Hesham S Al-Sallami (1), John Schollum (2), Michael Barras (3), Stephen B Duffull (1)
1) OPG, School of Pharmacy, University of Otago, New Zealand, (2) Dunedin School of Medicine, Dunedin, New Zealand, (3) Royal Brisbane & Women's Hospital, Brisbane, Australia
Objectives: Enoxaparin is a widely used anticoagulant in the treatment of thrombosis. Due to its narrow therapeutic window, monitoring of enoxaparin therapy is warranted in the clinical setting especially for patients who are at the extrema of body weight or have renal impairment.[1] A pilot study showed that clinicians do not find current dosing guidelines credible for patients at the cut-points of dose banding based on body weight (> 90 kg) or renal function (CLcr < 30 mL/min).[2] It has been proposed that model-based [3,4] dose-individualisation may result in improved attainment of the treatment target and subsequently better patient outcomes. Bayesian forecasting dosing methods employ the use of a dose-response model and a Bayesian maximum a posteriori (MAP) function in conjunction with patient response in order to estimate individual model parameters. A dosing tool (TCIWorks) was evaluated previously and found to have a higher probability in achieving target anti-Xa when compared to standard dosing.[5] Thus, based on predefined acceptable exposure levels, the dose for each patient can be optimised accordingly. Previously, an enoxaparin concentration target was identified as a peak (approx. 5 hours post-dose) anti-Xa concentration of > 500 IU/L and a trough (approx. 11 hours post-dose) anti-Xa concentration of < 500 IU/L. [1]
The objectives of this study was to compare individualised enoxaparin dosing against standard dosing in a prospective clinical feasibility trial.
Methods: Adult patients admitted to Dunedin Hospital, New Zealand, who were likely to receive treatment doses of enoxaparin for at least 48 hours were studied in a randomised, double-blind, parallel group clinical feasibility study. Patients were randomly assigned to either a TCIWorks-guided individualised dosing regimen or a standard treatment. The amount of the first dose was at the discretion of the prescribing doctor and followed standard enoxaparin dosing protocols. Subsequent doses were calculated using TCIWorks to achieve a peak anti-Xa concentration of > 500 IU/L and a trough anti-Xa concentration of < 500 IU/L. The adjusted dose was communicated blindly to a medical collaborator who possessed a stratified randomisation sequence and implemented dose changes. Patients in the control group received the same dose as prescribed whereas patients in the individualised group received an adjusted dose.
The two treatment groups were compared in terms of the incidence of bleeding or bruising events. Patients were followed up for 30 days following discharge from hospital for evidence of revascularisation or re-thrombosis.
Results: Twenty-two patients were recruited, 10 in the standard group and 12 in the individualised group. There were no differences in the demographic and medical information between the two groups. The median duration of enoxaparin treatment while in hospital was 3.7 days.
A total of eight patients (38%), 3 in the standard group and 5 in the individualised group, did not achieve the anti-Xa target after the first dose and an adjusted dose was estimated using TCIWorks. Doses were adjusted in all five patients in the individualised group. Three of these patients required two or more dose adjustments in order to reach target anti-Xa concentration.
A total of four safety events, all minor bleeding or bruising, occurred during enoxaparin treatment. Three events occurred in the standard dosing group and one event occurred in the individualised group. Both bruising events occurred in patients whose dose was recommended to be reduced to meet anti-Xa treatment target. There were no recurrent thromboembolic events in either arm during follow-up.
The trial was found to be feasible logistically and the time between the first and subsequent doses was adequate to measure anti-Xa concentration and calculate subsequent doses. However, acute coronary syndrome patients, who make up the bulk of enoxaparin treatment users in the acute setting, were often found to be not suitable for recruitment as enoxaparin treatment in this patient group is often short and is ceased once surgical revascularisation is achieved.
Conclusion: In this feasibility study, standard dosing of enoxaparin which is based on body weight and creatinine clearance was compared to individualised dosing where the patient’s response in addition to their covariates were used to inform dose selection. Suboptimal anti-Xa concentration was noted in 38% of patients following standard dosing. An adequately powered clinical trial is required in order to make statistically significant inferences.
References:
[1] Al-Sallami HS, et al. CPK 2010; 49(9):567-71
[2] Al-Sallami HS, et al. NZMJ 2010; 123(1313):62-7
[3] Green B, et al. BJCP 2003; 56(1):96-103
[4] Green B, et al BJCP 2005; 59(3):281-90
[5] Al-Sallami HS, et al. PAGE 2013 [http://www.page-meeting.org/?abstract=2063]
Reference: PAGE 28 (2019) Abstr 9011 [www.page-meeting.org/?abstract=9011]
Poster: Clinical Applications