Argatroban in the management of heparin-induced thrombocytopenia: a multicenter clinical trial

Abstract

IntroductionThe aim of this study was to collect data in France in patients with heparin-induced thrombocytopenia who required parenteral anticoagulation and for whom other non-heparin anticoagulant therapies were contraindicated including patients with renal failure, cross-reactivity to danaparoid or at high hemorrhagic risk.MethodsA total of 20 patients, of mean age 72 ± 10 years, were enrolled in this open-label, multicenter clinical study. Exploratory statistical data analysis was performed with descriptive interpretation of intra-individual comparisons using simple univariate statistics.ResultsThe diagnosis of HIT was confirmed in 16 subjects by an independent scientific committee. Fourteen patients (70 %) were in an intensive care unit during the course of the study. Patients were treated with argatroban for a mean duration of 8.5 ± 6.1 days. The mean starting dose of argatroban was 0.77 ± 0.45 μg/kg/min. Platelet recovery was rapid.aPTT and anti-IIa activity assays were used to monitor the dose of argatroban. The mean baseline aPTT value was 45.0 ± 9.8 sec and increased to 78.2 ± 35.8 sec two hours after initiating argatroban. At this time mean argatroban concentration was 0.34 ± 0.16 and 0.61 ± 0.28 μg/ml using ECT and TT measurements, respectively. New and/or extended thromboses were reported in 25 % of patients and major bleedings were documented in 15 %. Six patients died due to their underlying medical condition.ConclusionConsidering its hepatic elimination and its short half-life, argatroban can be considered as a safe therapeutic option in HIT patients at high hemorrhagic risk and with renal failure, particularly in an ICU setting.

Further evidence of the limitations of Activated Partial Thromboplastin Time to monitor Argatroban

“…One patient with normal baseline APTT had argatroban 0·40 μg/ml and SynFAx APTT 107·0 s/ratio 4·3. There is no consensus on the therapeutic range of argatroban but the most recent therapeutic range cited is 0·25–1·5 μg/ml (Tardy‐Poncet et al , ), which echoes other cited ranges (Guy et al , ). At a different time point during treatment the same patient had an argatroban 0·17 μg/ml; Pathromtin SL APTT 102·4 s/ratio 3·3; SynFAx 89·9 s/ratio 3·6.…”

“…(A) Only Syn FA x, APTT ‐ SP and Pathromtin SL produce ratios >3·0 whereas all the reagents produce ratios <1·5. Fifteen argatroban levels (black circles) were sub‐therapeutic [0·25–1·5 μg/ml (Tardy‐Poncet et al , )] but had therapeutic activated partial thromboplastin time ( APTT ) ratios (>1·5). Of the 15 samples, 13 were therapeutic with Syn FA x and Pathromtin SL n = 13, 12 with APTT ‐ SP , 10 with Actin FS , 8 with Synth AS il and 1 with Actin FSL n = 1.…”

“…Smythe et al () described a patient with antiphospholipid syndrome with a baseline Actin FSL APTT 69 s. The patient was monitored by a chromogenic anti‐IIa assay (therapeutic range cited as: 0·4–1·2 μg/ml) showing anti‐IIa levels/APTT: 0·2 μg/ml/102 s; 0·7 μg/ml/116 s; 0·9 μg/ml/>124 s; 2·2 μg/ml/>124 s. Tardy‐Poncet et al () reported data on 20 clinical trial patients with a mean baseline APTT 44·8 ± 9·8 s (PTT automate) and a mean APTT post‐infusion of 73·8 ± 20·7 (ratio 1·6). At a therapeutic ratio of 2·3 times baseline the APTT would exceed 100 s. The mean HTI argatroban concentration for these patients was 0·61 ± 0·28 μg/ml, which is well within their own cited range of 0·25–1·5 μg/ml (derived from control plasma spiked with argatroban) and other previously cited ranges (Guy et al , ).…”

Argatroban is stable in citrated whole blood for 24 hours

“…In addition to monitoring through APTT, it is possible to quantify the plasma argatroban concentration by various methods: Ecarin chromogenic Assay (ECA), HPLC, in‐house anti‐iia methods, dilute thrombin time methods (in‐house or HTI method), and ecarin clotting time (ECT). Tardy‐Poncet et al defined the argatroban plasma therapeutic range as 0.25‐1.5 μg/mL as this corresponded to the APTT range of 1.5‐3.0 times the baseline in their multicentre argatroban HIT trial; we have previously published that anything below 0.2 μg/mL is likely to be subtherapeutic …”

“…Fifteen samples showed a change of greater than 10%. The reality is that the small absolute differences at the lower end of therapeutic range give rise to a larger percentage change for example the largest percentage change is 33% in a sample that went from 0.18 μg/mL (subtherapeutic) to 0.24 μg/mL also below the target therapeutic range of Tardy‐Poncet et al …”