Argatroban Therapy In Heparin-induced Thrombocytopenia Research Articles

Argatroban therapy for heparin-induced thrombocytopenia in ICU patients with multiple organ dysfunction syndrome: a retrospective study

IntroductionHeparin-induced thrombocytopenia (HIT) is a serious, prothrombotic, immune-mediated adverse reaction triggered by heparin therapy. When HIT is diagnosed or suspected, heparins should be discontinued, and an alternative, fast-acting, parenteral, nonheparin anticoagulation such as argatroban should be initiated. Limited and inconsistent data exist about dosing of argatroban in intensive care unit (ICU) patients with critical illnesses.MethodsRetrospective analysis of 12 ICU patients with multiple organ dysfunction syndrome (MODS) treated with argatroban for suspected or diagnosed HIT.ResultsThe 12 ICU patients with a mean platelet count of 46,000 ± 30,310 had a mean APACHE II score of 26.7 ± 7.8 on ICU admission and a mean SAPS II score of 61.5 ± 16.3 on the first day of argatroban administration. A mean argatroban starting dose of 0.32 ± 0.25 μg/kg/min (min, 0.04; max, 0.83) was used to achieve activated partial thromboplastin times (aPTTs) >60 sec or aPTTs of 1.5 to 3 times the baseline aPTT. Adjustment to aPTT required dose reduction in six (50%) patients. Patients were treated for a mean of 5.5 ± 3.3 days. The final mean dose in these critically ill patients was 0.24 ± 0.16 μg/kg/min, which is about one eighth of the usually recommended dose and even markedly lower than the previously suggested dose for critically ill ICU patients. In all patients, desired levels of anticoagulation were achieved. The mean argatroban dose was significantly lower in patients with hepatic insufficiency compared with patients without hepatic impairment (0.10 ± 0.06 μg/kg/min versus 0.31 ± 0.14 μg/kg/min; P = 0.026). The mean argatroban dose was significantly correlated with serum bilirubin (r = -0.739; P = 0.006).ConclusionsICU Patients with MODS and HIT can be effectively treated with argatroban. A decrease in the initial dosage is mandatory in this patient population. Further studies are needed to investigate argatroban elimination and dosage adjustments for critically ill patients.

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).

Argatroban Therapy in Heparin-Induced Thrombocytopenia

Patients who develop heparin-induced thrombocytopenia (HIT) are at increased risk for morbidity and mortality if the disorder is not recognized and treated early. Upon initial suspicion of HIT, providers should promptly discontinue all heparin products and initiate an alternative form of anticoagulation without waiting for diagnostic test results confirming the presence of HIT antibodies. The direct thrombin inhibitor, argatroban (Argatroban), is a reasonable alternative anticoagulant in patients with HIT, based on its proven safety and efficacy, ease of use, and consistent response rate between individuals. Further clinical trials are warranted to evaluate and expand the use of argatroban in other thrombotic states.

Argatroban Therapy in Heparin-Induced Thrombocytopenia

Patients who develop heparin-induced thrombocytopenia (HIT) are at increased risk for morbidity and mortality if the disorder is not recognized and treated early. Upon initial suspicion of HIT, providers should promptly discontinue all heparin products and initiate an alternative form of anticoagulation without waiting for diagnostic test results confirming the presence of HIT antibodies. The direct thrombin inhibitor, argatroban (Argatroban), is a reasonable alternative anticoagulant in patients with HIT, based on its proven safety and efficacy, ease of use, and consistent response rate between individuals. Further clinical trials are warranted to evaluate and expand the use of argatroban in other thrombotic states.

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.

Argatroban therapy in heparin-induced thrombocytopenia

Argatroban is a direct thrombin inhibitor approved for anticoagulation in heparin-induced thrombocytopenia (HIT; in several countries) and in patients with or at risk of HIT undergoing percutaneous coronary intervention (PCI; in the USA). HIT is a relatively common extreme prothrombotic condition. When HIT is reasonably suspected, an alternative anticoagulant should be promptly initiated. In historical controlled studies, argatroban reduced new thrombosis, mortality from thrombosis and the composite of death, amputation or thrombosis, without increasing bleeding. With intravenous infusion, advantages include short half-life, easy monitoring and elimination primarily by hepatobiliary (rather than renal) means. In patients undergoing PCI, argatroban with or without glycoprotein IIb/IIIa inhibition leads to high rates of procedural success with low bleeding risk. Herein we review argatroban therapy for HIT and for PCI.

Argatroban Therapy for Heparin-Induced Thrombocytopenia in Acutely Ill Patients

Heparin-induced thrombocytopenia (HIT) is a prothrombotic, immune-mediated adverse reaction to heparin therapy. To evaluate clinical outcomes and effects of argatroban therapy in acutely ill HIT patients. Retrospective analysis. Hospital in-patient. Acutely ill patients with clinically diagnosed HIT from previous multicenter, historically controlled studies of argatroban therapy in HIT. Argatroban, adjusted to maintain activated partial thromboplastin times 1.5 to 3 times baseline, or historical control therapy (ie, no direct thrombin inhibition). We identified 488 patients who received argatroban (N = 390; mean dose of 1.9 microg/kg/min for a mean 6 days) or historical control therapy (N = 98) for HIT. The primary all-cause composite endpoint of death, amputation, or new thrombosis within 37 days occurred in 133 (34.1%) argatroban-treated patients and 38 (38.8%) controls (P = .41). Argatroban, versus control, significantly reduced the primary thrombosis-related composite endpoint of death because of thrombosis, amputation secondary to ischemic complications of HIT, or new thrombosis (17.7% vs 30.6%, P = .007). Significant reductions also occurred in new thrombosis and death because of thrombosis. Major bleeding was similar between groups (7.7% vs 8.2%; P = .84). Adverse outcomes were more likely to occur in patients who were initially diagnosed with HIT and thrombosis, had undergone cardiac surgery, were not white, or had more severe thrombocytopenia. In acutely ill HIT patients, argatroban, versus historical control, provides effective antithrombotic therapy without increasing major bleeding. Patients with more severe thrombocytopenia or HIT-related thrombosis on HIT diagnosis have a poorer prognosis, emphasizing the importance of prompt recognition/ treatment of HIT in acutely ill patients.

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.

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.

Heparin-Induced Thrombocytopenia from Venous Thromboembolism Treatment.

Heparin therapy for any indication, including venous thromboembolism (VTE), can be complicated by heparin-induced thrombocytopenia (HIT). The purpose of this retrospective study was to characterize the clinical experience of patients in whom HIT complicated heparin therapy for VTE and who were switched to argatroban therapy. From the previously reported prospective, multicenter, historical-controlled Argatroban-911 and Argatroban-915 studies of argatroban therapy in HIT, we identified all patients who developed HIT while on heparin therapy for pulmonary embolism and/or deep venous thrombosis and in whom heparin was discontinued and argatroban therapy initiated. The primary study end point was a composite of death, amputation, or new thrombosis within 37 days of argatroban initiation; we also evaluated a 37-day composite end point of thrombosis-associated events, including death due to thrombosis, amputation secondary to HIT, or new thrombosis. A total of 145 patients with VTE and HIT were included in our analysis. During heparin therapy before HIT was diagnosed, platelet counts decreased from daily mean values greater than 175x109/L to a mean±SD nadir of 78±67x109/L over the course of 5 days, and new thrombosis developed in 75 (52%) patients. After heparin was discontinued, patients received argatroban (mean dose 2.1±1.2 mcg/kg/min) for 6.8±4.3 days achieving mean activated partial thromboplastin times during therapy of 63±12 s. By day 6 of argatroban therapy, the mean platelet count had risen to >150x109/L. The primary end point occurred in 41 (28.3%) patients, and the thrombotic composite in 23 (15.9%) patients (Table 1). Seventeen (11.7%) patients, including 12 who had also experienced thrombosis while on heparin, developed new thrombosis after argatroban initiation, typically on the day argatroban was discontinued or later (n=10). Death due to thrombosis occurred in only 1 (0.7%) patient. Seven (4.8%) patients experienced major bleeding. We conclude that in heparin-treated patients with VTE, HIT-associated thrombosis often occurs before HIT is recognized, emphasizing the importance of platelet count monitoring and a high degree of suspicion for HIT in this setting. For VTE patients with HIT, argatroban provides effective anticoagulation, with outcomes comparable with those reported for argatroban-treated patients in whom HIT developed following heparin therapy for any indication. New thrombosis occurring after switching to argatroban therapy more typically occurs in patients with existing HIT-associated thrombosis and at/after argatroban discontinuation.Clinical Outcomesn(%)Outcomen=145Primary (all cause)*Thrombosis-related†,¥Composite end point41 (28.3)23 (15.9)Individual componentsDeath19 (13.1)1 (0.7)Amputation8 (5.5)6 (4.1)New thrombosis17 (11.7)17 (11.7)*All-cause death, all-cause amputation, or new thrombosis within 37 days. †Death due to thrombosis, amputation secondary to HIT, or new thrombosis within 37 days. ¥More than 1 outcome may have occurred in a single patient.

Heparin‐induced thrombocytopenia from venous thromboembolism treatment

We aimed to characterize the clinical experiences of patients in whom heparin-induced thrombocytopenia (HIT) complicated heparin therapy for venous thromboembolism (VTE) and who switched to argatroban. A retrospective analysis of previously reported prospective, multicentre, historical-controlled Argatroban-911 and Argatroban-915 studies of argatroban therapy in HIT. Inpatient. Patients (n = 145) administered heparin for VTE and who developed HIT were identified. Patients were treated with argatroban 2 mcg kg(-1) min(-1) for up to 14 days, adjusted to maintain activated partial thromboplastin times 1.5 to three times baseline. Patient characteristics, anticoagulation and outcomes were summarized. The primary end-point was a composite of death, amputation, or new thrombosis within 37 days of argatroban initiation. During heparin therapy, platelet counts decreased (mean +/- SD nadir: 78 +/- 67 x 10(9) L(-1)), and 75 (52%) patients developed thrombosis. After heparin was discontinued, patients received argatroban (mean dose 2.1 +/- 1.2 mcg kg(-1) min(-1)) for 6.8 +/- 4.3 days. By day 6 of argatroban therapy, the mean platelet count rose to >150 x 10(9) L(-1). The primary end-point occurred in 41 (28.3%) patients (values of 26-44% are reported for argatroban therapy of HIT from any heparin indication). Seventeen (11.7%) patients, including 12 who had also experienced thrombosis whilst on heparin, developed new thrombosis after argatroban initiation, typically on the day argatroban was discontinued or later (n = 10). Seven (4.8%) patients experienced major bleeding. For VTE patients with HIT, argatroban provides effective anticoagulation, with outcomes comparable with those reported for other argatroban-treated HIT patients. New thrombosis in this setting occurred most often in patients with existing HIT-associated thrombosis, before HIT recognition or either at/after argatroban discontinuation.