Argatroban monitoring: aPTT versus chromogenic assay
Authors: Ngochong Vu, Emily Jaynes, Carol Chan, Mike Dorsch, Steven Pipe, Cesar Alaniz
Journal: American Journal of Hematology (2016)

To the Editor: Argatroban is one of several intravenous direct thrombin inhibitors that are commonly used in the treatment of heparin-induced thrombocytopenia. Currently, the activated partial thromboplastin time (aPTT) is recommended for monitoring argatroban infusions 1. Therapeutic anticoagulation is defined as an aPTT level between 1.5 and 3 times the patients' baseline aPTT 2. Limitations of aPTT monitoring include prolonged aPTT secondary to coagulation factor deficiencies or blunting of aPTT levels in patients with supra-normal levels of coagulation factors 2, 3. Use of a chromogenic assay (indirectly determined anti-IIa level) for monitoring argatroban therapy may minimize inherent limitations of aPTT monitoring. Herein, we describe argatroban dosing requirements using anti-IIa monitoring compared to conventional aPTT monitoring. This was a single-center, retrospective study of adult patients initiated on an argatroban infusion for one year before, and after the conversion of argatroban monitoring from aPTT to anti-IIa levels. Therapeutic aPTT was 50–80 sec. Anti-IIa levels were determined using a chromogenic assay developed internally (reportable range 0–4 mcg/mL). The anti-IIa level therapeutic range was defined as 0.4–1.2 mcg/mL. A total of 147 patients were screened for inclusion, four of whom were excluded (one pediatric patient, two patients who did not have appropriate aPTT or argatroban levels drawn, and one patient had missing information on argatroban infusion). Sixty-eight patients were in the aPTT cohort and 75 patients were in the anti-IIa level cohort. There were fewer ICU patients in the aPTT cohort compared to the anti-IIa level cohort, 36 vs. 22 patients respectively (P = 0.06). Eight patients in the aPTT cohort had hepatic impairment compared to three in the argatroban cohort but this was not statistically significant (P = 0.116). Other patient characteristics were similar at baseline (Table 1). The median initial argatroban infusion for both cohorts was 2 mcg/kg/min (IQR, 0.53–2.00 and 0.50–2.00 for aPTT and anti-IIa respectively; P = 0.21). The mean duration of argatroban therapy for aPTT and anti-IIa cohorts was 5.6 ± 5.8 and 6.6 ± 6.6 days, respectively (P = 0.36). The mean number of labs per day for patients in the aPTT and argatroban group was 1.9 ± 1.5 and 1.7 ± 1.2 draws, respectively (P = 0.08). Patients monitored by aPTT required a higher dose of argatroban compared to patients monitored by anti-IIa levels, median 2.0 mcg/kg/min (0.65–2.69) vs. 0.65 mcg/kg/min (0.38–1.20) P < 0.001, respectively. The time to therapeutic anticoagulation was similar in both cohorts (aPTT, 20.58 ± 25.07 hr vs. anti-IIa level 15.04 ± 13.67 hr, P = 0.09). A total of 698 aPTTs were drawn in the aPTT cohort, of which 314 (45%) were within the therapeutic range. Conversely, 888 anti-IIa levels were drawn in the anti-IIa level cohort with 538 levels (60.5%) within therapeutic range (P <0.001). The mean aPTT and anti-IIa level were 55.36 ± 17.83 sec and 0.99 ±2.33 mcg/mL in their respective cohorts. Within the aPTT cohort there were 65 aPTT measurements with simultaneous anti-IIa levels in 21 patients. Twenty of the 65 aPTTs (31%) had an anti-IIa level that had a congruent interpretation (2 subtherapeutic, 17 therapeutic, and 1 supra-therapeutic). Eleven (17%) subtherapeutic aPTTs were therapeutic by anti-IIa levels. Further, 19 (29%) supra-therapeutic anti-IIa levels were either sub-therapeutic (7.7%) or therapeutic (22%) by aPTT measurements. Argatroban doses were not significantly different between non-critically ill and critically ill patients in the aPTT group (mean 2.04 ± 1.22 mcg/kg/min vs.1.59 ± 1.55 mcg/kg/min, P = 0.20) nor in the anti-IIa level group (mean 0.95 ± 0.62 mcg/kg/min vs. 0.78 ± 0.73 mcg/kg/min, P = 0.27). When comparing dosing requirements in ICU patients alone, the anti-IIa group had a significantly lower argatroban dose than the aPTT group (0.78 ± 0.73 mcg/kg/min vs. 1.59 ± 1.55 mcg/kg/min, P = 0.008, CI 0.21–1.41). There were five patients who had a new thrombotic event after argatroban initiation, three of which occurred in the aPTT cohort. The incidence of bleeding did not differ between the two groups (eight in aPTT vs. five in argatroban, P = 0.39). Our study shows that monitoring argatroban via anti-IIa levels significantly reduces argatroban dosing requirements without an increased incidence in thrombotic events. The use of anti-IIa level monitoring provides a more direct measure of anticoagulation compared to aPTT monitoring which is subject to wide variability. Limitations of this study include the retrospective review of the argatroban use rather than prospective data collection and analysis. This study was completed using two cohorts during two separate time frames. When considering safety and efficacy, monitoring anti-IIa levels was not found to be significantly different in the incidence of bleeding events or new thrombosis after argatroban initiation. Two of the eight bleeding events occurred in patients receiving higher than typical median infusion rates (3 and 5 mcg/kg/min). Use of anti-IIa monitoring with associated lower dosing requirements would be expected to decrease overall risk of bleeding. This study, however, was limited by sample size established by the set timeframe and was not adequately powered to detect a difference in bleeding or thrombosis. To our knowledge, this is the first study that compared aPTT to a chromogenic assay for monitoring argatroban. Use of an anti-IIa level monitoring decreased the amount of argatroban used for therapeutic anticoagulation while showing similar incidence of thrombosis and bleeding events. The cost per patient in the two cohorts varied considerably. The average cost per laboratory draw increased from $1 per aPTT draw to $10 per anti-IIa level draw. Assuming an average weight patient, the estimated cost of argatroban in patients in the aPTT cohort was estimated to be $7628 US dollars compared to $2766 US dollars in patients monitored with anti-IIa levels 4. In summary, the use anti-IIa level monitoring of argatroban, when compared to aPTT monitoring, led to a significant decrease in dosing requirements, with similar incidences of new thrombosis and bleeding. Ngoc Hong Vu,1 Emily Jaynes,1 Carol Chan,1 Mike Dorsch,1 Steven Pipe,2 and Cesar Alaniz1* 1Department of Pharmacy, University of Michigan Hospital and Health Centers, Ann Arbor, Michigan 2Pediatric Hematology–Oncology Division, Department of Pediatric and Communicable Disease, University of Michigan Hospital and Health Centers, Ann Arbor, Michigan