Monitoring of the oral anticoagulants apixaban and rivaroxaban to optimize individual safety and efficacy

The oral anticoagulants apixaban and rivaroxaban are administered at fixed doses without requiring routine monitoring. However, there is a dose and exposure dependency in efficacy and safety, and monitoring the anticoagulants may improve treatment outcomes. The aim of this thesis was to evaluate different laboratory methods for monitoring apixaban and rivaroxaban and to show the typical exposure levels in patients. Additionally, the study aimed to study the exposure in certain specific populations (i.e. those with obesity and renal impairment), to elucidate whether monitoring would be especially valuable for these patients.

In studies I and II, we evaluated various coagulation assays for the monitoring of apixaban and rivaroxaban. While PT-INR (venous) and aPTT were not sensitive enough to be used for this purpose, the anti-Factor Xa assay showed a strong correlation with LC/MS-MS. However, for precise estimations of apixaban/rivaroxaban concentrations in the lower range, LC-MS/MS is the preferred method to use. A large interindividual variability in trough concentrations was observed, 12-fold for apixaban (6-fold within the same dosage group) and 17-fold for rivaroxaban (17-fold for the standard dose and 3- fold for the reduced dose).

In study III, we explored the influence of obesity on apixaban trough and peak concentrations. A specific dose recommendation for obese patients may not be necessary given that the concentrations were largely similar to those in matched normal weight patients. However, obese patients exhibited an extensive 18-fold interindividual variability in trough concentrations. Consequently, monitoring apixaban concentrations could be valuable for specific obese patients to ensure optimal treatment outcomes

In study IV, we examined the impact of renal function on apixaban exposure in AF patients. Patients with moderate renal impairment had twice as high apixaban trough concentrations compared to patients with normal renal function. This indicates that the recommended 5 mg twice daily dose might be excessive for some patients with moderate renal impairment, and that monitoring ought to be recommended.

List of scientific papers

I. Skeppholm M, Al-Aieshy F, Berndtsson M, Al-Khalili F, Rönquist-Nii Y, Söderblom L, Östlund AY, Pohanka A, Antovic J, Malmström RE. Clinical evaluation of laboratory methods to monitor apixaban treatment in patients with atrial fibrillation. Thrombosis Research. 2015;136(1):148-53.
https://doi.org/10.1016/j.thromres.2015.04.030

II. Al-Aieshy F, Malmström RE, Antovic J, Pohanka A, Rönquist-Nii Y, Berndtsson M, Al-Khalili F, Skeppholm M. Clinical evaluation of laboratory methods to monitor exposure of rivaroxaban at trough and peak in patients with atrial fibrillation. European Journal of Clinical Pharmacology. 2016;72(6):671-9.
https://doi.org/10.1007/s00228-016-2060-y

III. Al-Aieshy F, Skeppholm M, Fyrestam J, Johansson F, Pohanka A, Malmström RE. Apixaban plasma concentrations in obese and normal weight patients. [Manuscript]

IV. Al-Aieshy F, Skeppholm M, Fyrestam J, Johansson F, Pohanka A, Malmström RE. Apixaban trough concentrations in atrial fibrillation patients with reduced renal function. [Manuscript]