Two High to Start? Targeting a New Starting Dose for Argatroban Infusions

Argatroban dosing is controversial and many practitioners utilize doses lower than the manufacturer-recommended starting dose (MRSD) of 2 µg/kg/min. Though several studies suggest lower doses maybe required, no study, to our knowledge, has compared reduced starting dose (RSD) argatroban versus MRSD.^1,2

Our institution has recently transitioned from MRSD to a RSD of 1 µg/kg/min in non–critically ill adults with normal hepatic function. All doses are adjusted to target an activated thromboplastin time (aPTT) of 45 to 90 seconds. We performed a retrospective, single-center study to assess the effect of RSDs on time to target aPTT versus MRSD in non–critically ill adults with normal hepatic function and known or suspected heparin-induced thrombocytopenia (HIT).

This project met criteria for institutional review board exemption. Consecutive non–critically ill adults with normal hepatic function and known or suspected HIT were identified via a medical record query from June 1, 2014, to August 31, 2018. Data were collected until at least 11 patients receiving RSD and MRSD were identified. We required at least 11 patients in each group to achieve 80% power to detect a 4-hour difference in the primary outcome, assuming a pooled standard deviation of 4 hours. Demographics, argatroban dosing information, and laboratory data were collected. Primary outcome was time to target aPTT in hours. Continuous data were compared using the Student t test or Mann-Whitney U test. Categorical data were compared using χ² or Fisher exact test. SPSS Statistics software (version 23.0; IBM Inc, Chicago, IL) was used. Comparisons were 2-tailed. A P value <.05 was considered statistically significant.

Thirty-three patients were included; 11 (11/33, 33.3%) received RSD (≤1 µg/kg/min) and 22 (22/33, 66.6%) received MRSD (2 µg/kg/min). Table 1 depicts subject demographics. Mean age, median weight, percent male gender, and median baseline aPTT values were similar between groups. Median dose (interquartile range [IQR]) to achieve target aPTT values was higher in the MRSD groups: RSD: 1.0 (0.6-1.9) µg/kg/min versus MRSD: 1.5 (0.6-1.9) µg/kg/min, P = .021. RSD had an initial aPTT <45 seconds more frequently (RSD: 41.7% vs MRSD: 4.5%, P = .014) and MRSD had an initial aPTT >90 seconds more frequently (RSD: 16.7% vs MRSD: 54.5%, P = 0.002). Median (IQR) time in hours to target aPTT was similar between groups (RSD: 3.0 [2.1-4.0] vs MRSD: 2.0 [2.0-3.0], P = .074). Median length of argatroban treatment (IQR) was similar between groups (RSD: 5 days [2-6 days] vs MRSD: 4 days [2-8.3 days], P = .925), and RSD and MRSD patients had a comparable median (IQR) number of dose adjustments (RSD: 1 [0-1] vs MSRD: 1 [0-2], P = .299). The median (IQR) percent time within the target aPTT range was also comparable within the first 5 treatment days (RSD: 86% [80% to 100%] vs MRSD: 87% [75% to 100%], P = .985).

Table 1.

Demographics and Baseline Characteristics.

Characteristics	Reduced Starting Dose (≤1 µg/kg/min), N = 11	Manufacturer-Recommended Starting Dose (2 µg/kg/min), N = 22	P
Age (years), mean (SD)	64.8 (9.2)	71.7 (10.8)	.069
Weight (kg), median (IQR)	78.9 (69.6-108.9)	78.8 (70.3-92.5)	.638
Total bilirubin (mg/dL), median (IQR)	0.5 (0.4-0.6)	0.5 (0.3-0.8)	.611
Male gender, n (%)	3 (27.2)	13 (59.1)	.085
Baseline aPTT (seconds), mean (SD)a	30.8 (5.1)	32.9 (8.1)	.372

Abbreviations: SD, standard deviation; IQR, interquartile range; aPTT, activated thromboplastin time.

^aBaseline aPTT was available in 31 patients. One patient from the reduced starting dose group and one patient from the manufacturer-recommended starting dose group did not have a baseline PTT.

RSD and MRSD produced similar median times to target aPTT and percent time within the target aPTT range in this cohort of non–critically ill adults with normal hepatic function and known or suspected HIT. Gilmore et al made a similar observation but ~75% of the non-RSD group received dosing lower than the MRSD, and the authors included patients with and without hepatic dysfunction.² Interestingly, RSD and MRSD more frequently resulted in an initial aPTT <45 seconds and >90 seconds, respectively. RSD and MRSD patients are initially at presumable increased risk for thrombosis and bleeding, respectively. The probability of HIT-related thrombosis is <2% during the first 6 argatroban days.³ Conversely, bleeding complications can occur at any time and in up to 21.9% while on argatroban.⁴ We feel the risk for bleeding outweighs the risk for thrombosis, as our time to target aPTT is generally ≤4 hours. For this reason, we will continue utilizing a RSD for argatroban in non-critically ill adults with normal hepatic function.

In conclusion, RSD and MRSD were associated with similar times to target aPTT in non–critically ill adults with normal hepatic function using argatroban for known or suspected HIT. Further research is required to identify the optimal argatroban starting dose in this population.