Variability and Clinical Characteristics of Anti-factor Xa Activity Treated with Rivaroxaban in Chinese Patients Aged ≥ 80 years: A Single-center Study

DOI: https://doi.org/10.21203/rs.3.rs-2726171/v1

Abstract

Introduction: Assessment of rivaroxaban concentrations is warranted in advanced age patients treated with rivaroxaban, which may instruct individual dose to reduce bleeding risk. Anti-Xa chromogenic assay has been demonstrated good correlation between rivaroxaban plasma concentration and anti-factor Xa activity (AXA) within the clinical therapeutic dose range. We aimed to assess the variability of AXA and explore clinical characteristics associated with AXA in patients over 80 years treated with rivaroxaban in daily practice.

Method: This study subjects were patients over 80 years treated with rivaroxaban hospitalized in the Department of Gerontology of Peking University First Hospital from 2016 to 2021. The medical data were extracted from electronic records: baseline characteristics, and AXA including trough and peak at day 3 and day 30 after rivaroxaban therapy. Inter- individual variability was calculated by mean ± SD, max-min and coefficient of variation (CV), which was calculated by(SD/mean) x 100. Intra- individual variability was assessed by paired-samples T test. Spearman and Pearson correlation analysis were used to evaluate the correlation between AXA and PT, APTT, INR, and clinical characteristics.

Result: A total of 145 Chinese patients over 80 years old taking rivaroxaban were included in this study, with an average age of 85.9 ± 4.2 years old, among which 101 were males (69.7%). There were 57 patients (39.3%) in rivaroxaban 5mg BID group and 88 patients (60.7%) in 2.5mg BID group. In terms of interindividual variation, the CV of AXA trough value in patients using rivaroxaban ranged from 58–77%, and the CV of AXA peak ranged from 48–53%. For intra-individual variability, there was no significant difference of the AXA between day 3 and day 30. Body weight was positively correlated with AXA peak of rivaroxaban 5mg BID group (r = 0.331, p = 0.019). ADL score was positively correlated with AXA trough (r = 0.264, p = 0.020) and AXA peak (r = 0.290, p = 0.010) in rivaroxaban 2.5 mg BID. In the rivaroxaban 2.5mg BID group, creatinine clearance was negatively correlated with AXA trough value (r = -0.400, p = 0.001), and also between AXA peak both in rivaroxaban 2.5 mg BID (r = -0.249, p = 0.029) and rivaroxaban 5 mg BID (r = -0.330, p = 0.018). There was a positive correlation present between PT peak and AXA peak, including rivaroxaban 5 mg BID (r = 0.308, p = 0.033) and rivaroxaban 2.5 mg BID (r = 0.430, p = 0.000), and between PT trough and AXA trough in rivaroxaban 5 mg BID (r = 0.406, p = 0.002). The correlation between APTT and AXA is not significant, except APTT peak and AXA peak in rivaroxaban 2.5 mg BID (r = 0.340, p = 0.000).

Conclusion: In this study, in Chinese patients treated with rivaroxaban for more than 80 years, there was significant inter-individual variation in AXA, but not significant intra-individual variation. It is recommended to measure AXA trough and peak into the effective treatment range at the initiation of rivaroxaban treatment in patients over 80 years. Creatinine clearance was inversely correlated with AXA, suggesting an increased risk of bleeding with reduced renal function. There was a significant correlation present between PT and AXA, while the correlation between APTT and AXA was poor.

Introduction

Rivaroxaban, a Factor Xa inhibitor, has been proposed over the last decade as one of the alternatives to vitamin K antagonists (VKAs) for the prevention of stroke in patients with non- valvular atrial fibrillation (NVAF) or the management of venous thromboembolism (VTE)[1, 2]. In large randomized clinical trials (RCTs) and observational studies, rivaroxaban was considered as or more effective than VKAs with a more favorable bleeding profile, and does not require titration or monitoring in clinical practice[36]. Aged patients are rare represented in clinical trials. The recommended dose of rivaroxaban in China is 20mg once daily, and 15mg once daily can be used for patients with low body weight and elderly patients (> 75 years old). However, multiple studies have shown no significant differences in bleeding events or thrombotic events with lower-than-recommended doses of rivaroxaban compared with standard-dose or warfarin[79]. In clinical practice, it is common to take less than the recommended dose of drugs, and most of them are adjusted by clinicians according to their clinical experience. The translation into clinical practice of RCTs results may therefore not give the same expected benefits in older patients and assessment of rivaroxaban concentrations may be warranted[1013]. So far, the guidelines have not defined the target range for rivaroxaban concentrations. Several studies reveal that higher rivaroxaban concentrations increase the bleeding risk while lower increase the risk of thromboembolic events[14, 15]. To establish whether measuring rivaroxaban concentrations may improve patient safety, it is crucial to know whether patients have stable rivaroxaban drug concentrations over time. Liquid chromatography (LC)-mass spectrometry (MS) is considered the gold standard of assessing rivaroxaban plasma concentrations, but the process is tedious and clinical practice is inconvenient[16]. Anti-Xa chromogenic assay has been demonstrated good correlation between rivaroxaban plasma concentration and anti-factor Xa activity (AXA) within the clinical therapeutic dose range [1721]. In this study, we aimed to assess the variability of AXA and explore clinical characteristics associated with AXA in patients over 80 years treated with rivaroxaban in daily practice.

Multiple diseases, consequent polypharmacy and individual difference, are highly prevalent in elderly patients treated with rivaroxaban in real life,

Method

This study was a retrospective cohort study. The study subjects were patients hospitalized in the Department of Gerontology, Peking University First Hospital from January 2016 to December 2021. Inclusion criteria were: ≥80 years of age, with anticoagulant indications, therapy receiving rivaroxaban, with complete clinical data. Exclusion criteria were: combined use of medium and strong p-glycoprotein inhibitors, such as ketoconazole, itraconazole, voriconazole, clarithromycin, erythromycin, combined use of CYP3A4 inducers, such as phenytoin sodium, carbamazepine, phenobarbital and other drugs, combined use of drugs that affect AXA, such as ordinary heparin, low molecular weight heparin. The dosages of rivaroxaban of the enrolled patients was designed by clinicians based on guidelines and clinical experience. The following clinical characteristics would lead clinicians to choose the lower dose of rivaroxaban (2.5mg BID) for patients with atrial fibrillation: Older age (≥ 90 years), lower body weight (≤ 60kg), frailty (ADL score ≤ 60 points), previous bleeding history, and combined use of antiplatelet drugs.

All the medical data included in the patients was extracted from the hospital's electronic medical records. The following information was collected: age, sex, height and weight, activities of daily living (ADL) score (Barthel-Index[22]), rivaroxaban dose, anticoagulation indication, CHA2DS2-VASc score and HAS-BLED score, comorbidity and disease history, comedication (e.g., antiplatelet agents, beta-blocker, diuretics, statin), creatinine clearance (calculated using Cockcroft–Gault equation). Prothrombin time (PT), activated partial thromboplastin time (APTT), international normalized ratio (INR), including trough and peak (before and 3 hours after each administration) at day 3. AXA including trough and peak (before and 3 hours after each administration) at day 3 and day 30. The ACL- TOP- 700 analyzer and Hemosil Liquid Anti-Xa (Werfen) were used to measure the AXA.

Baseline characteristics were analyzed according to rivaroxaban dose groups, continuous variables were expressed as mean ± SD, and categorical variables were expressed as numbers and percentages. The inter-individual variability of trough and peak AXA was assessed by calculating the mean value, range (maximum - minimum) and coefficient of variation (CV). The CV was calculated by the formula (SD/mean) x 100. The paired sample T test was used to assess intra-individual variation. In an explanatory analysis, Pearson correlation was employed to evaluate associations between AXA and PT, APTT, INR, and clinical characteristics in the measurement data that conform to normal distribution, while Spearman correlation was employed in the measurement data that do not conform to normal distribution. For patients with impaired renal function, creatinine clearance ≤ 50ml /min was the critical value. The score of ADL was ≤ 60, which was the critical value of self-care difficulty. BMI was classified according to the World Health Organization definition (< 18.5 as underweight, 18.5–24.9 as normal weight, 25-29.9 as overweight and > -30 as obese). All statistical analyses were performed using SPSS®Statistics (IBM SPSS Statistics for Windows, version 27.0) software.

Results

In total, we included 145 patients between January 2016 and December 2021, of whom 57 (39.3%) used rivaroxaban 5mg BID and 88 (60.7) used rivaroxaban 2.5mg BID. The mean age of the study population was 85.9±4.2 years old and 69.7%(101/145) were males. The average weight of the study population was 66.6±12.1 kg, the average body mass index (BMI) was 24.0 ± 3.9 kg/m², the ADL score was 72.1 ± 27.9 points and the average creatinine clearance was 61.3 ± 17.4 ml/min. The number of patients treated with rivaroxaban for NVAF was 88 (60.7%), and for VTE was 57 (39.3%). Among the patients with NVAF, CHA2DS2-VASc scoring 4.8 ± 1.3 points and HAS-BLED scoring 2.3 ± 0.9 points. In terms of complication and comedication, many patients were complicated with other diseases and combined with other agents (Table 1).

The AXA trough of rivaroxaban 5mg BID was 0.22 ± 0.15 IU/ml at day 3 and 0.24 ± 0.14 IU/ml at day 30, while the AXA peak was 0.64 ± 0.31 IU/ml at day 3 and 0.66 ± 0.35 IU/ml at day 30. The AXA trough of rivaroxaban 2.5mg BID was 0.13 ± 0.10 IU/ml at day 3 and 0.15 ± 0.11 IU/ml at day 30, while the AXA peak was 0.38 ± 0.20 IU/ml at day 3 and 0.43 ± 0.21 IU/ml at day 30. For inter-individual variability, the CV was 58% to 68% for trough values and 48% to 53% for peak values among patients using rivaroxaban 5 mg BID, while the CV was 73% to 77% for trough and 49% to 53% for peak in rivaroxaban 2.5mg BID (Table 2). Intra-individual variability was substantially lower, there were no statistic difference of the AXA between day 3 and day 30 besides the AXA trough of rivaroxaban 2.5 mg BID (t = -2.24, p = 0.029) (Table 3). 

Weight, ADL score, and creatinine clearance were correlated with AXA, while sex, age, comorbidity, and comedication were not (Table 4). There was a positive correlation present between weight and AXA trough (r = 0.331, p = 0.019) in rivaroxaban 5 mg BID. There was a positive correlation present between ADL score and AXA trough (r = 0.264, p = 0.020) in rivaroxaban 2.5 mg BID and AXA peak (r = 0.290, p = 0.010) in rivaroxaban 2.5 mg BID. In the rivaroxaban 2.5 mg BID group, creatinine clearance was negatively correlated with AXA trough (r = -0.400, p = 0.001), and also between AXA peak both in rivaroxaban 2.5 mg BID (r = -0.249, p = 0.029) and rivaroxaban 5 mg BID (r = -0.330, p = 0.018) (Table 4). Results were similar when ADL score and creatinine clearance were correlated as ordinal categorical variables, although the correlations were less strong.

Prothrombin time (PT), activated partial thromboplastin time (APTT), and international normalized ratio (INR) were correlated with AXA (Table 5). There was a positive correlation present between PT peak and AXA peak, including rivaroxaban 5 mg BID (r = 0.308, p = 0.033) and rivaroxaban 2.5 mg BID (r = 0.430, p = 0.000), and between PT trough and AXA trough in rivaroxaban 5 mg BID (r = 0.406, p = 0.002). There was a positive correlation present between INR trough and AXA trough in rivaroxaban 5 mg BID (r = 0.312, p = 0.022), and between INR peak and AXA peak in rivaroxaban 2.5 mg BID (r = 0.493, p = 0.000). The correlation is not significant between APTT and AXA, except APTT peak and AXA peak in rivaroxaban 2.5 mg BID (r = 0.340, p = 0.000). 

Discussion

In this study, in Chinese patients over 80 years of age treated with rivaroxaban, there was significant inter-individual variation in AXA, but not significant intra-individual variation. These findings are consistent with the study by Gulpen et al, who found significant changes in DOAC concentration in 164 patients with either rivaroxaban or Dabigatran, but no significant changes within patients over time[23]. In our study, AXA trough showed higher variability than AXA peak, a result consistent with similar pharmacokinetic studies [24]. We also found considerable variability in low-dose DOAC patients, a finding that has not been confirmed in previous studies, which may be related to the older age of the population included in this study and the lower dose of the drug [25].

For DOAC, underdosage means less benefit in preventing thromboembolism, overdose increases the risk of bleeding, and high variability is not a good characteristic. The high variability we found between individuals suggests that some patients may have been exposed to too high or too low concentrations of the drug rivaroxaban, so they may be at higher risk of bleeding or thrombosis. To reduce such complications, our findings suggest that it may be worthwhile in daily clinical practice to measure AXA trough and peak at initial treatment in patients over 80 years of age treated with rivaroxaban. If a patient’s AXA are then considered optimal, the patient may not need frequent measurements as AXA within an individual appear to be more stable (for example only once a year, or during sudden changes in interacting drugs or comorbidities).

Furthermore, this study showed some clinical characteristics (weight, ADL score, and CCr) were correlated with AXA. First, we found a possible positive correlation between weight and AXA in patients with rivaroxaban 2.5 mg BID, which differs from previous studies[2628]. One reason may be that this study population is Asian elderly with low overall body weight. Whether rivaroxaban can be safely used in patients with underweight is currently not well known, especially the Asian population. Second, we found a possible positive correlation between ADL score and AXA in patients with rivaroxaban 2.5 mg BID. ADL score (measured by Barthel-Index) has been shown to be the strong predictor of falls in very old adults[29]. Current guidelines suggested that anticoagulation is sometimes not recommended for people at risk of falls and for older people, even though age is factored into the bleeding risk score and falls are rarely a cause of major hemorrhage[30]. Our study showed that AXA was not higher in low ADL score population than in high ADL score population which may meant the bleeding risk was not higher. Whether receive anticoagulation for people at high risk of falls may needs more exploration. Third, we found that creatinine clearance was negatively correlated with AXA. Current guidelines recommend adjusting the dose of rivaroxaban when creatinine clearance is < 50 ml/min because of its renal excretion[31]. Our study showed that patients with moderately impaired renal function were still more likely to have higher grain concentrations when treated with reduced rivaroxaban, and therefore at increased risk of bleeding[32]. Last, we found that there was a significant correlation present between PT and AXA, while the correlation between APTT and AXA was poor.

The main strengths of this research were the first clinical study of AXA in Chinese patients treated with rivaroxaban, patients were over 80 years and from a single center and use of the same methods for AXA. Limitations included the retrospective design and the biases inherent to such data collection, and a possible center effect.

Conclusions

In this study, in Chinese patients treated with rivaroxaban for more than 80 years, there was significant inter-individual variation in AXA, but not significant intra-individual variation. It is recommended to measure AXA trough and peak at the initiation of rivaroxaban treatment in patients over 80 years, and if the patient’s AXA into the effective treatment range, this patient may not need frequent remeasuring. Weight and ACL score may be positively correlated with AXA, while inverse correlation between creatinine clearance and AXA. The risk of bleeding is not necessarily higher in aged with low body weight or falling to high risk for anticoagulant therapy, but increased with reduced renal function. There was a significant correlation present between PT and AXA, while the correlation between APTT and AXA was poor.

Declarations

Funding information

The authors would like to thank the project 2019BD019 supported by PKU- Baidu Fund.

Compliance with Ethical Standards

Conflict of Interest 

The authors declare that they have no conflict of interest.

Ethical Approval and Consent to Participate

According to Chinese law, this study was approved by the Biomedical Research Ethics Committee, Peking University First Hospital. Informed consent was waived by the Biomedical Research Ethics Committee, Peking University First Hospital. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Consent for Publication

Informed consent was obtained from individual participant included in the study to publish the manuscript.

Data availability'

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

Authors’ contributions

Conception or design of the work: RZ; data collection: RZ; data analysis and interpretation: RZ; drafting the article: RZ; critical revision of the article: JD, ML; final approval of the version to be published: RZ, JD, ML

Acknowledgement

The authors would like to thank the geriatrics Department of Peking University First Hospital for their support.

References

  1. Steffel J, Collins R, Antz M, et al., 2021 European Heart Rhythm Association Practical Guide on the Use of Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation [J], Europace, 2021, 23(10): 1612-1676.
  2. Barnes G D, Lucas E, Alexander G C, et al., National Trends in Ambulatory Oral Anticoagulant Use [J], The American Journal of Medicine, 2015, 128(12): 1300-1305.e1302.
  3. Bauersachs R, Berkowitz S D, Brenner B, et al., Oral rivaroxaban for symptomatic venous thromboembolism [J], N Engl J Med, 2010, 363(26): 2499-2510.
  4. Ruff C T, Giugliano R P, Braunwald E, et al., Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials [J], Lancet, 2014, 383(9921): 955-962.
  5. Patel M R, Mahaffey K W, Garg J, et al., Rivaroxaban versus warfarin in nonvalvular atrial fibrillation [J], N Engl J Med, 2011, 365(10): 883-891.
  6. Graham D J, Baro E, Zhang R, et al., Comparative Stroke, Bleeding, and Mortality Risks in Older Medicare Patients Treated with Oral Anticoagulants for Nonvalvular Atrial Fibrillation [J], Am J Med, 2019, 132(5): 596-604.e511.
  7. Sugrue A, Sanborn D, Amin M, et al., Inappropriate Dosing of Direct Oral Anticoagulants in Patients with Atrial Fibrillation [J], Am J Cardiol, 2021, 144: 52-59.
  8. Montrasio G, Reiner M F, Wiencierz A, et al., Prevalence and risk of inappropriate dosing of direct oral anticoagulants in two Swiss atrial fibrillation registries [J], Vascul Pharmacol, 2022: 107120.
  9. Ashraf H, Agasthi P, Shanbhag A, et al., Long-Term Clinical Outcomes of Underdosed Direct Oral Anticoagulants in Patients with Atrial Fibrillation and Atrial Flutter [J], Am J Med, 2021, 134(6): 788-796.
  10. Russo V, Attena E, Di Maio M, et al., Non-vitamin K vs vitamin K oral anticoagulants in patients aged > 80 year with atrial fibrillation and low body weight [J], Eur J Clin Invest, 2020, 50(11): e13335.
  11. Russo V, Carbone A, Rago A, et al., Direct Oral Anticoagulants in Octogenarians With Atrial Fibrillation: It Is Never Too Late [J], J Cardiovasc Pharmacol, 2019, 73(4): 207-214.
  12. Douxfils J, Adcock D M, Bates S M, et al., 2021 Update of the International Council for Standardization in Haematology Recommendations for Laboratory Measurement of Direct Oral Anticoagulants [J], Thromb Haemost, 2021, 121(08): 1008-1020.
  13. Kampouraki E, Abohelaika S, Avery P, et al., Elderly people are inherently sensitive to the pharmacological activity of rivaroxaban: implications for DOAC prescribing [J], J Thromb Thrombolysis, 2021, 52(1): 170-178.
  14. Ruff C T, Giugliano R P, Braunwald E, et al., Association between edoxaban dose, concentration, anti-Factor Xa activity, and outcomes: an analysis of data from the randomised, double-blind ENGAGE AF-TIMI 48 trial [J], Lancet, 2015, 385(9984): 2288-2295.
  15. Testa S, Paoletti O, Legnani C, et al., Low drug levels and thrombotic complications in high-risk atrial fibrillation patients treated with direct oral anticoagulants [J], J Thromb Haemost, 2018, 16(5): 842-848.
  16. Schmitz E M, Boonen K, van den Heuvel D J, et al., Determination of dabigatran, rivaroxaban and apixaban by ultra-performance liquid chromatography - tandem mass spectrometry (UPLC-MS/MS) and coagulation assays for therapy monitoring of novel direct oral anticoagulants [J], J Thromb Haemost, 2014, 12(10): 1636-1646.
  17. von Horn H, Rasmusson A, Söderblom L, et al., Using a low–molecular weight heparin–calibrated anti–factor Xa assay to assess the concentration of apixaban and rivaroxaban [J], Int J Lab Hematol, 2022, 44(1): 163-167.
  18. Billoir P, Barbay V, Joly L M, et al., Anti-Xa Oral Anticoagulant Plasma Concentration Assay in Real Life: Rivaroxaban and Apixaban Quantification in Emergency With LMWH Calibrator [J], Ann Pharmacother, 2019, 53(4): 341-347.
  19. Francart S J, Hawes E M, Deal A M, et al., Performance of coagulation tests in patients on therapeutic doses of rivaroxaban. A cross-sectional pharmacodynamic study based on peak and trough plasma levels [J], Thromb Haemost, 2014, 111(6): 1133-1140.
  20. Samuelson B T, Cuker A, Siegal D M, et al., Laboratory Assessment of the Anticoagulant Activity of Direct Oral Anticoagulants: A Systematic Review [J], Chest, 2017, 151(1): 127-138.
  21. Sukumar S, Cabero M, Tiu S, et al., Anti-factor Xa activity assays of direct-acting oral anticoagulants during clinical care: An observational study [J], Res Pract Thromb Haemost, 2021, 5(4): e12528.
  22. Mahoney F I, Barthel D W, FUNCTIONAL EVALUATION: THE BARTHEL INDEX [J], Md State Med J, 1965, 14: 61-65.
  23. Gulpen A J W, Ten Cate H, Henskens Y M C, et al., The daily practice of direct oral anticoagulant use in patients with atrial fibrillation; an observational cohort study [J], PLoS One, 2019, 14(6): e0217302.
  24. Testa S, Tripodi A, Legnani C, et al., Plasma levels of direct oral anticoagulants in real life patients with atrial fibrillation: Results observed in four anticoagulation clinics [J], Thromb Res, 2016, 137: 178-183.
  25. Chan N C, Coppens M, Hirsh J, et al., Real-world variability in dabigatran levels in patients with atrial fibrillation [J], J Thromb Haemost, 2015, 13(3): 353-359.
  26. Barsam S J, Patel J P, Roberts L N, et al., The impact of body weight on rivaroxaban pharmacokinetics [J], Res Pract Thromb Haemost, 2017, 1(2): 180-187.
  27. Borst J M, van Rein N, Bakker E, et al., Body weight is negatively associated with direct oral anticoagulant trough concentrations in dabigatran and apixaban users [J], Br J Haematol, 2020, 191(5): 941-944.
  28. Toorop M M A, van Rein N, Nierman M C, et al., Inter- and intra-individual concentrations of direct oral anticoagulants: The KIDOAC study [J], J Thromb Haemost, 2022, 20(1): 92-103.
  29. Thinggaard M, McGue M, Jeune B, et al., Survival Prognosis in Very Old Adults [J], J Am Geriatr Soc, 2016, 64(1): 81-88.
  30. National Institute for Health and Care Excellence: Clinical Guidelines [M]. Atrial fibrillation: diagnosis and management. London; National Institute for Health and Care Excellence (NICE) Copyright © NICE 2021. 2021.
  31. Parker K, Thachil J, The use of direct oral anticoagulants in chronic kidney disease [J], Br J Haematol, 2018, 183(2): 170-184.
  32. Reilly P A, Lehr T, Haertter S, 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], J Am Coll Cardiol, 2014, 63(4): 321-328.

Tables

Tables 1 to 5 are available in the Supplementary Files section.