Safety and efficacy of argatroban in patients with heparin-induced thrombocytopenia

Argatroban is a synthetic direct thrombin inhibitor. It is indicated for use in patients with heparin-induced thrombocytopenia (HIT). The greatest experience is in prevention and treatment of the disorder, but argatroban is also indicated for percutaneous coronary interventions in patients with HIT. There is somewhat limited experience with its use in a number of other clinical scenarios in these patients. The current data on the use of argatroban in patients with HIT are reviewed.     

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

Background 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 μg/kg/min (0.5 μg/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.Methods 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.Results 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 μg/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 μg/kg/min), duration of therapy (7 ± 6 days), or aPTTs (63 ± 17 s). Regression analyses showed a 0.1 μg/kg/min increase in dose (r ² = 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.Conclusions 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. Condensed Abstract 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 μg/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.     

Lepirudin for anticoagulation in patients with heparin-induced thrombocytopenia treated with continuous renal replacement therapy

Lepirudin is a potent, direct thrombin inhibitor used for anticoagulation in patients with heparin-induced thrombocytopenia type II (HIT). The half-life of lepirudin is prolonged in patients with renal insufficiency. Preliminary studies suggest that it is safe to use lepirudin in patients being treated with intermittent hemodialysis but information regarding its use with continuous renal replacement therapy (CRRT) is scarce. CRRT is used in acute care settings to remove fluid and uremic toxins in patients with renal failure with hemodynamic instability. Patients with HIT, renal failure, and hemodynamic instability pose a complex situation for clinical management. These patients require anticoagulation with nonheparin agents with simultaneous CRRT. There are no guidelines in the literature regarding the management of this patient group. We report our experience with lepirudin at managing four such patients with HIT, being treated with CRRT.     

Comparison of argatroban and fondaparinux for the management of patients with isolated heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is a serious complication of the administration of heparin and its derivatives. Non-heparin anticoagulants such as argatroban and fondaparinux are widely used in the management of HIT to compare the effectiveness of argatroban and fondaparinux in the resolution of thrombocytopenia and to compare clinical outcomes in patients with isolated HIT. A retrospective cohort analysis was performed at King Abdulaziz Medical City (KAMC) on patients diagnosed with isolated HIT between 31 Jan, 2014 and 30 June, 2017. Demographics data, non-heparin anticoagulants, related laboratory results, and clinical outcomes were retrieved and analysed. The cohort comprised a total of 95 adult patients who received either argatroban (56 patients) or fondaparinux (39 patients) for isolated HIT. The median age and sex distribution were similar in both argatroban and fondaparinux groups. The mean (+?SD) time (in days) for the resolution of thrombocytopenia was 3.5 (±?1.8) for patients who received argatroban and 3.7 (±?1.7) for patients administered fondaparinux (p?=?0.843). Thromboembolic events occurred in five patients (8.9%) administered argatroban and in three patients (7.7%) administered fondaparinux (p?=?0.382). There was no significant difference in the rates of bleeding or death (p?=?0.829); however, the small number of cases limits our ability to draw conclusions about these outcomes. In this retrospective study, fondaparinux and argatroban were similarly effective in resolving thrombocytopenia, preventing further thromboembolic events, and maintaining safety in patients with confirmed HIT. To confirm this observation, larger prospective studies are needed.     

Transitioning from argatroban to warfarin therapy in patients with heparin-induced thrombocytopenia.

Argatroban, a direct thrombin inhibitor used for thromboprophylaxis or treatment in heparin-induced thrombocytopenia (HIT), is routinely monitored using the activated partial thromboplastin time (aPTT) yet also prolongs the international normalized ratio (INR). Peritransitional INRs, aPTTs, anticoagulant dosing patterns, and outcomes were evaluated in 165 HIT patients who were transitioned, without guidelines, from argatroban to warfarin therapy. Argatroban (median doses: 1.5-2.0 mcg/kg/min) and warfarin (median dose: 5 mg initially with 3.8 mg/day thereafter) overlapped a median 4 days. Median (5-95th percentile) aPTTs (in seconds) and INRs, respectively, were 59.8 (38.8-82.9) and 3.2 (1.7-7.0) during argatroban monotherapy, 68.6 (44.5-104) and 5.3 (2.4-16) maximally during cotherapy, 59.9 (38.7-92.2) and 4.0 (2.2-11.6) immediately before argatroban cessation during cotherapy, and 36.0 (25.6-60.2) and 2.3 (1.3-7.3) within a median 10-12 hours after argatroban cessation. Major bleeding occurred in 1 (0.6%) patient pretransitionally and no patient during or after cotherapy. Eighteen (10.9%) patients experienced 19 peritransitional adverse outcomes (one death, two amputations, 16 new thromboses); these patients had more severe HIT than event-free patients (median baseline platelet count, 39 vs. 83 x 10(9)/L). Of 108 patients with post-transitional INR data, 43 achieved a therapeutic INR (prospectively defined as 1.9-3.5), 34 were subtherapeutic, and 31 were supratherapeutic, with no across-group trend in new thrombosis. Hence in the absence of guidelines, physicians transfer patients from argatroban to warfarin therapy with acceptably low complication rates in HIT, without systematically over- or under-dosing warfarin. Furthermore, INRs greater than 5 commonly occur in HIT patients during argatroban monotherapy and argatroban/warfarin cotherapy, without major bleeding.     

Dosing patterns and outcomes in African American, Asian, and Hispanic patients with heparin-induced thrombocytopenia treated with argatroban

We retrospectively evaluated dosing patterns and 37-day outcomes in argatroban-treated African American (n = 52), Asian (n = 13), and Hispanic (n = 14) patients with heparin-induced thrombocytopenia (HIT). The Asians required a lesser median dose (1.0 μg/kg/min) than the other groups (1.9 μg/kg/min, each) to achieve comparable activated partial thromboplastin times (medians: 61–69 s). Durations of therapy were similar (medians: 4.0–5.5 days). New thrombosis occurred in 11 (21%) African Americans, 1 (8%) Asian, and 1 (7%) Hispanic; of these 13 patients, 9 (69%) had baseline HIT-related thrombosis. Amputation occurred in 6 (12%) African Americans and 3 (21%) Hispanics; of these nine patients, 6 (67%) had diabetes. One (2%) African American and 1 (7%) Hispanic died from thrombosis. The composite of death due to thrombosis, amputation due to ischemic complications of HIT, or new thrombosis occurred in 14 (27%) African Americans, 1 (8%) Asian, and 4 (29%) Hispanics. Two (4%) African Americans and none others (0%) had major bleeding. These findings suggest that despite argatroban anticoagulation, African Americans and Hispanics may have worse outcomes in HIT than Asians. In minority patients with adverse HIT outcomes, baseline HIT-related thrombosis or diabetes is often present.     

Obstinate thrombosis during percutaneous coronary intervention in a case with heparin-induced thrombocytopenia with thrombosis syndrome successfully treated by argatroban anticoagulant therapy.

We describe a case of massive coronary thrombus after the coronary stenting due to heparin-induced thrombocytopenia with thrombosis syndrome (HITTS). Only argatroban was able to resolve the thrombus. This is the first case in which argatroban successfully treated massive thrombus during percutaneous coronary intervention in a patient with HITTS.     

Argatroban therapy in heparin-induced thrombocytopenia with hepatic dysfunction

STUDY OBJECTIVES: We evaluated the dosing requirements in argatroban-treated patients with heparin-induced thrombocytopenia (HIT) and hepatic dysfunction, and compared efficacy and safety outcomes with historical control patients. DESIGN: Retrospective analysis. SETTING: Inpatient setting. PATIENTS: Patients with hepatic dysfunction, defined as total bilirubin > 25.5 micromol/L (1.5 mg/dL), aspartate aminotransferase >100 IU/L, and/or alanine aminotransferase >100 IU/L, were identified from previous multicenter, historical-controlled studies of argatroban therapy in HIT. INTERVENTIONS: Argatroban, adjusted to maintain activated partial thromboplastin times (aPTTs) 1.5 to 3 times baseline in the experimental group, vs no direct thrombin inhibition in the historical control patients. MEASUREMENTS AND RESULTS: The analysis population included 82 argatroban patients and 34 historical control patients with hepatic impairment, of whom approximately 50% in each group had renal dysfunction (defined as a serum creatinine level > 1.3 mg/dL). The argatroban dosage was 1.6 +/- 1.1 microg/kg/min (mean +/- SD) over a mean 5-day course of therapy. Significantly lower doses were used in patients with elevated vs normal total bilirubin levels (0.8 +/- 0.6 microg/kg/min vs 1.7 +/- 0.8 microg/kg/min, p = 0.0063) and in patients with hepatic/renal dysfunction vs hepatic dysfunction alone (1.2 +/- 1.1 microg/kg/min vs 2.0 +/- 1.1 microg/kg/min, p < 0.001). The aPTT 24 h after argatroban initiation was 69 +/- 22 s, with 80% of patients having a therapeutic level of anticoagulation. Thirty-four argatroban-treated patients (41.5%) and 17 control patients (50.0%) experienced the 37-day composite end point of death, amputation, or new thrombosis (p = 0.32). Argatroban significantly reduced new thrombosis (8.5% vs 26.5%, p = 0.012). Major bleeding was similar between treatment groups (4.9% vs 2.9%, p = 0.684). CONCLUSIONS: Hepatic dysfunction affects argatroban dosing, with reduced doses required particularly in patients with serum total bilirubin levels > 25.5 micromol/L (1.5 mg/dL) or combined hepatic/renal dysfunction. Individual mean aPTT-adjusted doses typically remain > or = 0.5 microg/kg/min, supporting the recommendation of 0.5 microg/kg/min as a conservative initial dose for most patients with hepatic impairment. Argatroban, with proper initial dosing and monitoring, can provide safe and effective antithrombotic therapy in patients with HIT and hepatic impairment.     

Vascular surgery using argatroban in a patient with a history of heparin-induced thrombocytopenia.

For patients with a history of heparin-induced thrombocytopenia (HIT) who undergo cardiac or vascular surgery, the optimal anticoagulation substitute for heparin has yet to be established. Recombinant hirudin has been recommended; however, this agent is unsuitable for patients with renal dysfunction. Argatroban was used in the present patient who had a history of HIT and renal dysfunction and required peripheral vascular surgery. Argatroban was easy to monitor and control, regardless of renal function, and has advantages over other anticoagulants for such patients.     

Predictors of clinical outcome in patients with heparin-induced thrombocytopenia treated with direct thrombin inhibition

We aimed to identify predictors of poor outcome in patients with heparin-induced thrombocytopenia, a serious immune-mediated reaction to heparin. All patients were treated with direct thrombin inhibition therapy, as part of two prospective studies. We performed a risk factor analysis of adverse outcomes (defined as death, amputation, new thrombosis, or their composite within a 37-day study period) in 809 patients from two reported prospective studies of the direct thrombin inhibitor argatroban in clinically diagnosed heparin-induced thrombocytopenia. We initially identified from among 14 baseline variables the significant predictors of poor outcome in the first study (304 patients), and then tested our resultant hypothesis in the second, independent study (505 patients), using multivariate analysis. Seven significant predictors were identified in the first study; three were confirmed in the second study. The strongest relationship occurred between the baseline platelet count and the composite of death, amputation, or new thrombosis (P = 0.0001), with the most severely thrombocytopenic patients being at greatest risk. The other significant associations were between renal impairment and death (odds ratio = 2.13, 95% confidence interval = 1.23-3.66, P = 0.007), and between cardiovascular surgery (particularly peripheral vascular surgery) and amputation (odds ratio = 3.39, 95% confidence interval = 1.65-6.95, P = 0.0009). In conclusion, in patients with clinically diagnosed heparin-induced thrombocytopenia, the severity of the baseline thrombocytopenia is the best predictor of death, amputation or thrombotic progression. The identification of higher risk subgroups for poor outcomes, such as patients with more severe thrombocytopenia or a history of renal impairment or peripheral vascular surgery, could allow more targeted therapy.     

Dermatan sulphate in patients with heparin-induced thrombocytopenia

Patients with thromboembolic diseases who develop heparin-induced thrombocytopenia (HIT) type II require an alternative anticoagulation strategy. Dermatan sulphate (DS) was administered to five patients with thromboembolic diseases who developed HIT type II and showed an in vitro cross-reactivity with low molecular weight heparins. The platelet count and the extension of thrombosis were monitored during DS administration. In four of the five patients the platelet count rapidly increased after heparin was discontinued and DS started. A low platelet count persisted in the single patient with cross-reactivity to DS, up to 4 d after its discontinuation. None of the patients experienced thrombus extension, haemorrhagic side-effects or other adverse events.     

Argatroban anticoagulation in patients with heparin-induced thrombocytopenia

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is an intensely prothrombotic syndrome managed by discontinuation of heparin therapy and substitution of an alternative inhibitor of thrombin. We describe our experience with argatroban, a direct thrombin inhibitor, in patients with HIT or HIT with thrombosis (HITTS). METHODS: In this multicenter, nonrandomized prospective study, 418 patients with HIT were administered intravenous argatroban, 2 micro g/kg per minute, adjusted to maintain the activated partial thromboplastin time at 1.5 to 3 times the baseline value for a mean of 5 to 7 days. Comparisons were made with a historical control cohort (n = 185). The prospectively defined, primary efficacy end point was a composite of all-cause death, all-cause amputation, or new thrombosis in 37 days. Other end points included the components of the composite, death due to thrombosis, increased platelet count, and bleeding. RESULTS: In the HIT arm, the composite end point was significantly reduced in argatroban-treated patients vs controls (28.0% vs 38.8%; P =.04). In the HITTS arm, the composite end point occurred in 41.5% of argatroban-treated patients vs 56.5% of controls (P =.07). By time-to-event analysis of the composite end point, argatroban therapy was significantly better than historical control therapy in HIT (P =.02) and HITTS (P =.008). Argatroban therapy also significantly reduced new thrombosis in HIT and HITTS and death due to thrombosis in HITTS. There were no significant between-group differences in all-cause death or amputation. Platelet counts recovered more rapidly in argatroban-treated patients than in controls. Bleeding rates were similar between groups. CONCLUSION: Argatroban therapy, compared with historical control, improves outcomes, particularly new thrombosis and death due to thrombosis, in patients with heparin-induced thrombocytopenia.     

Further characterization of antibody and antigen in heparin-induced thrombocytopenia

Patients with immune heparin-induced thrombocytopenia (HIT) possess antibodies that bind to a complex of platelet factor 4 (PF4) and heparin. We observed that HIT antibodies will also bind to PF4 alone adsorbed on polystyrene ELISA wells but not to soluble PF4 in the absence of heparin. Having developed a technique to affinity-purify anti-PF4-heparin HIT IgG, we are able to provide the first estimates of the avidity of HIT IgG. HIT IgG displayed relatively high functional affinity for both PF4-heparin (Kd = 7-30 nM) and polystyrene adsorbed PF4 alone (Kd = 20-70 nM). Furthermore, agarose beads coated with PF4 alone were almost as effective as beads coated with PF4 plus heparin in depleting HIT plasmas of anti-PF4-heparin antibodies. We conclude that the HIT antibodies which bind to polystyrene adsorbed PF4 without heparin are largely the same IgG molecules that bind PF4-heparin and therefore most HIT antibodies bind epitope(s) on PF4 and not epitope(s) formed by part of a PF4 molecule and part of a heparin molecule. Binding of PF4 to heparin (optimal) or polystyrene/agarose (suboptimal) promotes recognition of this epitope.     

Evaluation of dose requirements for prolonged bivalirudin administration in patients with renal insufficiency and suspected heparin-induced thrombocytopenia

Bivalirudin, a direct thrombin inhibitor, is indicated for patients with suspected heparin-induced thrombocytopenia (HIT) with anticipated percutaneous coronary intervention (PCI). Data is limited on dose selection among patients with renal insufficiency, particularly with prolonged infusion durations. The study cohort comprised 73 patients with renal dysfunction who received bivalirudin for suspected HIT with or without acute coronary syndrome. We reviewed individual pharmacy and medical records for laboratory and bivalirudin dosing information, medical comorbidities, and adverse clinical outcomes during administration. When estimated glomerular filtration rate (eGFR) was calculated by the Cockcroft–Gault (CG; ml/min) formula, the average bivalirudin dose (mg/kg/h) achieving a therapeutic activated partial thromboplastin time (aPTT) was 0.07 ± 0.04, 0.15 ± 0.08, and 0.16 ± 0.07 for patients with eGFR between 15–30, 31–60, and >60, respectively. When eGFR was calculated by the modification of diet in renal disease (MDRD; ml/min/1.73 m²) formula, the average bivalirudin dose achieving a therapeutic aPTT was 0.07 ± 0.04, 0.12 ± 0.07, and 0.20 ± 0.07 for patients with eGFR between 15–30, 31–60, >60, respectively. The difference between the dose achieving a therapeutic aPTT for patients with eGFR >60 when calculated by MDRD versus CG was completely abolished when obese patients were excluded from the CG cohort. The results of our series of patients with renal dysfunction receiving prolonged duration of bivalirudin in the setting of acute coronary syndrome (ACS) suggests that dose adjustment is safe and should be considered for patients with moderate to severe renal impairment (eGFR < 60 ml/min/1.73 m²).     

Danaparoid for cardiopulmonary bypass in patients with previous heparin-induced thrombocytopenia

Anticoagulation for cardiopulmonary bypass in patients with heparin-induced thrombocytopenia requires the use of other anticoagulants. We report a case in whom this was achieved using the heparinoid danaparoid (Orgaran). Based on our experience and a review of the literature, we provide guidelines for managing these rare patients. A danaparoid dose substantially lower than that recommended by the manufacturer may minimize bleeding complications.     

Percutaneous interventions in patients with immune-mediated heparin-induced thrombocytopenia

The use of unfractionated heparin, the traditional antithrombotic agent during percutaneous coronary interventions (PCI), is associated with the risk of heparin-induced thrombocytopenia, a rare but often fatal clinical condition. This article focuses on several issues related to heparin-induced immune-mediated thrombocytopenia (HIT, type II) and alternative modes of periprocedural anticoagulation in patients with suspected or known HIT. The hypercoagulable state characterizing HIT, along with mechanical plaque disruption resulting from PCI place patients with HIT at particular risk of thrombosis during PCI. Given that a diagnosis of HIT precludes any further use of heparin, other treatment modalities are essential. Direct thrombin inhibitors are the drugs of choice in this challenging situation. These agents offer several advantages as anticoagulants for patients with HIT: (1) the ability to inhibit both thrombin that is bound to fibrin (clot-bound thrombin) and fluid-phase free thrombin; (2) rapid achievement of steady state; and (3) no cross-reactivity with HIT antibodies. Recent data on the use of bivalirudin, lepirudin, and argatroban in the setting of PCI in patients with HIT are encouraging. Optimal dosing regimens for argatroban, lepirudin, and bivalirudin should be further established in PCI patients.