Argatroban Dose Research Articles

Argatroban for anticoagulation in continuous renal replacement therapy*

Argatroban, a direct thrombin inhibitor, was evaluated for anticoagulation in continuous renal replacement therapy (CRRT) in critically ill patients with heparin-induced thrombocytopenia type II and acute renal failure. The investigation focused on predictors for the maintenance doses of argatroban with efficacy and safety of argatroban being secondary outcomes. Prospective, dose finding study. Two intensive care units (medical and surgical) of a university hospital. Medical and surgical patients (n = 30) with acute or histories of heparin-induced thrombocytopenia type II and acute renal failure with necessity for CRRT. CRRT with argatroban for anticoagulation. Critical illness severity scores Acute Physiology and Chronic Health Evaluation (APACHE)-II, Simplified Acute Physiology Score (SAPS) II, and the indocyanine green plasma disappearance rate (ICG-PDR) were correlated to the argatroban maintenance doses. These diagnostic tools can help to identify patients with the necessity for decreased argatroban doses. The following recommendations for argatroban dosing during CRRT could be determined: a loading dose of 100 microg/kg followed by a maintenance infusion rate (microg/kg/min), which can be calculated from the scores as follows: for APACHE II: 2.15-0.06 x APACHE II (r = -.81, p < 0.001); for SAPS II: 2.06-0.03 x SAPS II (r = -.8, p < 0.001); and for ICG-PDR: -0.35 + 0.08 x ICG-PDR (r = .89, p < 0.001). The efficacy and safety of anticoagulation during CRRT were determined by the steady state of blood urea nitrogen (32.16 +/- 18.02 mg/dL), mean filter patency at 24 hrs (98%), and the rate of bleeding episodes. Only two patients developed minor bleeding; no patient developed severe bleeding episodes. In critically ill patients with heparin-induced thrombocytopenia type II and necessity for CRRT critical illness scores (APACHE II, SAPS II) or ICG-PDR can help to predict the required argatroban maintenance dose for anticoagulation. These predictors identify decreased argatroban dosing requirements resulting in effective and safe CRRT.

Weight-Based Argatroban Dosing Nomogram for Treatment of Heparin-Induced Thrombocytopenia

Manufacturer recommendations for argatroban use in the setting of heparin-induced thrombocytopenia (HIT) state that the dosage should be titrated to a goal activated partial thromboplastin time (aPTT) of 1.5-3 times the baseline aPTT. The lack of a clear dosing strategy with argatroban may result in delayed stabilization of aPTT. There are no published nomograms to guide the dosing of argatroban. To study the anticoagulant effect and incidence of bleeding and thrombotic events in patients receiving argatroban, with doses determined using a weight-based nomogram. Patients with suspected or documented HIT at an 800-bed teaching community hospital were prospectively treated, in a nonrandomized, nonblinded manner, with argatroban; dosage adjustments were made according to 1 of 2 variations of a dosing nomogram: standard or hepatic/critically ill. The primary outcomes were time to aPTT stabilization and percentage of patients whose aPTTs were within the therapeutic range of 45-90 seconds at 6, 12, 24, 48, 72, and 96 hours. Secondary outcomes were the percentage of patients whose aPTTs were subtherapeutic, supratherapeutic, or above the therapeutic threshold of 45 seconds at each time interval; incidence of thrombotic events; number of dosage adjustments to achieve stabilization; and number of major bleeding events. Fifty-one patients were prospectively treated using the standard (n = 34) and hepatic/critically ill (n = 17) nomograms. Mean time to aPTT stabilization was 16.25 hours with the standard nomogram and 27.05 hours with the hepatic/critically ill nomogram. The percentages of patients with aPTTs within the therapeutic range at each time interval were 82.4%, 82.4%, 88.2%, 96.4%, 100%, and 100% with the standard nomogram and 58.8%, 82.4%, 76.5%, 93.3%, 100%, and 90.9% with the hepatic/critically ill nomogram. There were no thrombotic events after the initiation of argatroban. Three cases of major bleeding occurred. The nomogram is an effective dosing tool for achieving and maintaining therapeutic levels of anticoagulation.

Reducing Harm Associated with Anticoagulation

Argatroban is a hepatically metabolized, direct thrombin inhibitor used for prophylaxis or treatment of thrombosis in heparin-induced thrombocytopenia (HIT) and for patients with or at risk of HIT undergoing percutaneous coronary intervention (PCI). The objective of this review is to summarize practical considerations of argatroban therapy in HIT. The US FDA-recommended argatroban dose in HIT is 2 microg/kg/min (reduced in patients with hepatic impairment and in paediatric patients), adjusted to achieve activated partial thromboplastin times (aPTTs) 1.5-3 times baseline (not >100 seconds). Contemporary experiences indicate that reduced doses are also needed in patients with conditions associated with hepatic hypoperfusion, e.g. heart failure, yet are unnecessary for renal dysfunction, adult age, sex, race/ethnicity or obesity. Argatroban 0.5-1.2 microg/kg/min typically supports therapeutic aPTTs. The FDA-recommended dose during PCI is 25 microg/kg/min (350 microg/kg initial bolus), adjusted to achieve activated clotting times (ACTs) of 300-450 sec. For PCI, argatroban has not been investigated in hepatically impaired patients; dose adjustment is unnecessary for adult age, sex, race/ethnicity or obesity, and lesser doses may be adequate with concurrent glycoprotein IIb/IIIa inhibition. Argatroban prolongs the International Normalized Ratio, and published approaches for monitoring the argatroban-to-warfarin transition should be followed. Major bleeding with argatroban is 0-10% in the non-interventional setting and 0-5.8% periprocedurally. Argatroban has no specific antidote, and if excessive anticoagulation occurs, argatroban infusion should be stopped or reduced. Improved familiarity of healthcare professionals with argatroban therapy in HIT, including in special populations and during PCI, may facilitate reduction of harm associated with HIT (e.g. fewer thromboses) or its treatment (e.g. fewer argatroban medication errors).

Risk Factors for Major Bleeding in Patients With Heparin-induced Thrombocytopenia Treated With Argatroban: A Retrospective Study

We retrospectively characterized major bleeding events and their risk factors among 269 patients with clinically diagnosed heparin-induced thrombocytopenia (HIT) treated using argatroban (2 microg x kg(-1) x min(-1) initially, adjusted to achieve activated partial thromboplastin times (aPTTs) 1.5-3 times the baseline) in a prospective multicenter study. Patients received a median (range) dose of 1.9 (0.2-9.7) microg x kg(-1) x min(-1) for 5.6 (0.1-61) days. Average aPTTs during therapy were 61.6 (37-183) seconds. Major bleeding, most commonly gastrointestinal, occurred in 19 patients (7.1%) during therapy. Another patient suffered from intracranial hemorrhage 4 days after argatroban cessation. Bleeding was fatal in 2 patients (0.7%); each received multiple anticoagulants and thrombolytic therapy. Major bleeding was more likely to occur in patients with HIT-related thrombosis (odds ratio = 2.9, P = 0.039), pulmonary impairment (odds ratio = 20.3, P < 0.001), or an aPTT >100 seconds (odds ratio = 3.7, P = 0.010). Major bleeding rates associated with average aPTTs of <45, 45-67.5, 67.6-90, and >90 seconds, respectively, were 5.0% (1 of 20 patients), 5.6% (9 of 162 patients), 8.7% (6 of 69 patients), and 22% (4 of 18 patients). No significant effect of patient demographics, other baseline illnesses including hepatic or renal impairment, argatroban dose, or treatment duration was detected on major bleeding. Risk factors for major bleeding in argatroban-treated patients with HIT include baseline HIT-related thrombosis and pulmonary impairment. For minimizing bleeding risk during argatroban therapy for HIT, the aPTT should be routinely monitored and maintained at <90 seconds.

Dosing Patterns and Outcomes in African American, Asian, and Hispanic Patients with Heparin-Induced Thrombocytopenia Treated with Argatroban.

Nonwhites, as compared with whites, have increased risk for thromboembolic complications in heparin-induced thrombocytopenia (HIT) (Lewis et al, Chest 2006). To better characterize the risk in nonwhite patients, we retrospectively evaluated dosing patterns and clinical outcomes in African American, Asian, and Hispanic patients administered argatroban therapy for clinically diagnosed HIT. Patients were from previously reported, multicenter, prospective studies of argatroban therapy (2 mcg/kg/min, adjusted to achieve aPTTs 1.5–3 times baseline) in HIT (defined as an otherwise unexplained platelet count <100 x109/L, or 50% reduction in platelet count, following heparin therapy). For African American (n=52), Asian (n=13), and Hispanic (n=14) patient groups, baseline characteristics, therapeutic argatroban dose and duration, aPTTs during therapy, and clinical outcomes (death, including death due to thrombosis; amputation, including amputation secondary to ischemic complications of HIT; new thrombosis; and major bleeding within a 37-day period) were summarized and compared. Among groups, no differences were detected in demographic or baseline features, excepting weight (median values: 62, 77 and 85 kg, respectively, for Asians, African Americans, and Hispanics). Median baseline platelet counts were 45–71 x109/L, and approximately 50% of patients in each group had HIT-related thrombosis before argatroban was initiated. Each group received a similar duration of argatroban therapy (4.0–5.5 days), yet Asians needed a lesser dose (1.0 mcg/kg/ min, versus 1.9 mcg/kg/min in other groups) to achieve comparable aPTTs (61–69 s). New thrombosis occurred most often in African Americans (21%, versus 7–8% in other groups) and when baseline HIT-related thrombosis was present (9/13 events, 69%). Amputation occurred most often in Hispanics (21%, versus 0–12% in other groups) and when diabetes was present (6/9 events, 67%). Mortality was 21–31%, and mortality due to thrombosis was 0–7%. Asians had the lowest frequency of any thrombotic-related outcome (composite of death due to thrombosis, amputation secondary to ischemic complications of HIT, or new thrombosis: 8%, versus 27–29% in other groups). Two patients, each African American, experienced major bleeding (gastrointestinal), for an overall major bleeding rate of 2.5% and by-group rates of 0–4%. Although limited by small group sizes, our study is among the first to characterize outcomes in minority patients administered nonheparin therapy for HIT. Our findings suggest that, despite achieving comparable levels of anticoagulation with argatroban, African Americans and Hispanics are higher risk patients than Asians for poor outcomes in HIT and also that in minority patients with adverse outcomes, baseline HIT-related thrombosis or diabetes is often present.

Argatroban Anticoagulation in Patients following Cardiovascular Surgery and in ICU Patients with and without Renal-Replacement Therapy

Argatroban has been safely and effectively used in the prevention and treatment of heparin-induced thrombocytopenia (HIT). Current data suggest that special patient populations appear to respond rather sensitively to argatroban. This particularly applies to patients after cardiac surgery and patients needing intensive care unit (ICU) treatment. Due to its predominant hepatic elimination, argatroban is an interesting alternative option for patients needing renal replacement therapy (RRT). This article focuses on the argatroban dosing protocols in patients after cardiac surgery and ICU patients with and without RRT.

Argatroban Anticoagulation in Intensive Care Patients: Effects of Heart Failure and Multiple Organ System Failure

We retrospectively evaluated argatroban dosing patterns, clinical outcomes, and the effects of heart failure and multiple organ system failure on dosing requirements in 65 adult, intensive care patients administered argatroban anticoagulation for clinically suspected heparin-induced thrombocytopenia (n=56) or history of heparin-induced thrombocytopenia (n=9). Argatroban was initiated then titrated to achieve target activated partial thromboplastin times 1.5 to 3 times normal control (ie, 42-84 seconds). Overall, argatroban was initiated at 1.14+/-0.62 microg/kg/min (mean+/-SD) and administered for 11.4+/-9.5 days, with comparable dosing patterns between patients with suspected, versus previous, heparin-induced thrombocytopenia. Sixty-four (98.5%) patients achieved target activated partial thromboplastin times, typically following no or one dose adjustment. Therapeutic doses were lower in patients with, versus without, heart failure (0.58+/-0.28 vs 0.97+/-0.6 microg/kg/min, P= .042) and decreased as the number of failed organ systems increased from 1 to 2 to =3 (1.10+/-0.67 vs 0.87+/-0.47 vs 0.58+/-0.47 microg/kg/min, P= .008). From argatroban initiation until patient discharge or death, 11 (16.9%) patients (3 off argatroban) developed thromboembolic complications; 14 (21.5%) died (11 off argatroban, 7 from multiple organ system failure); and 1 (1.5%) required amputation. Nine patients (13.8%) experienced bleeding, none fatal. This experience suggests that argatroban administered at approximately 1 micro/kg/min provides adequate levels of anticoagulation in many intensive care unit patients with suspected or previous heparin-induced thrombocytopenia. Reduced doses are needed when heart failure or multiple organ system failure is present.

Efficacy and safety of argatroban in patients with heparin induced thrombocytopenia undergoing endovascular intervention for peripheral arterial disease

This study aimed to evaluate the efficacy and safety of argatroban during percutaneous interventions for peripheral arterial disease (PAD). Endovascular interventions are commonly used in patients with peripheral arterial disease. Heparin is routinely administered during these procedures, but cannot be used in patients with a history of heparin-induced thrombocytopenia (HIT). Argatroban is an approved direct thrombin inhibitor for treatment of patients with HIT. There are currently few data on the efficacy and safety of argatroban during endovascular interventions for PAD. Patients who underwent endovascular interventions for PAD on argatroban between 2002 and 2005 were identified from out database. Efficacy was evaluated using a composite of death, urgent revascularization, and amputation, while safety was assessed by TIMI major bleeding during the index hospitalization. A total of 48 patients undergoing lower extremity revascularization on argatroban were identified. Thirty two of these patients (67%) had antibody-confirmed HIT and the other 16 (33%) had suspected HIT. A mean dose of argatroban was 173.5 +/- 143 microg/kg bolus, followed by a 10.7 +/- 9.64 microg/kg/min infusion during the procedure. Twelve patients (25%) met the composite end point (two deaths, one urgent revascularization, nine amputations because of progressive peripheral arterial disease). TIMI major bleeding occurred in three (6%) patients. In patients with confirmed or suspected HIT undergoing endovascular intervention for PAD, argatroban appears to be effective and safe. A larger study is warranted to confirm these findings from a single center.

Reduced Argatroban Doses After Coronary Artery Bypass Graft Surgery

The Food and Drug Administration-approved argatroban dose for heparin-induced thrombocytopenia (HIT) is 2 microg/kg/min (0.5 microg/kg/min in hepatic impairment), adjusted to achieve activated partial thromboplastin time (aPTT) 1.5-3 times baseline. Recent data suggest that reduced doses are required after cardiovascular surgery. To characterize dosing requirements, aPTTs, factors affecting dosage, and clinical outcomes in patients administered argatroban after coronary artery bypass graft (CABG) surgery. Charts of 39 patients who underwent CABG surgery and were administered argatroban postoperatively for laboratory-confirmed HIT (n = 25), antibody-negative suspected HIT (n = 10), or previous HIT requiring anticoagulation (n = 4) were retrospectively reviewed. Patient characteristics, argatroban dosing information, aPTTs (target range 45-90 sec), and outcomes were summarized. Regression analyses explored potential effectors of dosage. Patient features, argatroban dosing patterns, and aPTTs were similar among groups. Many patients had laboratory evidence of some hepatic and/or renal dysfunction (median [range] bilirubin 1.0 [0.3-8.0] mg/dL, creatinine clearance 47 [18-287] mL/min). Overall, median argatroban doses were 0.5 microg/kg/min initially and 0.6 microg/kg/min during therapy (median duration 5.3 days). After argatroban initiation, aPTTs were greater than 90 seconds at first assessment in 4 patients (3 with abnormal hepatic function test results) initially administered 0.5, 1, 2, and 2 microg/kg/min, respectively. Within approximately 16 hours of therapy, 33 (85%) patients achieved consecutive therapeutic aPTTs. No association was detected between mean dose during therapy and preoperative ejection fraction, routine hepatic or renal function test results (other than blood urea nitrogen [BUN]), or surgery type. A clinically insignificant association existed between dose and BUN: there was an approximately 0.15 microg/kg/min dose decrease for each 10 mg/dL BUN increase. One patient developed thrombosis, 1 underwent finger amputation, 7 died (5 after argatroban cessation), and 4 had significant bleeding. These findings suggest that reduced initial argatroban doses (eg, 0.5 microg/kg/min), adjusted to achieve therapeutic aPTTs, provide rapid, adequate anticoagulation in postoperative CABG patients with presumed or previous HIT. Prospective study of reduced initial dosing in this setting is warranted.

Prospective Study of Direct Thrombin Inhibition with Argatroban in Pediatric Patients Requiring Nonheparin Anticoagulation.

This multicenter, open-label study evaluated the safe, effective dose of intravenous argatroban for prophylaxis or treatment of thrombosis in patients ≤16 years of age requiring nonheparin anticoagulation. The protocol-specified argatroban dose for systemic anticoagulation was 1.0 μg/kg/min (0.25 μg/kg/min for patients with impaired hepatic function; 0.5 μg/kg/min for patients <6 months old, reduced to 0.125 μg/kg/min with impaired hepatic function), adjusted to achieve activated partial thromboplastin times (aPTTs) 1.5–3 times the baseline value, or for procedures requiring immediate anticoagulation, an initial bolus then an infusion with doses varying by procedure (eg, 250 μg/kg bolus, then 15 μg/kg/min for cardiac catheterization, adjusted to achieve an activated clotting time of 200–300 seconds, with doses reduced if impaired hepatic function). Primary efficacy endpoints were the occurrence/recurrence of thrombosis and of thromboembolic complications including death and amputations resulting from the complication. Primary safety endpoints were major bleeding and death secondary to bleeding complications. The study population comprised 18 patients (age range: 1.6 weeks to 16.1 years; 12 males) with confirmed (8), suspected (5), or risk of (2) heparin-induced thrombocytopenia (HIT), or conditions such as heparin resistance or antithrombin deficiency (5); 2 patients met 2 inclusion diagnoses, and most had serious comorbidities. Overall, 17 patients received continuous argatroban, 6 underwent procedures, 5 received a bolus [median (range), 250 (11.2–250) μg/kg], and 14 completed the study. The median (range) treatment duration was 2.9 (<0.1–13.8) days. The median (range) infusion dose was 1.5 (0.38–13) μg/kg/min in 13 patients with normal hepatic function and 0.8 (0.4–0.9) μg/kg/min in 4 patients with serum total bilirubin >2.0 mg/dL secondary to hepatic impairment or cardiac complications. Of 11 patients administered 1.0 μg/kg/min initially, target aPTTs were achieved without dose adjustment in 4 patients by 2 h and with no or little dose adjustment in 8 patients by 9 h and all patients by 26 h. Within the 30-day follow up, 5 patients had 6 thrombotic events (2 patients had an event during therapy). No patient required amputation or died due to thrombosis during therapy. In each patient with confirmed HIT, the platelet count recovered during treatment. Two critically ill patients had major bleeding (each event was fatal): 1 patient died 2 days after argatroban cessation due to cerebral infarction and intracranial hemorrhage, and 1 patient on extracorporeal membrane oxygenation for heart failure had fatal subarachnoid bleeding on study day 25. The most frequent treatment-emergent adverse events were hypokalemia, constipation and hypotension (n=5, each). In this first prospective study of direct thrombin inhibition in both infants and children requiring nonheparin anticoagulation, argatroban was well tolerated and rapidly provided adequate levels of anticoagulation for noninterventional or interventional needs in seriously ill pediatric patients.

Polyphosphate Shortens the Clotting Time of Hemophilic and Anticoagulated Plasma.

Introduction: Inorganic polyphosphate (polyP) is a negatively charged polymer of phosphate units linked by high energy phosphoanhydride bonds. Dense granules of human platelets contain abundant polyP which is released in response to thrombin stimulation. We recently reported that polyphosphate is a potent hemostatic regulator, accelerating blood clotting by activating the contact pathway, promoting factor V activation, and abrogating tissue factor pathway inhibitor function. We now report that polyP shortens the clot time of hemophilic plasmas and plasmas containing a variety of anticoagulant drugs.Methods: Citrated plasmas were obtained from normal donors, patients receiving coumadin, and individuals with severe hemophilia A or B. In some experiments, clinically relevant concentrations of unfractionated heparin, enoxaparin, or argatroban were added to normal plasma. In other experiments, therapeutic concentrations of FIX, FVIII, or FVIIa were added to hemophilic plasma. Clotting was initiated by dilute thromboplastin.Results: Adding 33 uM polyP to normal plasma shortened clot times at all doses of heparin (by 37–55%), enoxaparin (by 35–57%), and argatroban (by 28–59%; see Figure). PolyP shortened clot times of plasmas from coumadin patients (by 29–39%) with INR values ranging from 1.7 to 4.8. PolyP also shortened the clot times of plasma from patients with hemophilia A (by 54–75%) and B (by 51–79%). PolyP alone shortened clot times of hemophilia A or B plasma equivalent to adding 6 to 15 nM recombinant FVIIa, and the polyP effect was additive to that of FVIIa, FVIII or FIX.Conclusions: PolyP shortened the in vitro clot time for all plasmas tested and was additive with replacement of missing clotting factors or recombinant FVIIa for hemophilic plasmas. These results suggest that treatment with polyP may be useful for reversal of anticoagulation in patients treated for thrombophilia, or for treatment of bleeding episodes in patients with hemophilia. Furthermore, polyP could potentially reduce the dose of replacement clotting factors or recombinant FVIIa needed to treat bleeding episodes in hemophilia. [Display omitted]

A Case Series Describing the Use of Argatroban in Patients on Extracorporeal Circulation

Anticoagulation for extracorporeal life support (ECLS) is routinely achieved using heparin, which can be difficult in patients suspected of having heparin-induced thrombocytopenia. We describe a case series of five patients in which we used argatroban, a direct thrombin inhibitor, as an alternative to heparin for systemic anticoagulation during ECLS in patients suspected to have heparin-induced thrombocytopenia. Argatroban was used to achieve target systemic anticoagulation for activate clotting times between 210 and 230. Duration of argatroban use while on ECLS ranged from 6 to 184 hours. Argatroban dosage ranged from 0.2 to 3.5 microg/kg/min. Activated clotting times showed good agreement with aPTT. In conclusion, we illustrate that argatroban is a reasonable alternative to heparin anticoagulation for patients requiring ECLS.

Argatroban Therapy in Women with Heparin-Induced Thrombocytopenia

Women have increased risk of developing heparin-induced thrombocytopenia (HIT), a serious, immune-mediated prothrombotic condition, and have a worse prognosis when affected. We compared gender differences for treatment and outcomes in HIT patients administered argatroban therapy. From a multicenter retrospective registry of argatroban-treated patients, we identified females (n = 42) and males (n = 50) with clinically diagnosed HIT who were administered argatroban <or=10 microg/kg/min. Upon diagnosis of HIT, heparin was discontinued. Continuous intravenous argatroban was instituted, adjusted to achieve activated partial thromboplastin times (aPTTs) 1.5-3 times baseline. Between-gender comparisons were made of argatroban dosing, aPTT responses, and clinical outcomes (death, amputation, new thrombosis, major bleeding). At baseline, females and males were generally well matched, excepting platelet count (medians, 101 x 10(9)/L vs. 170 x 10(9)/L, p = 0.01), with 9 (21%) females and 19 (38%) males having HIT-related thrombosis. Typically, argatroban was initiated and maintained at 1.0-1.1 mug/kg/min for approximately 6 days, irrespective of gender. No differences were detected between females and males in aPTTs during therapy (respective medians, 57.3 vs. 59.5 seconds) or time to therapeutic aPTTs (7.3 vs. 10.3 hours), or platelet count recovery (2.5 vs. 7.4 days). Of patients with available data, 20 of 35 (57%) females and 19 of 35 (54%) males were converted to warfarin. The composite end point of death, amputation, or new thrombosis within 37 days of argatroban initiation occurred in 10 (24%) females and 8 (16%) males (p = 0.43). Within 37 days, 7 (17%) females and 7 (14%) males died (2 while on argatroban), 1 (2%) female required amputation (off argatroban), and 3 (7%) females and 2 (4%) males developed new thrombosis (3 while on argatroban). Major bleeding occurred in 1 (2%) female and 1 (2%) male. Argatroban can be used effectively and safely to manage HIT in females, with dosing requirements, aPTT responses, and clinical outcomes comparable to those in men. Future, larger studies are warranted in establishing the unique characteristics of HIT in females.

Argatroban in Extracorporeal Membrane Oxygenation

The objective of this study was to assess the required dose and anticoagulatory effect of argatroban (Mitsubishi, Pharma Deutschland GmbH, Düsseldorf, Germany), a direct thrombin inhibitor approved for anticoagulation in patients with heparin-induced thrombocytopenia (HIT) undergoing extracorporeal membrane oxygenation (ECMO). Nine consecutive patients undergoing ECMO for severe acute respiratory distress syndrome (ARDS) and presenting with suspected HIT were treated with a continuous argatroban infusion. Coagulation variables were measured and dose adjustments of argatroban were performed to target for an activated partial thromboplastin time (aPTT) of 50 to 60 s. The first patient received argatroban 2 microg/kg/min as recommended by the manufacturer. This resulted in excessive anticoagulation and severe bleeding. The consecutive eight patients received a 10-fold lower dose (0.2 microg/kg/min). This dose sufficiently increased aPTT time from 46 +/- 6 s to 65 +/- 14 s (P < 0.001) and thrombin time from 18 +/- 8 s to 45 +/- 11 s (P = 0.001). The maintenance dose averaged 0.15 microg/kg/min. Duration of argatroban infusion for ECMO averaged 4 +/- 1 days and no oxygenator or extracorporeal system clotting was observed. In three of nine patients (33%), HIT was confirmed. Argatroban is a feasible and effective anticoagulant for patients with suspected HIT undergoing ECMO. However, a dose 10-fold lower than that recommended by the manufacturer is sufficient to achieve appropriate anticoagulation in critically ill patients undergoing ECMO.

Argatroban Anticoagulation for Heparin-Induced Thrombocytopenia in Elderly Patients

Argatroban, a direct thrombin inhibitor that has reduced clearance in elderly versus younger volunteers, is used for thromboprophylaxis or treatment in heparin-induced thrombocytopenia (HIT). To evaluate the effect of aging on argatroban therapy, including dosage, anticoagulant responses, clinical outcomes and factors influencing those responses, in elderly patients with HIT or a history of HIT. This was a retrospective multicentre database analysis of 118 inpatients treated with argatroban at six medical centres between August 2001 and January 2005. Sixty-two adults aged >/=65 years were administered argatroban for clinically diagnosed HIT (n = 54) or a history of HIT (n = 8). Argatroban infusion was adjusted to achieve activated partial thromboplastin times (aPTTs) 1.5-3 times baseline. All study measures and analyses were prospectively defined. Argatroban dosage patterns, aPTTs and platelet count responses, and 37-day outcomes (death, amputation, new thrombosis, major bleeding) were summarised for patients stratified by age (65-74 years [n = 31]; 75-84 years [n = 26]; >/=85 years [n = 5]) to identify possible age-related trends. Regression analyses explored relationships between dose and patient age, liver function and renal function. Cox proportional hazards models evaluated the effect of age, dose, gender, aPTT and platelet count on the risk of new thrombosis. In each age group, the median argatroban dosage was initially 1.0 microg/kg/min and was generally maintained at or near that dose during therapy (median, 5-7 days). Therapeutic aPTTs occurred within 11.5 hours; the median aPTT during therapy was 54.7 seconds, without obvious trend by age. By regression analysis, the initial and mean argatroban dosages decreased 0.08-0.09 microg/kg/min with each 0.2 mg/dL increase in serum creatinine, but no association was detected between dose and patient age, serum total bilirubin, calculated creatinine clearance or blood urea nitrogen. Platelet counts recovered within 6-7 days of initiating therapy, without apparent trend by age. No patient experienced amputation or major bleeding, and no patient in the oldest group died or had new thrombosis. Overall, 13 (21%) patients died (9 in the 65-74 years group; 1 receiving argatroban) and 5 (8%) had new thrombosis (4 in the 65-74 years group; 2 receiving argatroban), comparing favourably with previously reported rates, irrespective of patient age. By univariate (but not multivariate) analysis, the risk of new thrombosis decreased with increasing argatroban dose (hazard ratio 0.020; 95% CI 0.001, 0.757; p = 0.035). No effect of age or the other covariates considered on thrombotic risk was detected. Argatroban at a median initial dosage of 1.0 microg/kg/min, adjusted to achieve median aPTTs of 54.7 seconds during therapy, generally provided safe, adequate anticoagulation across a wide age range in elderly patients with HIT or a history of HIT. In these elderly patients, age was not a significant determinant of argatroban dosage or thrombotic risk. Prospective evaluation of this initial dose of argatroban in the elderly is warranted.

Argatroban for anticoagulation during cardiac surgery

The aim of this study was to report our experience and review the published data on argatroban administration during adult cardiac surgery. The information on all reported cases of argatroban use in adults, during cardiac surgery was reviewed, including that of the patient described here. This analysis focused on patient characteristics, type of surgery, argatroban dosing schedule, monitoring of anticoagulation and outcomes. Twenty-one cases have been reported. Fifteen patients underwent off-pump surgical procedures with the argatroban dose adjusted to maintain an activated clotting time (ACT) range between 200 and 300 s. Three intraoperative thrombi occurred in two patients when the ACT was <280 s. None had coagulopathy. Six cases reported the use of argatroban during on-pump cardiac surgery dosed to keep the ACT >400 s. Intraoperative thrombotic complications were not reported in this group; however, one clot in the pump was noted after the procedure when the ACT was between 300 and 350 s. All six cases required larger volumes of perioperative blood products and three had severe coagulopathy. Of the 21 cases, seven had an indication for continued anticoagulation following surgery. Four cases did not report further use of argatroban after surgery. Three patients received argatroban after surgery without complications. Recommendations for how to use argatroban during cardiac surgery are proposed. Argatroban, with ACT monitoring, might be safely used for anticoagulation during cardiac surgery.

Argatroban Anticoagulation for Heparin-Induced Thrombocytopenia in Obese, Versus Non-Obese, Patients.

Argatroban, a parenteral direct thrombin inhibitor used for prophylaxis or treatment of thrombosis in heparin-induced thrombocytopenia (HIT), is routinely administered in accordance with patient body weight and activated partial thromboplastin time (aPTT) response. The effect of obesity (BMI >30) on argatroban therapy in HIT however is not well described. In this retrospective analysis of a 118-patient, multicenter HIT registry database, we evaluated argatroban doses, aPTTs, and clinical outcomes in obese, vs. non-obese, argatroban-treated adults with clinically diagnosed HIT or history of HIT. Patients lacking sufficient data to calculate BMI, administered argatroban at doses required during angioplasty, or with a baseline (pre-argatroban) platelet count >150x109/L were excluded. Argatroban was infused and adjusted to achieve aPTTs 1.5–3 times baseline, at the treating physician's discretion. We identified 41 patients for analysis: 21 non-obese (BMI 17.3–28.9, median 22.9; 52% female) and 20 obese (BMI 30.1–50.8, median 34.8; 55% female). Two patients (1 per group) had history of HIT requiring acute anticoagulation; 39 patients had HIT (median baseline platelet count of 85 and 92x109/L, respectively, in non-obese and obese patients), including 9 (5 obese) with baseline HIT-related thrombosis. Indications for heparin therapy, typically cardiac- or surgery-related, were similar between the non-obese and obese groups. Median argatroban doses were 1.0 μg/kg/min initially in each group, and 1.0 and 1.2 μg/kg/min in the non-obese and obese groups, respectively, during therapy (median 5.4 and 6.3 days, respectively). Therapeutic aPTTs occurred within a median 5.6 and 5.0 h, respectively, with median aPTTs during therapy of 60.5 and 58.7 s. By regression analysis, BMI did not significantly affect argatroban dose. Platelet counts recovered (>100x109/L or 1.5 times baseline) within 4.3 and 2.4 days for the non-obese and obese HIT patients, respectively. Within 37 days of argatroban initiation, death occurred in 7 (33%) non-obese and 5 (25%) obese patients (1 in each group while on argatroban); amputation in 0 (0%) non-obese and 1 (5%) obese patient (off argatroban); new thrombosis in 1 (5%) non-obese and 3 (15%) obese patients (2 while on argatroban); and major bleeding in 1 (5%) non-obese (off argatroban) and 0 (0%) obese patient. Cox regression analysis failed to identify any significant risk factors (BMI, obesity, gender, argatroban dose, baseline platelet count, aPTT) for new thrombosis. We conclude that argatroban dose requirements, aPTT responses, and clinical outcomes are generally comparable between obese vs. non-obese patients with HIT or history of HIT. These findings support the use of body weight-adjusted (and aPTT-adjusted) argatroban dosing for safe, effective anticoagulation, irrespective of patient BMI.

Argatroban Anticoagulation for Heparin-Induced Thrombocytopenia in Elderly Patients.

Argatroban, a direct thrombin inhibitor, is used for prophylaxis or treatment of thrombosis in heparin-induced thrombocytopenia (HIT). Although its clearance is reduced in elderly, vs younger, healthy volunteers (4.3 vs 5.0 mL/min/kg), argatroban therapy in elderly patients with HIT has not been specifically described. In this retrospective analysis of a 118-patient, multicenter registry database, we evaluated argatroban dosing, anticoagulant responses, and clinical outcomes in adults aged ≥65 years with clinically diagnosed HIT or history of HIT administered argatroban therapy. From the registry, we identified 62 argatroban-treated patients with HIT (n=54) or history of HIT (n=8). Baseline characteristics, argatroban doses and responses, and outcomes were summarized for patients overall and stratified by age (65–74 years, n=31; 75–84 years, n=26; ≥85 years, n=5). Indications for anticoagulation were similar among groups, typically cardiac-related. Argatroban was infused and adjusted to achieve activated partial thromboplastin times (aPTTs) 1.5–3 times baseline. In each group, the initial median argatroban dose as determined by the treating physician was 1.0 mg/kg/min (a similar initial dose was used for all registry patients, irrespective of age) and maintained at or near that dose during therapy (median, 5–7 days). Overall, therapeutic aPTTs occurred within 11.5 hours; the median aPTT during therapy was 54.7 seconds. By regression analysis, mean argatroban dose decreased ~0.1 mg/kg/min with each 0.2-mg/dL increase in serum creatinine but was unaffected by patient age, total serum bilirubin, calculated creatinine clearance, or blood urea nitrogen. Platelet counts in HIT patients increased a median 41% from baseline during therapy. Within 37 days of argatroban initiation, 13 (21%) patients died (1 while on argatroban), 5 (8%) had new thrombosis (2 while on argatroban), and none experienced amputation or major bleeding. The oldest group had no event. By univariate regression analysis, the risk of developing new thrombosis decreased with increasing mean argatroban dose (hazard ratio=0.020; 95% CI, 0.001–0.757; p=0.035), yet was not significantly affected by age, gender, baseline platelet count, or mean aPTT. We conclude that argatroban at a median initial dose of 1.0 mg/kg/min, adjusted to achieve aPTTs 1.5–3 times baseline, provides safe and effective anticoagulation in elderly patients with HIT or history of HIT. For patients ≥65 years old, age is not a significant factor determining therapeutic argatroban doses or thrombotic risk.

Effect of renal function on argatroban therapy in heparin-induced thrombocytopenia

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

Correction: Résumé—Argatroban Dosing of Patients with Heparin-Induced Thrombocytopenia and an Elevated aPTT Due to Antiphospholipid Antibody Syndrome

Correction: Résumé—Argatroban Dosing of Patients with Heparin-Induced Thrombocytopenia and an Elevated aPTT Due to Antiphospholipid Antibody Syndrome