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Clinical evaluation of laboratory methods to monitor exposure of rivaroxaban at trough and peak in patients with atrial fibrillation

  • Pharmacodynamics
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Abstract

Purpose

The one-dose daily regime of rivaroxaban could cause a pronounced variability in concentration and effect of which a deeper knowledge is warranted. This study aimed to evaluate the typical exposure range and effect of the direct factor Xa (FXa)-inhibitor rivaroxaban in a cohort of well-characterized patients with atrial fibrillation (AF).

Methods

Seventy-one AF patients (72 ± 8 years, 55 % men) were treated with rivaroxaban 15 mg/20 mg (n = 10/61) OD. Trough (n = 71) and peak (n = 30) plasma concentrations determined by liquid chromatography-tandem mass-spectrometry (LC-MS/MS) were compared to the coagulation assays anti-FXa for rivaroxaban, prothrombin time-international normalized ratio (PT-INR) (venous samples and point-of-care assay (POC) CoaguChek XS Pro), and aPTT.

Results

Median rivaroxaban plasma concentrations by LC-MS/MS were 34 (range 5–84) and 233 ng/ml (range 120–375) at trough and peak, respectively. A strong correlation between LC-MS/MS and the anti-FXa assay was found (p < 0.001) for both trough (r 2 = 0.92) and peak (r 2 = 0.91) samples. PT-INR results from the POC assay, but not from the conventional PT assay, correlated significantly with LC-MS/MS in peak samples exclusively (r 2 = 0.41, p < 0.001).

Conclusions

In “real-life” AF patients treated with rivaroxaban, we observed a pronounced variability in plasma concentrations at trough and to a lesser extent at peak measured by LC-MS/MS. The anti-FXa assay performed well upon rivaroxaban levels in a normal exposure range, although LC-MS/MS remains the only method that covers the whole concentration range with accuracy. Interestingly, the POC assay for PT-INR could be useful to indicate high exposure to rivaroxaban in emergency situations although further validation is required.

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Acknowledgments

The authors are grateful toward Annika Östlund and Lisbeth Söderblom for their help with the laboratory methods, and toward Lena Gabrielsson for skilful care of the study population. This study was supported by grants from The Coagulation Research fund of Karolinska Institutet, the Foundation Sigurd, and Elsa Goljes memory; from the Stockholm County Council and its Drug and Therapeutics Committee; from the Swedish Heart-Lung Foundation; and from The Swedish Society of Medicine.

Contributions to the manuscript

FAA—patient inclusion, data analyses, literature search, and writing and reviewing the manuscript

REM—responsible for the study design. Performed data analyses and interpretation and writing and reviewing the manuscript

JA—responsible for setup and validation of the rivaroxaban anti-Xa assay and reviewing the manuscript

AP—responsible for setup and validation of LC-MS/MS assay for rivaroxaban and writing the corresponding methods section of the manuscript

YR—setup and validation of LC-MS/MS assay for rivaroxaban and writing the corresponding methods section of the manuscript

MB—setup and validation of the rivaroxaban anti-Xa assay and reviewing the manuscript

FAK—recruiting patients and reviewing the manuscript

MS—responsible for the study design, patient inclusion, and sampling. Performed data analysis and interpretation and writing and reviewing the manuscript

Author information

Authors and Affiliations

  1. Department of Medicine Solna, Karolinska Institutet & Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden

    Fadiea Al-Aieshy & Rickard E Malmström

  2. Department of Coagulation Research, Institute for Molecular Medicine and Surgery, Karolinska Institutet & Department of Clinical Chemistry, Karolinska University Hospital, Stockholm, Sweden

    Jovan Antovic & Maria Berndtsson

  3. Department of Laboratory Medicine Huddinge, Division of Clinical Pharmacology, Karolinska Institutet & Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden

    Anton Pohanka & Yuko Rönquist-Nii

  4. Department of Clinical Sciences, Cardiology Unit, Karolinska Institutet, Danderyds Hospital, Stockholm Heart Center, Stockholm, Sweden

    Faris Al-Khalili

  5. Department of Medicine Solna, Karolinska Institutet & Department of Cardiology, Danderyds Hospital, Stockholm, Sweden

    Mika Skeppholm

  6. Clinical Pharmacology, Drug Safety and Evaluation Sector, L7:03, Karolinska University Hospital Solna, -17176, Stockholm, SE, Sweden

    Fadiea Al-Aieshy

Authors
  1. Fadiea Al-Aieshy
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  2. Rickard E Malmström
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  3. Jovan Antovic
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  7. Faris Al-Khalili
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  8. Mika Skeppholm
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Corresponding author

Correspondence to Fadiea Al-Aieshy.

Ethics declarations

The study was performed in accordance with the Declaration of Helsinki and was approved by the Ethical Review Board in Stockholm, Sweden. The subjects were enrolled from the coagulation centre at Danderyd’s Hospital in the Stockholm County, during December 4, 2012, to December 19, 2014, and before participating, oral and written informed consent was attained

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Conflicts of interest

Dr. F Al-Khalili received honorarium for acting as speaker for Bayer, Boehringer Ingelheim, and Pfizer. Dr. J Antovic has received speakers’ honoraria and support for attendance at scientific meetings from Stago. None of the other authors declare any conflict of interest related to this work.

Electronic Supplementary Material

Supplementary figure 1

Correlation between individual trough and peak rivaroxaban plasma concentrations (15 and 20 mg OD, n = 30) measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). (PPTX 82 kb)

Supplementary figure 2

Correlation between rivaroxaban trough plasma concentrations measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and glomerular filtration rate estimated by the Cockcroft-Gault formula (CCG) (20 mg OD, n = 61). The regression line is added. (PPTX 70 kb)

Supplementary figure 3

Rivaroxaban trough plasma concentrations (20 mg OD, n = 61) measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in relation to CHADS2 score (0–1 and ≥2). The box plots show median, upper and lower quartile with extension to points still within 1.5 interquartile range from the quartiles, points farther away are shown as outliers. (PPTX 66 kb)

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Al-Aieshy, F., Malmström, R.E., Antovic, J. et al. Clinical evaluation of laboratory methods to monitor exposure of rivaroxaban at trough and peak in patients with atrial fibrillation. Eur J Clin Pharmacol 72, 671–679 (2016). https://doi.org/10.1007/s00228-016-2060-y

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  • DOI: https://doi.org/10.1007/s00228-016-2060-y

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