Apixaban Levels in Octogenarian Patients with Non-valvular Atrial Fibrillation
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.
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.
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.
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.
ClinicalTrials.gov Identifier number NCT02623049.
Angiotensin-converting enzyme inhibitor
Anti-factor Xa activity
Analysis of covariance
Analysis of variance
Activated partial thromboplastin time
Angiotensin receptor blocker
Area under the curve
Body mass index
Twice a day
Chronic heart failure
Chronic kidney disease
Coefficient of variation
Cytochrome P450 3A4
Direct oral anticoagulant
Food and Drug Administration
International normalized ratio
International Society on Thrombosis and Haemostasis
Non-valvular atrial fibrillation
Optical density generated per minute
Time to reach maximum (peak) plasma concentration
Upper limit of normal
The authors would like to thank Maya Arlyuk, Irina Genin and Keren Yoskovitch for their technical support during this study.
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.
Compliance with Ethical Standards
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.
Pfizer pharmaceuticals funded the study (unrestricted grant).
Rabin Medical Center Institutional Review Board (#0590-15) approved the study.
The patients agreed to participate in the research and signed informed consent for study participation.
- 8.European Medicines Agency. Eliquis—summary of product characteristics. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002148/WC500107728.pdf. Accessed 10 May 2018
- 17.Alexander JH, Andersson U, Lopes RD, Apixaban for Reduction of Stroke and Other Thromboembolic Complications in Atrial Fibrillation (ARISTOTLE) Investigators, et al. Apixaban 5 mg twice daily and clinical outcomes in patients with atrial fibrillation and advanced age, low body weight, or high creatinine: a secondary analysis of a randomized clinical trial. JAMA Cardiol. 2016;1(6):673–81.CrossRefGoogle Scholar
- 20.Reilly PA, Lehr T, Haertter S, RE-LY Investigators, et al. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol. 2014;63(4):321–8.CrossRefGoogle Scholar