The study aimed to establish whether body mass index (BMI) ≥ 35 kg/m2 has an influence on trough plasma concentration of apixaban in patients with atrial fibrillation. Obesity is associated with physiological changes that have an impact on a large number of body systems; they cause an increase in the volume of distribution and the volume of blood, an increase in cardiac function, and lean body weight (6–8,17). Blood flow to the liver is changed, chronic inflammation and cytokines released influence some cytochrome P450 expression (CYP 450)(10,36), activity of CYP3A enzymes decreases(7,16,18). In addition, there is a trend towards an increased activity of the following enzymes: CYP2D6, CYP2C19, CYP2C9, CYP1A2 (28). 25% of orally administered apixaban is metabolized by the liver, mainly by CYP3A4/5 with a little involvement of CYP1A2, 2C8, 2C9, 2C19, 2J2. Therefore, the effect on the liver metabolism of apixaban cannot be predicted.
Apixaban concentrations were measured in a limited number of studies. In one study subjects with body weight over 120 kg (19 participants) had approximately 31% lower apixaban maximum plasma concentration (Cmax) compared to controls (16 participants) who weighed 65–85 kg(21).
In a prospective study carried out from 2017 through 2019, apixaban plasma concentrations were measured in patients weighing > 120 kg and dosed 5 mg twice daily. Peak and trough concentrations were measured in 14 and 11 patients respectively (20). No concentrations were below the 5th percentile range of concentrations published by the manufacturer. There was no linear relationship between drug concentration and body weight or BMI.
In a post hoc analysis of the ARISTOTLE trial, in which results were stratified by body weight, 982 patients (5.4% of 18193) were in the high weight group (> 120 kg) (37). the researchers concluded that apixaban, compared to warfarin, was effective and safe in patients with extreme obesity, although the percentage of participants weighing over 140 kg was extremely low (38).
This is the first prospective study examining blood levels of apixaban in patients with atrial fibrillation compared to a control group, to study the influence of obesity and body mass index on trough plasma concentrations of the drug. Other studies that attempted to evaluate the effect of obesity on plasma concentration of apixaban were retrospective and with small sample size. The only prospective study cited by the clinical guidelines of the International Society on Thrombosis and Haemostasis (ISTH) and by the drug brochure was that of Upreti and colleagues (21), who measured apixaban plasma concentration after administration of single oral dose of 10 mg apixaban in 18 healthy subjects. A prospective study was published in 2020 on patients receiving apixaban at full and appropriate dose and in steady-state, but without comparison control group with similar characteristics (20).
Our study results indicate a 29% decrease in median trough levels in patients dosed 5 mg twice daily with a BMI ≥ 35 kg/m2. These findings are consistent with a previous study in which maximal serum concentrations (Cmax) of apixaban in subjects with high body weight were 31% lower than the control group who weighed 65 to 85 kg(21).
In the current study, additional variables were found to affect trough levels, e.g. weight, age, and glomerular filtration rate, however, no correlation was found between BMI and apixaban trough levels in multivariate analysis. Body mass index in patients with high body weight does not seem to be an appropriate indicator for predicting apixaban levels whereas patient’s weight is a more suitable indicator.
Despite the decrease in Cmin in patients with high body weight, the majority of the results were in the predicted range, and it's unlikely that a dose adjustment is necessary for patients with BMI ≥ 35 kg/m2, however, further prospective studies are needed to confirm the results.
Although all median values in all subgroups were within the predicted range of the drug, its numerical value was higher in both study groups. In patients who were on 5 mg twice daily dose and had BMI < 35 kg/m2, the median concentration of apixaban was as twice as high as the manufacturer's predicted value, and in patients with BMI ≥ 35 kg/m2 1.5 times higher. These higher values are possibly due to the different commercial kit used in our hospital, we used HemosIL Liquid anti-Xa kit while Apixaban concentrations cited in several databases were tested in a commercial kit named Rotachrom® Heparin Anti-Xa assay. According to the prescribing information using different kits can result in different results (39) but no data exist on differences in apixaban plasma concentrations results using the two different kits.
Our patients were older than the patients in the ARISTOTLE cohort (median age of 70 years). Previous studies have indicated a direct relationship between drug concentration and patient’s age; a 30% increase in area under the curve (AUC) was observed in patients over 65 years old, compared with patients under 65 years (26,40). In our study, a significant direct correlation was observed between trough levels and patients’ age. In addition, our patients had worse renal function in comparison to the Aristotle cohort, only 15% of study participants in the ARISTOTLE trial had chronic kidney disease stage 3. Since 27% of apixaban dose is eliminated through the kidneys, impaired renal function may lead to increased plasma concentrations (41,42). In the current study (in 5 mg twice daily dose group) an inverse relationship between plasma concentration and eGFR was observed.
Patients receiving 5 mg twice daily with trough levels that exceed the optimal threshold (concentration higher than 300 ng/ml), represent “real-world” patients in whom dose reduction is not required according to the dose reduction criteria investigated in the large phase III trials. On the other hand, exceeding the effective range therapeutic range concentrations has the potential to cause an increased risk of bleeding and effect treatment safety. Therefore, prospective studies are recommended to evaluate the need for plasma levels measurement in such clinical situations.
The results presented above indicate that in real-life patients, especially in complex hospitalized patients with a combination of several factors that contribute to an increased drug plasma concentration, different values may be obtained than the ones shown in patients selected for clinical trials.
We did find a 44% difference in mean trough levels between patients weighing over 120 kg and patients with BMI < 35kg/m2 however the number of patients who weighed over 120 kg was very small (five patients), therefore, no conclusion can be drawn regarding their cases.
Our study has limitations. First, statistical analysis was performed on only 59 patients of the 60 recruited to the study, although we assume that this had little effect on our results. The second limitation was the fact that we included patients receiving either 5 mg or 2.5 mg apixaban twice-daily doses and as a result the sample size in each subgroup especially in 2.5 mg twice daily group was small. therefore no valid conclusions can be drawn regarding this subgroup. In addition, the wide variability of trough levels makes it difficult to draw conclusions due to the sample size included. To validate these results it would be necessary to conduct similar study on larger sample size.
Our study cohort included hospitalized patients with co-morbidities, consequently, there may have been other factors that affected plasma concentration of the drug.
The commercial kit used to measure plasma concentrations in the study was HemosIL Liquid anti-Xa, which is available in “Haemek” medical center. It's different from the kit used in clinical trials for testing plasma concentration, that is Rotachrom®Heparin Anti-Xa assay which may have influenced the results.