A rationale for the routine monitoring of anti-activated factor X (anti-Xa) during enoxaparin treatment
Hesham S Al-Sallami(1), Michael A Barras(2), Bruce Green(3), Stephen B Duffull(1)
(1) School of Pharmacy, University of Otago, Dunedin, New Zealand; (2) Therapeutic Advisory Service, Mater Heath Services, Brisbane, Australia; (3) Model Answers Ltd, Brisbane, Australia
Objectives: Enoxaparin is a low molecular weight heparin (LMWH) used in the treatment of thrombosis. Unlike unfractionated heparin (UFH), no routine monitoring of plasma activity is recommended for enoxaparin treatment. The activity of enoxaparin in plasma is determined by assaying anti-activated factor X (anti-Xa). The aim of this study is (1) To identify an anti-Xa treatment target for enoxaparin. (2) To determine whether routine monitoring of anti-Xa concentrations in patients receiving enoxaparin treatment is warranted.
Methods: From a cohort study (Motalescot, 2004) and through a meta-analysis of a randomised controlled trial (Barras, 2008), a target peak and trough anti-Xa concentration was obtained. Based on this target, and using a two-compartment PK model for enoxaparin, 10000 virtual patients were simulated with a dosing regimen of 1 mg/kg total body weight twice daily. Patients with creatinine clearance < 30 mL/min were excluded. Activated partial thromboplastin times (aPTTs) were also simulated for UFH when it was given as a constant infusion at 1500 units/hour assuming a Michaelis-Menton PK model with an empirical PD model linking concentration to aPTT.
Results: The target anti-Xa concentration of enoxaparin for effectiveness and safety was 5 mg/L. Twice daily dosing regimens that achieve this target have peak concentrations that exceed 5 mg/L and trough concentrations that fall below 5 mg/L. Based on this target, 46% of patients had peak or trough concentrations outside the proposed target. This figure was comparable to the UFH heparin model where 52% of patients had an aPTT outside the target range (1.5-2.5 x initial aPTT).
Conclusions: Based on the current dosing practice for enoxaparin only 54% of patients are dosed optimally. This success rate is as poor as with UFH. Given that monitoring PD endpoints is strongly recommended with UFH, it follows that the same approach should also apply for enoxaparin and probably should be generalised to all LMWHs.
References:
[1] Montalescot et al (2004) Circulation, 110, 392-398
[2] Barras et al (2008) CPT, 83, 882-888
