Anti-Xa trough levels for therapeutic LMWH treatment monitoring, a pilot study

Low molecular weight heparins (LMWHs) are often used in therapeutic doses for
prevention of cerebrovascular accidents in patients with atrial fibrillation or
for treatment of venous thromboembolic events. In the hospital they are often
used when oral anticoagulation is recently started or temporary discontinued
(bridging). Since both over- and under dosage may be associated with important
clinical outcomes (increased bleeding risk and ischemic event risk
respectively), adequate dosing is highly important. While both bodyweight and
renal function are known to contribute to variability in response and safety,
according to several international guidelines, monitoring of indirect
hemostatic parameters (i.e. anti-Xa concentrations) is currently advised in
special populations, such as patient with renal insufficiency or obese
patients. According to these guidelines, anti-Xa peak levels should be measured
as safety and efficacy parameter for both special population patient groups.
However, the evidence for the reported target peak values seems weak and a
clear correlation with bleeding risks or effect in these patient populations is
lacking. Also from a pharmacokinetic point of view, there seems to be no
rationale to measure the peak concentration as a proxy for drug accumulation in
patients with renal dysfunction. As such, there is to date increasing awareness
that anti-Xa trough levels should be evaluated, as it may better correlate with
bleeding risk. In this pilot study we propose to evaluate trough concentrations
in addition to peak concentrations as a potential marker for safety monitoring
of LMWH in special patient populations.

Primary objective: To evaluate anti-Xa trough levels in addition to anti-Xa
peak levels in patients with renal insufficiency or obesity.

Secondary objectives: To explore relations between patient characteristic such
as creatinin clearance, bodyweight (TBW or LBW) or age and anti-Xa peak and
trough levels.

Other objectives: to report on anti-Xa pharmacokinetics such as AUC, clearance
and halflife.

The current study is a prospective observational pilot study, including
hospitalized users of nadroparin in therapeutic doses of 86 IE/kg twice daily
according to standard of care. For each patient, an anti-Xa trough- and peak
level are collected on the third and the fifth day of therapy (steady state).
Renal function, bodyweight and body length are measured in standard care.
Patients with varying renal functions and body weights are included to gain
more insight in the influence of this parameters. Since this is a pilot study,
six patients are included for each subgroup (see table), which is an accepted
number for exploratory pharmacokinetic studies.

For this study, anti-Xa trough- and peak levels are collected through vena
puncture on the third and the fifth day of nadroparin therapy, which patients
receive as standard of care. Peak samples are considered standard of care for
patients with renal insufficiency or obesity. The trough samples will be
combined with routine blood collections if possible, otherwise will be obtained
specifically for the study. We consider two (to four) additional vena punctures
as negligible risk for participating patients.