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Apixaban Levels in Octogenarian Patients with Non-valvular Atrial Fibrillation

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Abstract

Background

There is a paucity of data on apixaban levels among octogenarians with non-valvular atrial fibrillation (NVAF). We aimed to compare apixaban levels between octogenarians (with and without dose reduction) and younger patients, to assess the frequency of high and above-range drug levels.

Methods

A cross-sectional, prospective study of 80 patients treated with apixaban for NVAF was conducted. Apixaban levels were compared among octogenarians treated with 5 mg twice daily (bid), octogenarians with appropriately reduced dose (2.5 mg bid), octogenarians with inappropriately reduced dose and younger patients (age < 70 years). Trough and peak levels were measured by a chromogenic assay calibrated for apixaban and compared to predicted manufacturer levels.

Results

A significant proportion of the cohort had above-range trough [n = 11 (13.8%)] and peak [n = 16 (20%)] levels, especially octogenarians with the 5-mg bid dosage [n = 6 (30%) for trough and n = 8 (40%) for peak]. No significant differences were found in the trough or peak geometric mean (GM) levels among the groups, apart from the peak GM levels between the 5-mg octogenarian group and the other two 2.5-mg bid octogenarian groups (p = 0.0004). The frequency of apixaban peak levels within the upper quartile was significantly higher in the 5-mg octogenarian group compared to the other groups [n = 12 (60%) of measurements, p = 0.019), whereas trough levels were comparable between groups.

Conclusion

High and above-range peak apixaban steady-state levels are highly prevalent in octogenarians receiving the appropriate dosage of 5 mg bid for NVAF stroke prevention. Age above 80 strongly affects apixaban levels.

Trial Registration

ClinicalTrials.gov Identifier number NCT02623049.

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Abbreviations

ACE-I:

Angiotensin-converting enzyme inhibitor

AF:

Atrial fibrillation

AFXa:

Anti-factor Xa activity

ALT:

Alanine aminotransferase

ANCOVA:

Analysis of covariance

ANOVA:

Analysis of variance

aPTT:

Activated partial thromboplastin time

ARB:

Angiotensin receptor blocker

AST:

Aspartate aminotransferase

AUC:

Area under the curve

BMI:

Body mass index

bid:

Twice a day

CHF:

Chronic heart failure

CKD:

Chronic kidney disease

CrCl:

Creatinine clearance

CV%:

Coefficient of variation

CYP3A4:

Cytochrome P450 3A4

DOAC:

Direct oral anticoagulant

FDA:

Food and Drug Administration

GM:

Geometric mean

INR:

International normalized ratio

ISTH:

International Society on Thrombosis and Haemostasis

NVAF:

Non-valvular atrial fibrillation

OD/min:

Optical density generated per minute

P-gp:

P-glycoprotein

sCr:

Serum creatinine

SD:

Standard deviation

T max :

Time to reach maximum (peak) plasma concentration

ULN:

Upper limit of normal

Xa:

Factor Xa

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Acknowledgements

The authors would like to thank Maya Arlyuk, Irina Genin and Keren Yoskovitch for their technical support during this study.

Author information

Author notes

  1. Ran Nissan and Galia Spectre contributed equally to this work.

Authors and Affiliations

  1. Internal Medicine B, Beilinson Hospital, Rabin Medical Center, 39 Jabotinsky Street, 49100, Petah Tikva, Israel

    Ran Nissan, Hefziba Green, Shai Shimony, Lisa Cooper & Alon Grossman

  2. Pharmacy Services, Beilinson Hospital, Rabin Medical Center, 39 Jabotinsky Street, 49100, Petah Tikva, Israel

    Ran Nissan

  3. Beit Rivka Geriatric Rehabilitation Center, 4 Hachamisha St, 49245, Petah Tikva, Israel

    Ran Nissan & Avital Hershkovitz

  4. Coagulation Unit, Institute of Hematology, Beilinson Hospital, Rabin Medical Center, 39 Jabotinsky Street, 49100, Petah Tikva, Israel

    Galia Spectre

  5. The Coagulation Laboratory, Beilinson Hospital, Rabin Medical Center, 39 Jabotinsky Street, 49100, Petah Tikva, Israel

    Sigal Nakav

  6. Bio-Statistical Unit, Rabin Medical Center, 49100, Petah Tikva, Israel

    Tzippy Shochat

  7. Cardiology Institute, Assaf Harofe Medical Center, 70300, Zrifin, Israel

    Shmuel Fuchs

  8. Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    Galia Spectre, Avital Hershkovitz, Hefziba Green, Tzippy Shochat, Alon Grossman & Shmuel Fuchs

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  1. Ran Nissan
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  2. Galia Spectre
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Contributions

RN designed the study, collected data and wrote the manuscript; GS designed the study, recruited patients and wrote the manuscript; AH recruited patients and reviewed the manuscript; HG recruited patients and reviewed the manuscript; SS recruited patients; LC recruited patients; SN performed drug-level analysis and reviewed the manuscript; TS performed the statistical analysis; AG reviewed the manuscript; SF designed the study, recruited patients and wrote the manuscript.

Corresponding author

Correspondence to Ran Nissan.

Ethics declarations

Conflict of interest

Dr. Galia Spectre reports receiving lecture fees (honorarium) from Pfizer. Ran Nissan, Avital Hershkovitz, Hefziba Green, Shai Shimony, Lisa Cooper, Sigal Nakav, Tzippy Shochat, Alon Grossman and Shmuel Fuchs declare that they have no potential conflicts of interest that might be relevant to the contents of this article.

Funding

Pfizer pharmaceuticals funded the study (unrestricted grant).

Ethical approval

Rabin Medical Center Institutional Review Board (#0590-15) approved the study.

Informed consent

The patients agreed to participate in the research and signed informed consent for study participation.

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Nissan, R., Spectre, G., Hershkovitz, A. et al. Apixaban Levels in Octogenarian Patients with Non-valvular Atrial Fibrillation. Drugs Aging 36, 165–177 (2019). https://doi.org/10.1007/s40266-018-0613-8

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  • DOI: https://doi.org/10.1007/s40266-018-0613-8

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