Does atorvastatin therapy change the anti‐Xa activity in xabans‐treated patients with atrial fibrillation?

Abstract Atorvastatin and direct oral factor Xa inhibitors (xabans) are frequently co‐administrated in patients with atrial fibrillation (AF). However, no studies investigating the possibility of the pharmacologic interaction between these agents have been conducted. The aim of this prospective observational study was to determine the impact of atorvastatin therapy on anti‐Xa activity in xabans‐treated patients with AF. We enrolled 115 AF patients on long‐term rivaroxaban (52 patients) and long‐term apixaban (63 patients) therapy. Long‐term atorvastatin (40 mg once daily) was administrated to 28 rivaroxaban‐treated patients and to 28 apixaban‐treated patients. Trough and peak samples were tested for anti‐Xa activity with drug‐specific anti‐Xa chromogenic analysis. For rivaroxaban, there were no significant differences in trough activity (45.5 ± 39.5 ng/ml vs. 46.2 ± 30.1 ng/ml; p = .34) and peak anti‐Xa activity (179.2 ± 108.8 ng/ml vs. 208.1 ± 104.1 ng/ml; p = .94) between atorvastatin‐treated patients and those without atorvastatin. Similarly, atorvastatin did not impact the trough activity (127.7 ± 71.1 ng/ml vs. 100.8 ± 61.1 ng/ml; p = .12) or peak anti‐Xa activity (213.8 ± 103.6 ng/ml vs. 179.3 ± 72.9 ng/ml; p = .14) among apixaban‐treated patients with AF. This observational study did not show a significant impact of atorvastatin on trough and peak anti‐Xa activity in xabans‐treated patients with AF.

cytochrome P450 (CYP) 3A4, and is a substrate of glycoprotein-P (P-gp). [6][7][8] Similarly, xabans are metabolized by CYP 3A4 and CYP2J2, and are substrates of P-gp 1-3 ; therefore, there is a theoretical possibility of drug interaction between atorvastatin and direct oral factor Xa inhibitors. Unfortunately, no studies of this possible interaction in patients with AF have been conducted. 9 Therefore, the aim of this prospective observational study was to determine the impact of atorvastatin therapy on the anti-Xa activity in direct factor Xa inhibitors-treated patients with AF.

| PATIENTS AND ME THODS
We enrolled consecutive patients with AF on long-term rivaroxa- age ≥80 years, body weight <60 kg. Long-term atorvastatin (40 mg once daily) was administered for dyslipidemia, stroke or cerebrovascular disease, and ischemic heart disease. The study design matched the one used in our prior NOACs pharmacology studies. [10][11][12] We used an observational design. All samples were taken during the inhospital stay. We tested the trough samples (24 h after the previous drug dose in rivaroxaban-treated patients, and 12 h for apixabantreated patients; at 7:00 a.m) and peak samples (2 h after the next drug dose administration for rivaroxaban-treated patients, and 3 h for apixaban-treated patients; at 9:00 and 10:00 a.m.), used healthcare professional compliance verification, and allowed an attending physician-based decision on concomitant medication. Similarly, the exclusion criteria, namely a disabling or recent stroke, recent or pending surgery, known inherited bleeding disorders, uncontrolled hypertension, the need for anticoagulation for disorders other than AF, severe renal dysfunction (glomerular filtration rate <15 mL/ min/1.73 m 2 ), active liver disease and extreme body weight (body mass index <18 kg/m 2 and >40 kg/m 2 ), matched those used in our previous studies. Rivaroxaban therapy lasted on average 110 days prior to sample taking, apixaban therapy lasted 117.5 days, and atorvastatin was taken on average 90.5 days prior to blood sampling, respectively. This study was performed according to all ethical standards defined by the Declaration of Helsinki and approved by the local ethical committee (Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava). The patients agreed to participate in the research. All samples were taken after obtaining a written informed consent to participate in the study. Rivaroxaban and apixaban anti-Xa activity (ng/ml) was determined using drug-specific anti-Xa chromogenic analysis. 13

| Statistical analysis
Data analysis was performed using STATISTICA v 5.0 (StatSoft, Tula, USA). Data were checked for normality with the Shapiro-Wilk test (data are displayed as mean ± standard deviation in case of normally distributed ones and as median and range in case of asymmetrically distributed ones); a t-test was used in the case of normally distributed data or a Mann-Whitney U test was used when data distribution was asymmetrical. The p-value of <.05 was considered as a statistically significant difference.

| Nomenclature of targets and ligands
Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guide topha rmaco logy. apixaban 2.5 mg twice daily for 32 patients and apixaban 5 mg twice daily for 31 patients) were enrolled in our study. Long-term atorvastatin (40 mg once daily) was administrated to 28 rivaroxaban-treated patients (8 patients for dyslipidemia, 11 patients for cerebrovascular diseases, and 9 patients for ischemic heart disease) and to 28 apixaban-treated patients (9 patients for dyslipidemia, 10 patients for cerebrovascular diseases, and 9 patients for ischemic heart disease). There were no significant differences in the length of rivaroxaban and apixaban therapy, concomitant therapy (except of atorvastatin) or basic demographic data (Table 1)

| DISCUSS ION
Atorvastatin, probably the most frequently used agent for the treatment of cardiovascular diseases, significantly reduces future cardiovascular mortality in the settings of the primary and secondary prevention of these diseases. 17,18 However, it could modulate drug metabolism, and therefore create an unexpected drug interaction with direct oral factor Xa inhibitors, as the metabolism of these directly acting anticoagulants is dependent on CYP and P-gp

| Limitations
Our study had several limitations. First, the low sample size is probably the most important limitation. Second, the non-randomized design is another limitation, and thus the data derived from our study do not have the evidentiary power of data derived from a randomized trial, and lack sufficient power to arrive at definitive conclusions. Nevertheless, due to robust data confirming the ben-

| CON CLUS ION
This observational study did not show a significant impact of atorvastatin on trough and peak anti-Xa activity in direct oral factor Xa inhibitors-treated patients with AF, which suggests that atorvastatin could be safely co-administrated with direct oral factor Xa inhibition.
However, due to limited data and other limitations, further studies will be needed to adopt final conclusions.

ACK N OWLED G M ENTS
This study was supported by the research project APVV 16-0020

E TH I C A L A PPROVA L A N D I N FO R M CO N S E NT
This research was conducted according to ethical standards and ap-