Comparison of Anti-Xa Activity in Patients Receiving Apixaban or Rivaroxaban

Abstract

Background: There is no established method for monitoring the anticoagulant effects of apixaban and rivaroxaban. Linear correlation between serum levels and anti-Xa activity has been shown, with r² ranging from 0.88 to 0.99. However, there are minimal data in patients receiving apixaban 5 mg twice daily or rivaroxaban 20 mg once daily. Objective: To evaluate the anti-Xa activity and serum levels at those doses and compare the trough anti-Xa activity. Methods: This was a single-center prospective study,approved by the institutional review board. Patients on an inappropriate dose or receiving an interacting drug were excluded. Blood samples were drawn 0.5 to 3 hours before a dose for both agents, 2 to 3 hours after an apixaban dose, and 12 to 16 hours after a rivaroxaban dose. Anti-Xa activity and serum levels were determined, and correlation was done via regression analysis. Trough anti-Xa activity was compared using a t-test. Results: The study enrolled 88 patients receiving each drug. The r² values were 0.79 and 0.87 for apixaban and rivaroxaban, respectively. The mean trough anti-Xa activity was 1.79 ± 0.96 IU/mL for apixaban and 1.25 ± 0.88 IU for rivaroxaban (P < 0.01). The trough sample was drawn a mean of 1.3 and 1.8 hours prior to the next dose for apixaban and rivaroxaban, respectively (P < 0.01). Conclusions: Good correlation was shown between anti-Xa activity and serum levels. The clinical utility of monitoring anti-Xa activity and the significance of the difference in trough anti-Xa activity for these agents remains to be established.

Keywords

apixaban rivaroxaban monitoring

The factor Xa inhibitor oral anticoagulants are increasing in use, and current guidelines recommend them either as an alternative to¹ or preferred over warfarin.² Three agents are currently marketed: apixaban, rivaroxaban, and edoxaban. Currently, there is no established method for monitoring the degree of anticoagulation of these agents. However, a method to accomplish this would be beneficial in several situations, such as presentation for acute bleeding or a thrombotic event, need for an urgent procedure, change in renal or hepatic function, or assessment of a potential drug interaction. The most promising method to assess the concentration of the factor Xa inhibitors, and by inference their relative effects on anticoagulation status, is measurement of chromogenic anti-factor Xa activity. Numerous small studies have found linear correlation between serum levels of apixaban and rivaroxaban and anti-Xa activity, with r² values ranging from 0.88 to 0.99.^3-12 Several different commercial assays have been utilized, and comparable results have been reported.^4,7-9 Published studies evaluating one of the assays during the clinical use of either agent at doses commonly used in the United States for the treatment of atrial fibrillation or venous thromboembolism have generally included small numbers of patients.^5-12 The purpose of this study was to evaluate the anti-factor Xa activity and corresponding serum levels of the drug in patients receiving apixaban or rivaroxaban during the course of clinical practice. We also sought to compare the trough anti-Xa activity of the 2 agents.

Methods

All patients 18 years or older receiving apixaban 5 mg twice daily or rivaroxaban 20 mg once daily for at least 1 week and enrolled in the Anticoagulation Clinic were eligible. Patients were excluded if they were on an inappropriate dose of either agent based on the Food and Drug Administration–approved dosing or if they were receiving amiodarone, dronedarone, ketoconazole, or rifampin. Eligible participants were offered enrollment on beginning therapy until the target was reached. At the time of enrollment, patients were counseled to take their anticoagulant within 30 minutes of the same time(s) each day for at least a week prior to presenting for lab testing to ensure that they were at steady state. The study was approved by the hospital institutional review board, and all patients provided informed consent.

Apixaban-treated patients had a trough sample drawn 0.5 to 3 hours prior to a dose and a peak sample 2 to 3 hours following a dose. Rivaroxaban-treated patients had a trough sample drawn 0.5 to 3 hours before a dose and a sample12 to 16 hours following a dose. Peak samples of rivaroxaban were not obtained for practical reasons because the majority of patients were taking the dosage between 5 and 8 pm. Anti–factor-Xa activity was determined by the hospital laboratory using the Stago STA-Liquid Anti-Xa assay via the established method for the test. The samples were run on the Stago Sta Compact device and the results reported according to the standard Sta-Multi Hep calibrator that is used for heparin and low-molecular-weight heparins. The reportable range was 0 to 1.87 IU/mL, and values exceeding that were determined by dilution of the sample with plasma 2 to 4 times and rerun until the results were within linearity. The samples were then frozen and shipped in a dry ice cooled container to the Drug Metabolism and Pharmacokinetics laboratory at the Walter Reed Army Institute of Research. Serum levels of the drugs were determined by via ultraperformance liquid chromatography–tandem mass spectrometry using a Waters ACQUITY UPLC and an AB Sciex 4000 QTRAP system.

Correlation of serum level to anti-Xa activity was determined via linear regression analysis. The effect of age, renal function, and weight on anti-Xa activity was also determined via regression analysis. The mean trough anti-Xa activity for the drugs was compared via a t-test. It was postulated that this measurement would be higher for apixaban based on corresponding half-lives and dosing schedules; however, the amount of the difference is unknown. A sample size calculation revealed that 80 patients were needed in each group to detect a 40% difference in the mean anti-Xa activity with a power of 80% and an α of 0.05. Enrollment was set at 88 patients in each group to allow for a 10% drop-out rate. Patient characteristics were compared via a t-test or χ² test according to the type of data analyzed.

Results

Enrollment was offered to 193 patients, and 176 patients were enrolled between April 2015 and September 2016. The median follow-up period was 13 months (range = 1-19 months). The demographics of the patients are presented in Table 1. A total of 95% of the samples were drawn, and 91% occurred in the specified time interval. Samples drawn at an inappropriate time were excluded from the anti-Xa range analysis, resulting in 320 levels assessed.

Table 1.

Patient Characteristics.

	Apixaban	Rivaroxaban	P
n	88	88
Male/Female	52/36	60/28	0.27
Age (years)^a	69 ± 14	60 ± 15	<0.01
CrCl (mL/min)^a	77 ± 24	83 ± 23	0.016
Weight (kg)^a	91 ± 16	98 ± 17	<0.01
Atrial fibrillation/Venous thrombosis	70/18	49/39	<0.01

Abbreviation: CrCl, creatinine clearance.

Values are means ± SD.

The anti-Xa activity and serum level correlations are presented in Figures 1 and 2. Both correlation coefficients were statistically significant with P <0.01. Some samples were not saved for shipment resulting in 84% of the apixaban samples and 67% of the rivaroxaban samples having a corresponding serum level. The mean serum levels for apixaban at trough and peak were 88 (range = 4-348) ng/mL and 161 (range = 51-370) ng/mL, respectively. The mean serum level for rivaroxaban at trough was 63 (range = 10-214) ng/mL. The results for both agents had a normal distribution. The assay performed similarly for both agents. The correlation was superior at the trough level for apixaban compared with the peak: r² = 0.90 versus 0.68, respectively. The correlation of the trough and interim anti-Xa activity to serum level was similar for rivaroxaban: r² of 0.84 versus 0.86, respectively.

Figure 1.

Correlation of all serum levels and anti-Xa activity for apixaban.

Figure 2.

Correlation of all serum levels and anti-Xa activity for rivaroxaban.

The anti-Xa activity results at trough are presented in Table 2. Apixaban had a significantly higher activity despite a mean sampling time that was significantly closer to the absolute trough. The 25 to 75 interquartile range was also higher for apixaban. However, the range was greater. Age, renal function, and weight were more strongly associated with the anti-Xa activity of apixaban than rivaroxaban. The peak data for apixaban and interim level data for rivaroxaban are presented in Table 2. The 25 to 75 interquartile range was wide for both agents. Similar to the trough data, age and renal function were most strongly associated for each agent.

Table 2.

Anti-Xa Activity and Correlation.

	Apixaban	P	Rivaroxaban	P
Trough
Anti-Xa activity (IU/mL)^a	1.79 ± 0.96		1.25 ± 0.88	<0.01^b
Time before dose (hours)^a	1.3 ± 0.8		1.8 ± 0.8	<0.01^b
25-75 Interquartile range (IU/mL)	1.1-2.45		0.7-1.5
r, Age	0.50	<0.01^c	0.30	<0.01^c
r, CrCl	−0.51	<0.01^c	−0.33	<0.01^c
r, Weight	−0.33	<0.01^c	0.13	0.24^c
	Peak		Interim
Anti-Xa activity (IU/mL)^a	2.81 ± 0.99		2.42 ± 1.16
25-75 Interquartile range (IU/mL)	1.9-3.7		1.65-3.24
r, Age	0.45	<0.01^c	0.33	<0.01^c
r, CrCl	−0.38	<0.01^c	−0.36	<0.01^c
r, Weight	−0.26	0.018^c	0.09	0.46^c

Abbreviation: CrCl, creatinine clearance.

Values are means ± SD.

Comparison between apixaban and rivaroxaban results.

P value for correlation coefficient.

Two minor bleeding events occurred during the trial, both in patients receiving apixaban. A patient had epistaxis and hemorrhoidal bleeding. The corresponding trough anti-Xa activity was 3.2 IU/mL, and the peak was 4.24 IU/mL. The other patient experienced hematuria. The peak anti-Xa level was 3.8 IU/mL, and the trough was 2.0 IU/mL. No thrombotic events occurred during the study.

Discussion

In this population of patients treated with apixaban and rivaroxaban, the STA-Liquid Anti-Xa assay yielded a strong correlation with the serum levels. This assay has previously been shown to correlate well in multiple studies and is widely available.^3-5,10-13 This suggests that it could be utilized as a clinically reliable monitoring tool. The r² determined was lower than that in the majority of prior trials; however, this was the largest trial assessing the assay.

Al-Aieshy et al⁵ assessed the performance of the STA-Liquid Anti-Xa assay in 61 patients treated with rivaroxaban 20 mg daily. The authors reported an r² of 0.92 at trough for the participants and 0.79 at peak in the subset of 30 patients in whom it was measured. Another trial investigated the assay in 60 patients receiving apixaban 5 mg twice daily. Sampling was done at trough, and the authors reported an r² of 0.9.¹⁰ In these trials, the authors prepared drug-specific calibrators using plasma from volunteers spiked with known concentrations of the study drugs. Beyer et al¹² conducted a study in 10 patients on rivaroxaban 20 mg daily and 9 patients on apixaban 5 mg twice daily. The authors reported an r² of 0.99 using the standard Sta-Multi Hep calibrator of the assay.¹² All 3 studies showed a strong association between the anti-Xa activity and the drug serum level.

Different assays have been used to assess the correlation in other trials. The Stago Rotachrom assay, which is no longer marketed, yielded an r² of 0.88 in 116 patients receiving apixaban 5 mg twice daily for the treatment of venous thromboembolism.⁸ Another trial compared 3 different assays in 74 patients receiving rivaroxaban 20 mg daily and 52 patients receiving apixaban 5 mg twice daily. The authors reported an r² of 0.98 to 0.99 for all 3 assays.⁷

Our study was designed to directly compare the trough anti-Xa activity. Only 1 prior trial of 14 volunteers was designed as a comparison, and it utilized venous thrombosis prophylaxis doses.¹⁴ The trough anti-Xa activity was lower for rivaroxaban in that trial as well. The Beyer et al¹² trial referenced previously provided some additional insight to the comparison. Sampling times were not prespecified and were highly variable in relation to dosing time. The authors calculated trough levels for the drugs that were similar but did not specify how these data were determined.¹² The higher trough anti-Xa activity for apixaban found in our trial was expected based on the dosing schedule and half-lives of the agents.^15,16 The elimination half-life of rivaroxaban is 5 to 9 hours in patients aged 20 to 45 years with normal renal function and 11 to 13 hours in those 60 to 76 years of age. The elimination half-life of apixaban is approximately 12 hours. Therefore, the half-life for rivaroxaban in a patient is at best equal to that of apixaban, and it is dosed only once versus twice daily. The clinical significance of the higher trough value for apixaban is unknown. It is possible that this may result in a decreased thrombotic risk. For practical reasons, we did not obtain peak levels of rivaroxaban. The 12- to 16-hour postdose interim level was not much lower than the peak anti-Xa activity for apixaban. Furthermore, the interquartile ranges for the apixaban peak and rivaroxaban interim level overlapped to a high degree. This suggests that the peak level for rivaroxaban would be significantly higher than that of apixaban. This higher peak level could be associated with an increased risk of bleeding.

It should be noted that the average peak anti-Xa activity for apixaban and interim results for rivaroxaban fell outside of the linear range published for the STA-Liquid Anti-Xa assay. In fact, the correlation coefficient for apixaban was lower at the peak measurement than the trough; however, there was no difference between the 2 rivaroxaban sampling times. A prior study assessed several assays and reported divergent results at higher concentrations for the STA-Liquid Anti-Xa assay as well as some of the other assays tested.¹⁷ However, 2 studies using different anti-Xa assays reported comparable r² values at low and high concentrations.^3,4 This difference for apixaban found in our study may have resulted from the dilution of the specimens, introducing systematic error that may result in a bias with respect to anti-Xa activity at high concentrations compared with direct concentration measurement by ultra-performance liquid chromatography–tandem mass spectrometry. Alternatively, bias at higher concentrations could be an artifact caused by saturation in the anti-Xa assay, resulting in lower sensitivity at higher drug levels.

A wide range of serum levels and anti-Xa activity were found for both drugs at each of the time points tested. This suggests that these standard doses are producing variable degrees of anticoagulation. This finding is consistent with that of multiple other studies.^5,10,18,19 There are minimal data available assessing the correlation of serum levels or anti-Xa activity of a factor Xa inhibitor to outcomes. Sakaguchi et al²⁰ measured anti-Xa activity at peak and trough in 94 patients receiving rivaroxaban using a different chromogenic anti-Xa activity assay. They reported that the peak anti-Xa level was significantly higher in those patients with major and nonmajor clinically relevant bleeding. Additional support for an association between drug level and outcomes was reported in the ENGAGE AF-TIMI 48 trial.²¹ Patients on the highest edoxaban dosage of 60 mg had the highest mean trough anti-Xa activity and the lowest rate of stroke. Patients on the lower dosages and corresponding lower anti-Xa activity had lower rates of major bleeding. Similar results were reported for the direct thrombin inhibitor dabigatran, where an increased risk of stroke was shown with lower serum levels and an increased risk of bleeding with higher levels.²² Interestingly, both bleeding events that occurred in our trial occurred in patients with high peak anti-Xa activity.

Renal function was more strongly associated with anti-Xa activity at trough for apixaban than rivaroxaban. However, it is the only parameter used for dose reduction recommendations for rivaroxaban, whereas apixaban includes both age and weight. Age had the same strength of association as renal function on anti-Xa activity for rivaroxaban. In this study, age had a similar moderate association to anti-Xa activity as renal function for apixaban, which is consistent with the dosing recommendations, whereas the association for weight was weak. All 3 parameters were weakly associated for rivaroxaban. To our knowledge, this is the first study to investigate the association of these parameters to anti-Xa activity.

A potential limitation of this study is that we did not prepare drug-specific calibrators for the assay. Correlation between serum level and anti-Xa activity using prepared calibrators or low-molecular-weight heparin calibrators has been investigated in several studies. All 3 trials reported comparable correlation between the 2 calibrators used.^8,9,23 Notably, none of these studies used the STA-Liquid Anti-Xa assay. No specific calibrators for rivaroxaban and apixaban were available at the time of our study. Stago has recently marketed one for each of the factor-Xa inhibitors; however, they are intended for research purposes only and are not currently approved by the US Food and Drug Administration for use in a clinical laboratory. Therefore, the specific calibrators are likely not available in most institutions at this time. The high degree of correlation we demonstrated suggests that the standard MultiHep calibrator for the STA-Liquid Anti-Xa assay can be used to monitor the anticoagulant effect of rivaroxaban and apixaban in the interim until the drug-specific calibrators are approved for routine use.

Another limitation of our study is that the actual time of dosing in relation to when the blood was drawn could not be determined. Indeed, some patients presented to the laboratory at times outside of the target intervals. Additionally, adherence to the medication in the period prior to the blood draw could not be confirmed.

The wide range of serum levels and corresponding anti-Xa activity measured in our population along with the potential that clinical events are associated with concentrations at the extremes suggests that the ability to monitor the anticoagulant effect of rivaroxaban and apixaban would be beneficial. Routine monitoring is not necessary, but an anti-Xa assay is recommended in the urgent periprocedural period.²⁴ However, the “safe” level is unknown. Monitoring of anti-Xa activity would also be beneficial in patients presenting either with thrombotic events or major bleeding because it would help establish a therapeutic range. Patients at extremes of weight may also be candidates. Few patients <50 kg were included in the clinical trials,^25-27 and the International Society of Thrombosis and Haemostasis has recommended that factor Xa inhibitors should not be used in patients weighing >120 kg, because of limited clinical data and concerning pharmacokinetic/pharmacodynamic data.²⁸ Patients with low body weight could be tested to determine if they have high anti-Xa activity and may benefit from dose reduction, and those weighing >120 kg could be tested to determine if they have low anti-Xa activity, which could suggest that an alternative therapy should be chosen. Additionally, it may also be advantageous in patients with hepatic dysfunction, a change in renal function, or with a potential drug interaction. Patients near the cutoff for dose reduction and those with questionable adherence could also qualify. In all these scenarios, the question remains: What is the target that is both effective and safe? Is the interquartile range found in our study a starting point? Establishing a target range would help identify patients who are at risk for bleeding and thrombotic events that could potentially be avoided by an adjustment from the standard dosage.

Conclusion

In conclusion, we found that the STA-Liquid Anti-Xa assay correlated well with the serum level for apixaban and rivaroxaban. The trough level for apixaban was higher than that of rivaroxaban. Further study is needed to determine which patients would benefit from monitoring and what the therapeutic range is. The drugs are marketed as not needing to be monitored, which is comparable to the recommendation for low-molecular-weight heparins when they were launched. However, there are now established ranges for those agents. A significant difference between the oral factor Xa inhibitors and the low-molecular-weight heparins is that the latter are dosed based on body weight, and apixaban and rivaroxaban have only 2 approved dosages.

Footnotes

Acknowledgements

The authors would like to thank Gary Brunson for helping with the sample collection and Richard Vankluyve for performing the anti-Xa assays. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the view of the Department of the Army or the Department of Defense.

Authors’ Note

A portion of this research was presented as a poster at the American College of Clinical Pharmacy Annual Meeting in October 2016.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

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