and thrombin time (TT) in peripheral blood of these patients at 24 hours post initial therapy. Results: We found that plasma TT prolonged after 24 hours of argatroban treatment. Activated partial thromboplastin time (aPTT) showed slightly increased prolongation after 24 hours of argatroban treatment. PT also showed slightly prolonged after treatment; however, there was no difference from the basal line. We further investigated the relationship between the level of TT and the clinical effectiveness and safety of intravenous argatroban therapy. We found that when TT was between 40 and 80 seconds, intravenous argatroban effectively promoted the complete recovery rates without increasing the risk of hemorrhage. Conclusion: Our study implies that TT assay might be useful for guiding regular dose of agratroban for therapy.

SARS-CoV-2 Vaccine-Induced Immune Thrombotic Thrombocytopenia with Venous Thrombosis, Pulmonary Embolism, and Adrenal Haemorrhage: A Case Report with Literature Review

Vaccine-induced immune thrombotic thrombocytopenia (VITT) with venous thrombosis is a rare complication of SARS-CoV-2 vaccination with ChAdOx1 (AstraZeneca) and AD26.COV2.S (Johnson & Johnson, New Brunswick, NJ, USA) associated with high mortality. At present, there are no known differences in the pathophysiology or risk factors of VITT with the AstraZeneca vaccine (ChAdOx1) compared with the Johnson & Johnson vaccine (AD26.COV2.S). Herein, we present the case of a healthy 39-year-old patient with VITT after having received the vaccine Ad26.COV2.S. Ten days after vaccination, the patient developed a deep vein thrombosis and subsequent pulmonary embolism. A computed tomography scan of the abdomen showed adrenal gland bleeding and an adrenocorticotrophic hormone stimulation test diagnosed adrenal insufficiency. Therapy with intravenous immunoglobulin, argatroban and hydrocortisone was initiated immediately after diagnosis. The patient left the hospital 22 days after admission with the diagnosis of adrenal insufficiency but otherwise in good health. To the best of our knowledge, five cases of VITT and adrenal bleeding have been described to date in the literature but the presented case was the first to occur after immunisation with the vaccine of Johnson & Johnson. In summary, VITT-associated adrenal dysfunction is a very rare complication of vaccination with an adenoviral vector-based COVID-19 vaccine.

Papilledema due to Vaccine-Induced Thrombocytopenia

A 45-year-old woman received the AstraZeneca vaccine for novel SARS-CoV-2 (COVID-19). Eight days later, she noticed flank pain, blurry vision, severe headaches, and generalized weakness. Computed tomography body scans demonstrated pulmonary embolism and bilateral adrenal hemorrhages. Magnetic resonance imaging/Venography scans of her brain revealed thrombosis of multiple cerebral dural sinuses (Fig A-B, arrows). She was thrombocytopenic and had positive heparin-induced thrombocytopenia assay. Diagnosis of vaccine-induced thrombotic thrombocytopenia (VITT) was made and treatment with intravenous argatroban, immunoglobulins, and hydrocortisone commenced.

Branch atheromatous disease and treatment.

Branch atheromatous disease (BAD) is a subtype of ischemic stroke caused by perforating arteries occlusion due to proximal atherosclerosis of the arteries. Early neurological deterioration and recurrent stereotyped transient ischemic attacks are typical clinical manifestations of BAD. The optimal treatment for BAD has not been determined. This article explores a possible mechanism of BAD and effective treatment measures to prevent early progression and attack of transient ischemic events. This article explains the current status of intravenous thrombolysis, tirofiban, and argatroban for BAD and subsequent prognosis.

Thrombotic thrombocytopenia following ChAdOx1 nCov-19 vaccination

Serious thromboembolic events with concurrent thrombocytopenia, sometimes accompanied by bleeding, have occurred very rarely following administration of the ChAdOx1 nCoV-19 vaccine. We report the case of a 59-year-old male with an unremarkable medical history who presented to the emergency department with increasing breathlessness five days after receiving the first dose of ChAdOx1 nCov-19. The patient’s blood results showed mild thrombocytopenia and a very high D-dimer, and a pulmonary embolism was confirmed through a CT pulmonary angiogram, which led to a provisional diagnosis of vaccine-induced immune thrombotic thrombocytopenia. The condition was then treated with immunoglobulin and intravenous argatroban in line with the guidance from the Expert Haematology Panel focussed on Vaccine-induced Thrombosis and Thrombocytopenia before conversion to apixaban.

Argatroban as an Alternative Anticoagulant in Impella Supported Patients

<h3>Purpose</h3> To investigate the safety and efficacy of argatroban in preventing thrombotic complications in patients with suspected heparin-induced thrombocytopenia (HIT) treated with axillary flow left ventricular assist device (Impella). <h3>Methods</h3> We performed a retrospective observational case-series of patients who were supported on Impella and anticoagulated with argatroban due to suspected HIT. The electronic medical record was reviewed for safety events including hemorrhagic or embolic stroke, bleeding and Impella motor thrombosis. <h3>Results</h3> We identified six patients who met inclusion criteria. Three patients were definitively diagnosed with HIT. In each case argatroban was used as the Impella purge solution and intravenous argatroban was administered as needed to maintain a PTT target of 50-80 seconds. The purge solution was formulated as argatroban 25mg in 500mL of dextrose 5% water. The Impella controller was programmed to a heparin purge fluid concentration of "0 IU/ml". Only one patient had a bleeding event; this involved minor bleeding from the endotracheal tube. Prior to initiation of argatroban; the PTT in this patient was elevated secondary to hepatic dysfunction which likely predisposed to bleeding. No patient developed a hemorrhagic or embolic stroke, or Impella motor thrombosis. <h3>Conclusion</h3> In this case series, the use of argatroban was a safe and effective alternative to heparin in patients with suspected HIT supported with Impella. Only one patient had a bleeding event that was attributed to underlying coagulopathy secondary to hepatic dysfunction and not from argatroban. In all patients argatroban was effective in preventing Impella motor thrombosis. Currently, the Impella console can only be programmed to administer heparinized purge solution which is a barrier to the use of alternative anticoagulants. Further investigation is needed to support the use of alternative anticoagulants in patients treated with Impella.

Coagulation management in patient with heparin induced thrombocytopenia undergoing heart transplantation: is ROTEM helpful?

Introduction Heparin induced thrombocytopenia (HIT) is frequent in patients under extracorporeal membrane oxygenation (ECMO) or ventricular assist device support (VAD). Therapeutic plasma exchange (TPE) and use of direct thrombin inhibitors (DTI) as argatroban have proven to be useful. However, monitoring its effect can be difficult as activated clotting time (ACT) or standard coagulation tests (prothrombin time (PT) and activated partial thromboplastin time (aPTT)) lack enough reliability. Coagulation assessment during surgery may be challenging, especially during heart transplantation (HT) where there is narrow margin to metabolize DTI. Methods A 51-year-old male presented a myocardial infarction with cardiac arrest and arrhythmic storm requiring support with ECMO and VAD. The patient needed HT and was anticoagulated with intravenous argatroban for 3 weeks before surgery because of HIT (31000 thrombocytes/μL). Four TPE were performed and four intravenous doses of specific gammaglobulin (1g/kg) were given achieving negative values of anti-PF-4 antibodies. Argatroban infusion was stopped 6 hours before surgery. Results The coagulation test pre-surgery showed 98000 thrombocytes/μL, PT 39%, aPTT 55,1s fibrinogen 3,5g/L, haemoglobin 93g/L. Intraoperative anticoagulation was established with full dose unfractionated heparin and tranexamic acid was given (20mg/kg bolus+6mg/kg/h infusion). After coming off by-pass, anticoagulation was reverted with protamine and 2 units of PRBC, 1000mL fresh frozen plasma (FFP), two platelet pools and 1200IU 4-factor-prothrombin-complex-concentrate (PCC; Prothromplex®: 1200IU factor II, 1000IU factor VII, 1200IU factor IX and 1200IU factor X) were administered empirically. Despite being ACT back to baseline, significant diffuse bleeding was clinically noticed. ROTEM was performed showing prolonged EXTEM, INTEM and HEPTEM clotting time (CT). A second dose of PCC was administered and one unit of PRBC was transfused. Because no improvement was noticed, a second ROTEM was performed showing increased CT in all tests, with no heparin contribution (table 1). A litre of FFP was then administered with significant reduction of bleeding, allowing for chest closure. No further significant blood loss was observed in intensive care. The patient was weaned from mechanical ventilation on day 4 and discharged from the ward after 21 days. No thrombotic/bleeding events were noticed during the hospital stay. Discussion ROTEM was useful detecting coagulation factors deficiency in an appropriate time. Unexpected prolongation of CT after PCC administration may suggest residual thrombin inhibition by argatroban, that was neutralized with FFP administration.

Sudden onset of sleep caused by hypothalamic infarction: a case report

BackgroundHypothalamic lesions, such as tumors and demyelinating diseases, reportedly cause abnormal sleepiness. However, stroke involving the hypothalamus has rarely been described. Here, we report a patient with infarction restricted to the hypothalamus who presented with sudden onset of sleep.Case presentationA 42-year-old woman with a history of migraine without aura presented with irresistible sleepiness and developed several episodes of sudden onset of sleep. Neurological examinations were unremarkable except for partial left Horner syndrome. Brain magnetic resonance imaging (MRI) revealed a high-intensity lesion restricted to the left hypothalamus on diffusion-weighted and fluid-attenuated inversion recovery MRI images. Cerebrospinal fluid (CSF) orexin-A levels obtained on hospital day 3 after her sleepiness had resolved were normal (337 pg/mL; normal > 200 pg/mL). Serum anti-nuclear and anti-aquaporin 4 (AQP4) antibodies and CSF myelin basic protein and oligoclonal band were negative. A small hypothalamic infarction was suspected, and the patient was treated with intravenous edaravone and argatroban, as well as oral clopidogrel. Three months later, there had been no clinical relapse, and the hypothalamic lesion had almost disappeared on follow-up MRI. No new lesion suggestive of demyelinating disease or tumor was observed.ConclusionHypothalamic stroke should be considered a cause of sudden onset of sleep.

Effect of an activated charcoal product (DOAC Stop™) intended for extracting DOACs on various other APTT-prolonging anticoagulants.

Background The aim of the study was to investigate the specificity of an activated charcoal-based product (DOAC Stop™) initially intended for the specific extraction of direct oral anticoagulants (DOACs) from test plasmas on a range of other anticoagulants. Methods Test plasmas were prepared by adding various anticoagulants to pooled normal plasma at concentrations prolonging an activated partial thromboplastin time (APTT) test by a factor of 1.5-3. These plasmas were treated with DOAC Stop™ for 5 and 20 min. Then APTTs were repeated and residual anticoagulant concentrations estimated from dose-response curves. Results The activated charcoal (AC)-based product was found to extract DOACs efficiently. It also bound the intravenous anticoagulants argatroban and lepirudin, but it had no effect on heparin, enoxaparin or danaparoid in plasma. Among other APTT-inhibiting agents that might be present in test plasmas from patients, it extracted protamine, aprotinin and polymyxin. It had no effect on annexin V, thrombomodulin, a typical lupus anticoagulant, a factor VIII antibody, activated protein C or its activator, but it did bind some cationic inhibitors of the APTT with molecular weight below approximately 30 kDa. Conclusions The AC-based product extracted DOACs efficiently with no effect on heparin-type anticoagulants. It did bind argatroban and hirudin-type anticoagulants, which might occur in plasmas from some inpatients, and APTT results obtained after its use should be interpreted after due consideration of patient medications.

Targeting Coagulase Activity in Staphylococcus aureus Bacteraemia: A Randomized Controlled Single-Centre Trial of Staphylothrombin Inhibition.

Staphylococcus aureus (S. aureus) bacteraemia is frequent and carries a high morbidity and mortality. Coagulases secreted by S. aureus initiate blood coagulation by directly activating prothrombin. This pathogen-activated coagulation is insensitive to most antithrombotic drugs, with the exception of small molecule direct thrombin inhibitors (DTIs). DTIs inhibit the coagulase-prothrombin complex, or staphylothrombin, and improve outcome in preclinical models of S. aureus infection. A single-centre, randomized, controlled feasibility and safety trial of staphylothrombin inhibition with DTIs in patients with S. aureus bacteraemia. Consecutive eligible adult patients with S. aureus positive blood cultures in the University Hospitals Leuven (Belgium) were randomized 1:1 to DTI (oral dabigatran 110 mg twice daily or intravenous argatroban according to activated partial thromboplastin time [aPTT]) for 7 to 10 days, or subcutaneous enoxaparin 40 mg once daily. Primary outcomes were feasibility and safety of DTI in patients with S. aureus bacteraemia. Secondary outcomes include D-dimer evolution (day 0-4) as marker of coagulation activation; inflammatory and microbiological parameters; and clinical outcomes including metastatic infections. Thirty-one percent (94/303) of screened patients were enrolled. Dabigatran plasma levels inhibited staphylothrombin. Clinically relevant bleeding (5/47 vs. 5/47) and thrombotic (7/47 vs. 7/47) complications were similar in both groups. Coagulase inhibition with DTIs was associated with a trend towards faster D-dimer decrease at day 4 (-662 ± 249 ng/mL vs. -40 ± 213 ng/mL for DTI-treated patients vs. control; p = 0.06) and a numerically lower number of persistently positive blood cultures. No differences in inflammatory parameters or other clinical outcomes were observed. Targeting staphylothrombin with DTIs is feasible in a subset of S. aureus bacteraemic patients, with comparable safety to standard thromboprophylaxis. In future studies of staphylothrombin inhibition, feasibility can be further improved by rapid diagnostics and by strategies without concomitant anticoagulant effect.

Non-Warfarin Oral Anticoagulants in Heparin-Induced Thrombocytopenia

Introduction: Heparin-Induced Thrombocytopenia (HIT) is an antibody-mediated reaction where exposure to heparin products (unfractionated and, less commonly, low molecular weight heparins) leads to a paradoxical prothrombotic state. Current treatment guidelines recommend immediate cessation of all heparin products and initiation of a non-heparin anticoagulant. This is typically accomplished with argatroban and then transitioning to a vitamin K antagonist once platelets have recovered. An attractive alternative is the use of the non-warfarin oral anticoagulants (NOACs) in the treatment of HIT, namely the direct Xa inhibitors apixaban and rivaroxaban which have already proven safe and effective for the treatment of venous thromboembolism.Methods: We designed a retrospective analysis of all patients at the University of Virginia with a positive serotonin release assay (for a definitive diagnosis of HIT) that were treated with either apixaban or rivaroxaban since September 2011. Results from heparin induced platelet antibody testing were also recorded. Patients were reviewed for recurrent thrombi, severe bleeding or other complications that led to changes in their management.Results: Eleven patients were identified based on the inclusion criteria. All patients had a positive serotonin release assay despite 4/11 (36%) testing negative for heparin induced platelet antibody. All patients received intravenous argatroban or bivalirudin at the time of diagnosis and were transitioned to an oral anticoagulant at time of hospital discharge. 9/11 (81%) were treated with apixaban and 2/11 (19%) were treated with rivaroxaban. Zero patients developed recurrent thrombi (summarized in Table 1). One patient in each group developed major bleeding leading to discontinuation of anticoagulation. Of these, both had additional risk factors for bleeding prior to initiation of anticoagulation (one with concurrent clopidogrel use after coronary artery bypass grafting and prior bleeding from gastric varices; the other with previously diagnosed metastatic squamous cell lung cancer). Of the remaining 9 patients, safe and effective anticoagulation with a NOAC was noted for up to18 months without adverse effects.Conclusion: Apixaban and rivaroxaban, along with all forms of anticoagulation, should be used with caution in patients with risk factors for severe bleeding. These medications, however, showed to be a safe and effective first line outpatient regimen for patients with HIT. Further prospective studies are needed before their use should be accepted as standard of care.Table 1Patients with Heparin-Induced Thrombocytopenia Treated with Non-Warfarin Oral AnticoagulantPatientHeparin Induced Platelet Antibody (%)Serotonin Release Assay (%)AnticoagulantLength of Therapy (in months)Bleeding ComplicationsThrombotic ComplicationsCurrent Plan1-+ (93)Apixaban8NoNoContinue2+ (110)+ (100)Apixaban2*NoNoContinue3+ (81)+ (53)Apixaban13NoNoContinue4-+ (91)Apixaban9NoNoContinue5+ (108)+ (100)Apixaban16NoNoContinue6-+ (92)Apixaban6NoNoContinue7+ (126)+ (100)Apixaban2†GastrointestinalNoOff since bleed8-+ (30)Rivaroxaban1‡HemoptysisNoOff since bleed9+ (107)+ ( 77)Apixaban10NoNoContinue10+ (89)+ (44)Apixaban6NoNoContinue11+ (106)+ (67)Rivaroxaban18NoNoContinue*No evidence of thrombosis at diagnosis, only thrombocytopenia†severe bleeding from known gastric varices; also on clopidogrel for CAD‡moderate hemoptysis secondary to known squamous cell lung cancer DisclosuresOff Label Use: Apixaban and rivaroxaban use in patients with heparin-induced thrombocytopenia.

Argatroban for Preventing Occlusion and Restenosis after Extracranial Artery Stenting

Background/Aims: Restenosis following extracranial artery stenting is a limitation that affects long-term outcomes. Effective and satisfying pharmacological strategies in preventing restenosis have not been established. This study aimed to evaluate whether argatroban, a direct thrombin inhibitor, could reduce the risk of in-stent restenosis after extracranial artery stenting. Methods: One hundred and fourteen patients hospitalized between August 2010 and August 2011 were enrolled. Patients were randomly assigned to argatroban (n = 58) and blank control groups (n = 56). The patients in the argatroban arm were treated with 10 mg of intravenous argatroban twice daily 2 days before and 3 days after the stenting procedures. Patients were followed for 12 months after the procedure. During follow-up, restenosis and target revascularization were analyzed. Recurrent cerebrovascular and cardiovascular events and deaths were also compared between the groups. Results: One patient in the stenting group withdrew immediately after the procedure due to unsuccessful stenting. Restenosis occurred in 4 patients (7.4%) in the argatroban group and in 11 patients (21.6%) in the control group during the 6- to 9-month angiographic follow-up period (p = 0.032). Nine months after the procedures, argatroban-treated patients had a trend towards a lower incidence of target revascularization compared with the controls (5.4 vs. 13.7%, p = 0.188). No major bleeding events or other adverse events occurred in the argatroban group. Conclusion: This pilot clinical trial is the first that uses argatroban to prevent restenosis in ischemic cerebrovascular disease, and suggests that intravenous administration of argatroban is effective and safe in preventing restenosis after extracranial artery stenting. Larger randomized controlled clinical trials are warranted.

Monitoring the Direct Thrombin Inhibitors

1. George A. Fritsma, MS MT (ASCP)[⇑][1] 1. The Fritsma Factor, Your Interactive Hemostasis ResourceSM, Fritsma & Fritsma LLC, Birmingham, AL 1. Address for Correspondence: George A. Fritsma MS MT (ASCP), The Fritsma Factor, Your Interactive Hemostasis ResourceSM, Fritsma & Fritsma LLC, 153 Redwood Drive, Birmingham, AL 357173, 205-655-0687, George{at}fritsmafactor.com. 1. Diagram the physiology of the direct thrombin inhibitors 2. Distinguishe between argatroban and bivalirudin. 3. Provide the means for monitoring direct thrombin inhibitors. The direct thrombin inhibitors (DTIs), intravenous argatroban and bivalirudin and oral dabigatran, reversibly bind and inactivate free and clot-bound thrombin without activating antithrombin (AT, antithrombin III, ATIII), thereby suppressing coagulation at the final stage of the cascade.1 Argatroban or bivalirudin are substituted for unfractionated heparin (UFH) or low molecular weight heparin (LMWH) when heparin-induced thrombocytopenia with thrombosis (HIT) is suspected or confirmed, as they do not interact with the HIT antibody.2 When HIT is suspected, the risk of either venous or arterial thrombosis is 50% for 30 days after heparin withdrawal unless argatroban or bivalirudin is employed. Coumadin is contraindicated in HIT as it is prothrombotic for the first 5 days of administration. Dabigatran has been cleared for prevention of venous thromboembolic (VTE) disease in Europe and Canada and for prevention of stroke in atrial fibrillation in the US. As the first new oral anticoagulant cleared by the FDA since 1954, dabigatran is beginning to take its place in the formulary. Laboratory scientists are challenged to find clinically effective means to monitor its plasma concentration. Argatroban Argatroban (Novostan®; GlaxoSmithKline, Research Triangle Park, NC) is a non-protein l-arginine derivative with a molecular weight of 527 Daltons.3 Argatroban was FDA-cleared in 1997 for anticoagulation in HIT.4 Argatroban may be used for prophylaxis, treatment, and also for anticoagulation during percutaneous cardiac intervention (PCI, cardiac catheterization) for patients with HIT.5 The physician initiates the argatroban intravenous infusion at 2 μg/kg/min or in patients with liver disease at 0.5 μg/kg/min. During PCI, a bolus of… ABBREVIATIONS: APTT or PTT - activated partial thromboplastin time; AT - antithrombin; CAD – coronary artery disease; DTI - direct thrombin inhibitor; DVT - deep venous thrombosis; ECT-ecarin clotting time; FDA - US Food and Drug Administration; HIT - heparin-induced thrombocytopenia with thrombosis; INR - international normalized ratio; LMWH - low molecular weight heparin; PE - pulmonary embolism; PCI - percutaneous intervention (cardiac catheterization); PiCT - prothrombinase-induced clotting time; PT - prothrombin time; RI - reference interval; RUO - research use only; TCT - thrombin clotting time; TPA - tissue plasminogen activator; UFH - unfractionated heparin; VTE - venous thromboembolism. 1. Diagram the physiology of the direct thrombin inhibitors 2. Distinguishe between argatroban and bivalirudin. 3. Provide the means for monitoring direct thrombin inhibitors. [1]: #corresp-1

E-008 Intra-arterial treatment of cerebral vasospasm

IntroductionAneurysmal subarachnoid hemorrhage (SAH) is associated with high morbidity and mortality primarily attributed to the delayed onset of cerebral vasospasm. Patient outcomes after aneurysmal SAH have considerably improved largely due...

Rationale and design of the PREVENT-HIT study: A randomized, open-label pilot study to compare desirudin and argatroban in patients with suspected heparin-induced thrombocytopenia with or without thrombosis

Background: Desirudin, a bivalent direct thrombin inhibitor (DTI), is approved by the US Food and Drug Administration for the prevention of deep vein thrombosis, which may lead to pulmonary embolism, in patients undergoing elective hip replacement surgery. It became available in the United States in March 2010. Objective: The goal of the present article was to provide an overview of the rationale and design of the PREVENT-HIT study, a randomized, prospective, openlabel, active drug-controlled, exploratory trial comparing the clinical and economic utility of desirudin versus argatroban in patients with suspected heparin-induced thrombocytopenia (HIT), with or without thrombosis. Summary: The PREVENT-HIT study was designed to enroll ∼120 patients from 20 to 25 US centers. All eligible patients were required to be aged ≥18 years. Patients with suspected HIT with or without thrombosis were divided into 2 treatment arms and randomized to receive treatment with desirudin or argatroban in a 1:1 ratio using a block randomization method. Arm A comprised patients who were naive to DTI therapy; arm B included patients whose condition was previously stabilized with intravenous argatroban. Desirudin was administered as a fixed-dose injection (15 or 30 mg SC q12h in patients without or with thrombosis, respectively). Argatroban was administered by continuous intravenous infusion in accordance with approved prescribing information or institutional prescribing guidelines at each study site. The primary efficacy outcome measure included the occurrence of any of the following up to 30 days after study drug discontinuation: new-onset or worsening thrombosis requiring discontinuation of study drug; amputation; or all-cause mortality. Other outcomes that were assessed included platelet recovery, bleeding, and pharmacoeconomic parameters. In addition, adverse events and other safety parameters were evaluated. Study enrollment began in November 2008 and ended in December 2009 due to slow enrollment (N = 16). The study results will be published separately. Conclusion: The results from the PREVENT-HIT study should enhance understanding of the comparative clinical and economic utility of desirudin and argatroban in patients with HIT with or without thrombosis.

Treatment for Patients with Acute Ischemic Stroke Presenting beyond Six Hours of Ischemic Symptom Onset : Effectiveness of Intravenous Direct Thrombin Inhibitor, Argatroban

The objectives of this study were to analyze the outcome and hemorrhagic risk of intravenous (IV) argatroban in patients with acute ischemic stroke presenting beyond six hours of ischemic symptom onset. Eighty patients with acute ischemic stroke who were admitted to the hospital beyond six hours from ischemic symptom onset were retrospectively analyzed. We could not perform IV thrombolysis or intra-arterial thrombolysis because of limited time window. So, IV argatroban was performed to prevent recurrent thrombosis and progression of infarcted area. The outcome was assessed by the National Institute of Health Stroke Scale (NIHSS) score and related hemorrhagic risk was analyzed. Also, each outcome was analyzed according to the initial stroke severity, subtype, and location. The median NIHSS was 8.0 at admission, 4.1 upon discharge, and 3.3 after three months. A good outcome was achieved in 81% of patients upon discharge and 88% after three months. Symptomatic hemorrhage occurred in only two patients (3%). IV argatroban was effective regardless of initial stroke severity, subtype, and location. IV argatroban may be an effective and safe treatment modality for acute ischemic stroke presenting beyond six hours of ischemic symptom onset.

Argatroban

Argatroban, a highly selective direct thrombin inhibitor, is indicated for use as an anticoagulant for the treatment and prophylaxis of thrombosis in patients with heparin-induced thrombocytopenia (HIT), and in patients undergoing percutaneous coronary intervention (PCI) who have, or are at risk for, HIT. Intravenous argatroban improved clinical outcomes and was generally well tolerated in adults with HIT or HIT with thrombosis syndrome (HITTS). In two pivotal, open-label, historically controlled studies in adults with HIT, the incidence of the primary composite endpoint (all-cause death, all-cause amputation, or new thrombosis) was significantly lower in argatroban recipients than in historical controls, and more argatroban recipients than historical controls stayed event-free during the study according to a Kaplan-Meier analysis. In adults with HITTS in these trials, although the incidence of the primary composite endpoint did not differ significantly between argatroban recipients and historical controls, a Kaplan-Meier analysis showed that more patients receiving argatroban than historical controls remained event-free during the study. Major and minor bleeding rates in argatroban recipients were generally similar to those in historical controls in these studies. Argatroban was also an effective anticoagulant in patients with HIT undergoing PCI in three small, uncontrolled trials, pooled data from which showed that most (>or=95%) patients achieved a satisfactory outcome of the PCI procedure and adequate anticoagulation (coprimary endpoints). It was generally well tolerated in these patients, with the incidence of major bleeding being <or=1.1%. The efficacy and safety of argatroban in pediatric patients has not been established. However, a small uncontrolled, preliminary study suggests that it may be useful in seriously ill pediatric patients requiring nonheparin anticoagulation.

Anticoagulation with argatroban in a parturient with heparin-induced thrombocytopenia

Unfractionated heparin and low-molecular-weight heparin are currently the anticoagulants of choice for the prevention of recurrent thromboembolic disease during pregnancy. However, heparin-induced thrombocytopenia contraindicates the use of unfractionated heparin and low-molecular-weight heparin. We describe a patient who was admitted to our hospital with deep vein thrombosis at 18 weeks of gestation and who developed heparin-induced thrombocytopenia during her antenatal care. Therapeutic anticoagulation was initially achieved with argatroban, then changed to fondaparinux. During early labor, fondaparinux was discontinued and intravenous argatroban was substituted. Argatroban was discontinued during transition to active labor. After return of a normal partial thromboplastin time, combined spinal-epidural analgesia was induced for routine completion of labor and vaginal delivery. We discuss the decisions made in the maintenance of this patient’s anticoagulation during the peripartum period as well as timing of her neuraxial labor analgesia.