Initial rivaroxaban dosing in patients with atrial fibrillation

Abstract Background Rivaroxaban is a non‐vitamin K oral anticoagulant and has been approved for prevention of stroke and systemic embolism in patients with non‐valvular atrial fibrillation (AF). Current labeling recommends 20 mg once a day (q.d.) as a standard dose and a reduced dose of 15 mg q.d. in patients with renal impairment. Hypothesis The aim of this study was to analyze the adherence to current labeling concerning initial rivaroxaban dosing and to determine whether potential lack of such adherence is medically justified. Methods Patients with AF initiated on rivaroxaban between January 1, 2016 and January 31, 2017, were identified in the Heart Center Leipzig database. Health records were screened to identify prescribed rivaroxaban dose, presence or absence of renal impairment, patient characteristics, further dosing‐relevant diagnoses and co‐medication with antiplatelet drugs and non‐vitamin K oral anticoagulants (NOACs). Results We identified a total of 378 consecutive patients. In 282 cases (74.6%), rivaroxaban was prescribed in a standard dose and in 96 (25.4%) in a reduced dose. Out of 96 patients receiving a reduced dose, 50 (52.1%) did not meet labeling criteria for dose reduction. In uni‐ and multivariate regression analysis, estimated glomerular filtration rate (eGFR) (odds ratio [OR] 0.34, 95% confidence interval [CI] 0.12‐0.95, P = .04) was the only independent predictor of rivaroxaban underdosage. Conclusions In clinical practice, rivaroxaban dosing is frequently incoherent with labeling. In this study, rivaroxaban was often administered underdosed. Potentially inappropriate dose reduction was significantly associated with eGFR, the same factor that is used as criterion for dose adjustment.


| INTRODUCTION
Atrial fibrillation (AF), with its prevalence of 3% in adults, is the most common cardiac arrhythmia worldwide. 1 Patients with AF have an increased risk of stroke and systemic thromboembolism. The rate of ischemic stroke among these patients is 4-to 5-fold higher than among those without AF. 2 The therapy of non-valvular AF concentrates on reducing these risks. Commonly, dose-adjusted vitamin K antagonists (VKAs) were considered the first-choice medication; however, the introduction of non-vitamin K oral anticoagulants (NOACs) provided a considerable advancement in the field.
The Rivaroxaban vs Warfarin in Non-valvular Atrial Fibrillation (ROCKET AF) trial began the clinical use of rivaroxaban-a NOAC and an oral direct factor Xa inhibitor. Its effectiveness and safety of usage was proven to be at least equal to dose-adjusted warfarin, in spite of fixed dosing, few drug and food interactions and without the need for continual laboratory monitoring. 3,4 However, rivaroxaban's clearance is determined by renal function, which constitutes the need for dose adjustment in patients with renal impairment. The European Medicines Agency (EMA) recommends 20 mg once a day (q.d.) as a standard dose in patients with estimated glomerular filtration rate (eGFR) ≥50 mL/min and a reduced dose of 15 mg q.d. in patients with renal impairment and eGFR of 15 to 49 mL/min. 5 These recommendations were established in accordance with a pharmacokinetic model in which the creatinine clearance measurement showed a heightened rivaroxaban exposure in correlation with decreased renal functions.
Serum rivaroxaban concentrations increased significantly with a creatinine clearance <50 mL/min. 6,7 As suggested by recently registered data, rivaroxaban is commonly dosed inadequately. Such cases occurred among patients with normal as well as insufficient renal function, causing potential over-or underdosing. [8][9][10][11] Research provides information on how such instances influence drug's safety and effectiveness. Improper dose reduction may increase the risk of cardiovascular hospitalization, while lack of a decreased dose in cases with severe renal disorder may raise all-cause mortality and the risk of bleeding. [9][10][11] The aim of this study was to analyze the adherence to current labeling concerning initial rivaroxaban dosing in clinical practice and to identify factors associated with inappropriate dose reduction.

| Patient population
This retrospective study was performed using the Heart Center Leipzig database to identify consecutive patients with AF initiated on rivaroxaban between January 1, 2016 and January 31, 2017. Patients treated with rivaroxaban due to other conditions (treatment or prophylaxis of venous thromboembolism, prophylaxis of acute coronary syndrome), with valvular AF (mitral stenosis or artificial heart valves) or for whom the renal function was not documented, were not included ( Figure 1).
over the last 6 months before choosing the dosing pattern and may influence the treatment were also included in the analysis.

| Renal function and off-label dosing
The main outcome was coherence or incoherence of the first rivaroxaban prescribing order with the package insert (PI) labeling.
Patients with an eGFR ≥50 mL/min and a prescribed reduced dose of 15 mg q.d were categorized as potentially underdosed. An eGFR of 15 to 49 mL/min classified patients with prescribed dose of 20 mg q.d. as being potentially overdosed. Treatment was considered appropriate if it was consistent with the EMA-guidelines. Furthermore, the physician letters were searched for reasons for the off-label treatment.

| Statistical analysis
All statistical analyses were conducted by using IBM SPSS Statistics 24.0 (Armonk, New York). Data are presented as mean ± SD, raw numbers and percentages. The cohort differences were assessed by statistical tests of significance (χ 2 for categorical variables, t test for continuous variables). The identification of independent predictors of sub-optimal rivaroxaban therapy was made by multivariate regression analysis, that included variables with a P-value <.1 found in univariate analysis. A P-value of <.05 was considered statistically significant.

| RESULTS
A total of 378 patients with non-valvular AF who were initiated on rivaroxaban were identified.

| Predictors of rivaroxaban underdosage
In  As mentioned above, the ORBIT-AF II registry considered the dosing of patients being on rivaroxaban, dabigatran, and apixaban. In this study, apixaban had the highest inappropriate dosing rate (13.9%), followed by rivaroxaban (12.3%) and dabigatran (8.0%). Most inappropriately dosed patients were the ones who were underdosed. In comparison with patients taking rivaroxaban (8.0% being potentially underdosed and 4.8% being potentially overdosed), patients on dabigatran were prescribed an inappropriately low (7.5%) and high (0.5%) dose less often. On the other hand, apixaban was prescribed underdosed more frequently (11.8%) and overdosed more rarely (2.1%). However, there is a big disproportion between the numbers of patients receiving each medication. Rivaroxaban, with the number of 3078, was the most commonly prescribed NOAC in this study. 2235 patients were on apixaban and only 425 patients received dabigatran.
The main finding of another retrospective study performed in the Heart Center Leipzig in 2016-Initial apixaban dosing in patients with AF, was that apixaban was frequently dosed inappropriately in patients with AF, with underdosing being more common than overdosing. 12  only. Compared to the results in our study, the frequency of potentially underdosed patients was clearly rarer (13.2% vs 28.6%), whereas the frequency of potentially overdosed ones was almost equal (2.9% vs 2.3%). The difference of the off-label underdosing might be caused by comparably more complicated guidelines for apixaban which require a dose reduction in case of at least two of these three conditions being met: serum creatinine ≥1.5 mg/dL, body weight ≤ 60 kg, and/or age ≥ 80 years. 13 In multivariate regression analysis, we could prove that the decision for a lower than recommended dose of rivaroxaban is significantly associated with patients' eGFR, the same factor that is used as criterion for dose adjustment in the EMA-approved PI of rivaroxaban. increased significantly with a creatinine clearance <50 mL/min. 6,7 We could see that physicians often decided for a reduced dose in patients with eGFR closer to the cut-off value compared with patients receiving doses consistent with the PI. Among patients without a renal indication for dose reduction, the ones who received a reduced dose exhibited worse renal function than those who received a stan-  9 Hence, further research is required to prove the connection between off-label dosing of rivaroxaban and patients' health. In daily practice only prescribing the right dose to the right patient can assure the achieving of the results that NOACs demonstrated in randomized clinical trials.

| LIMITATIONS
This study has some limitations. It was a retrospective study and the data were from a single medical center. Additionally, not all concomitant medicines that might impact rivaroxaban treatment were collected. Last, no data was available, as to whether the dose was corrected and the association with clinical outcomes (eg, strokes, systemic embolism) was not reported.

| CONCLUSIONS
In routine clinical practice, the prescribed rivaroxaban doses in patients with non-valvular AF are often incoherent with EMA labeling. In this study, inappropriate rivaroxaban dosing occurred in patients with normal and insufficient renal function, with potential underdosing being more common (13.2% vs 2.9%). Inappropriate dose reduction was significantly associated with eGFR, the same factor that is used as a crite-