Critical appraisal of evidence for anti-Xa monitoring and dosing of low-molecular-weight heparin in renal insufficiency

Abstract

Introduction: Several guidelines advise to monitor therapeutic LMWH therapy with peak anti-Xa concentrations in renal insufficiency with subsequent dose adjustments. A better understanding of the clinical association between peak anti-Xa concentrations and clinical outcomes is mandatory, because misunderstanding this association could lead to erroneous, and potentially even harmful, LMWH dose adjustments Areas covered: We reviewed the evidence of the widely applied therapeutic window for anti-Xa peak concentrations and report on the evidence for pharmacokinetic dose reduction in renal insufficiency, limitations of peak and trough anti-Xa concentration monitoring. Expert opinion: The added value of peak anti-Xa monitoring in patients with renal insufficiency, receiving a dose reduced for pharmacokinetic changes, is not supported by data. Enoxaparin and nadroparin should be adjusted to 50-65% and 75-85% of the original dose for patients with a creatinine clearance (CrCL) of <30 ml/min and 30-60 ml/min, respectively. Tinzaparin should be adjusted to around 50% of the original dose for patients with a CrCL of <30 ml/min. In case anti-Xa monitoring is applied, trough concentration anti-Xa monitoring is preferred over peak monitoring, aiming at a maximum concentration of 0.4 IU/mL for once-daily dosed tinzaparin and 0.5 IU/mL for twice-daily dosed enoxaparin and nadroparin.

The effect of renal impairment and obesity on anti-Xa peak and trough levels in patients receiving therapeutic doses of nadroparin: a comparison with control patients

“…Correspondingly, the pop PK analysis demonstrated anti-Xa peak levels below 0.6 IU/mL for simulated control patients with normal nadroparin dosages. Although this therapeutic range is used in daily care, previous publications confirm our findings of less than 50% of patients with neither renal impairment nor obesity achieving peak levels within this range [ 8 , 12 , 20 – 24 ]. Similar results were found in a more recent study of Hornung et al in patients with renal impairment [ 25 ], in which 38% of anti-Xa peak levels were below this range.…”

“…Based on these observations, routinely anti-Xa monitoring would be unnecessary in patients with renal impairment after adequate correction for pharmacokinetic differences [ 8 ]. Aiming in these patients at peak levels of 0.6–1.0 IU/mL would result in overexposure compared to patients without renal insufficiency.…”

“…However, for specific patient populations, such as patients with renal impairment or obesity, LMWH-dose adjustments and/or anti-Xa peak level monitoring is recommended in guidelines [ 5 – 7 ]. Since an analytical laboratory method for LMWH concentrations in blood is unavailable, anti-Xa levels are used as proxy for LMWH exposure [ 8 ].…”

“…To date, there is only limited evidence for anti-Xa peak level monitoring, since a clear correlation with bleeding risk or antithrombotic efficacy in these patient populations is lacking [ 8 ]. Also from a pharmacokinetic point of view, monitoring peak levels as a proxy for drug accumulation of a solely renally excreted drug in patients with renal impairment seems to be less sensitive than monitoring trough levels [ 8 , 14 ].…”

Is the current therapeutic dosage of nadroparin adequate for neonates and infants under 8 months with thromboembolic disease? a population pharmacokinetic study from a national children’s medical center

“…P Mismetti et al investigated whether renal function influences the pharmacokinetic pattern and observed that anti-Xa clearance of nadroparin in elderly healthy patients (creatinine clearance: 62 ± 6 mL/min) was 1.4 times lower than in young healthy patients (creatinine clearance: 114 ± 15 mL/min) ( Mismetti et al, 1998 ). An expert review suggested adjusting nadroparin to 50%–65% and 75%–85% of the original dose for patients with a creatinine clearance of <30 mL/min and 30–60 mL/min, respectively ( Broek et al, 2022 ). In a review article by Nagge et al, it was concluded that renal insufficiency affects the clearance of each LMWH differently.…”