Toward Genetic Testing of Rivaroxaban? Insights from a Systematic Review on the Role of Genetic Polymorphism in Rivaroxaban Therapy

Abstract

Background: Investigations into the rivaroxaban response from the perspective of genetic variation have been relatively recent and wide in scope, whereas there is no consensus on the necessity of genetic testing of rivaroxaban. Thus, this systematic review aims to thoroughly evaluate the relationship between genetic polymorphisms and rivaroxaban outcomes.

Methods: The PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Chinese databases were searched to 23 October 2022. We included cohort studies reporting the pharmacogenetic correlation of rivaroxaban. Outcomes measured included efficacy (all-cause mortality, thromboembolic events and coagulation-related tests), safety (major bleeding, clinically relevant non-major bleeding [CRNMB] and any hemorrhage), and pharmacokinetic outcomes. A narrative synthesis was performed to summarize findings from individual studies according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and the reporting guideline for Synthesis Without Meta-Analysis.

Results: A total of 12 studies published between 2019 and 2022 involving 1364 patients were included. Ten, one, and six studies focused on the ABCB1, ABCG2, and CYP gene polymorphisms, respectively. Pharmacokinetic outcomes accounted for the majority of the outcomes reported (n = 11), followed by efficacy (n = 5) [including prothrombin time (PT) or international normalized ratio (n = 3), platelet inhibition rate (PIR) or platelet reactivity units (PRUs; n = 1), thromboembolic events (n = 1)], and safety (n = 5) [including major bleeding (n = 2), CRNMB (n = 2), any hemorrhage (n = 1)]. For ABCB1 gene polymorphism, the relationship between PT and ABCB1 rs1045642 was inconsistent across studies, however there was no pharmacogenetic relationship with other efficacy outcomes. Safety associations were found in ABCB1 rs4148738 and major bleeding, ABCB1 rs4148738 and CRNMB, ABCB1 rs1045642 and CRNMB, and ABCB1 rs2032582 and hemorrhage. Pharmacokinetic results were inconsistent among studies. For ABCG2 gene polymorphism, no correlation was observed between ABCG2 rs2231142 and dose-adjusted trough concentration (Cmin/D). For CYP gene polymorphisms, PIR or PRUs have a relationship with CYP2C19 rs12248560, however bleeding or pharmacokinetic effects did not show similar results.

Conclusions: Currently available data are insufficient to confirm the relationship between clinical or pharmacokinetic outcomes of rivaroxaban and gene polymorphisms. Proactive strategies are advised as a priority in clinical practice rather than detection of SNP genotyping.

Clinical trials registration: PROSPERO registration number CRD42022347907.

Full text

Vol.:(0123456789)
Clinical Pharmacokinetics
https://doi.org/10.1007/s40262-024-01358-3
SYSTEMATIC REVIEW
Toward Genetic Testing ofRivaroxaban? Insights fromaSystematic
Review ontheRole ofGenetic Polymorphism inRivaroxaban Therapy
YiMa1,2,3· ZaiweiSong1,2,3· XinyaLi1,2,3,4· DanJiang1,2,3,4· RongshengZhao1,2,3· ZhanmiaoYi1,2,3
Accepted: 13 February 2024
© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2024
Abstract
Background Investigations into the rivaroxaban response from the perspective of genetic variation have been relatively recent
and wide in scope, whereas there is no consensus on the necessity of genetic testing of rivaroxaban. Thus, this systematic
review aims to thoroughly evaluate the relationship between genetic polymorphisms and rivaroxaban outcomes.
Methods The PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Chinese databases were
searched to 23 October 2022. We included cohort studies reporting the pharmacogenetic correlation of rivaroxaban. Out-
comes measured included efficacy (all-cause mortality, thromboembolic events and coagulation-related tests), safety (major
bleeding, clinically relevant non-major bleeding [CRNMB] and any hemorrhage), and pharmacokinetic outcomes. A narra-
tive synthesis was performed to summarize findings from individual studies according to the Preferred Reporting Items for
Systematic Reviews and Meta-Analyses and the reporting guideline for Synthesis Without Meta-Analysis.
Results A total of 12 studies published between 2019 and 2022 involving 1364 patients were included. Ten, one, and six
studies focused on the ABCB1, ABCG2, and CYP gene polymorphisms, respectively. Pharmacokinetic outcomes accounted
for the majority of the outcomes reported (n=11), followed by efficacy (n=5) [including prothrombin time (PT) or inter-
national normalized ratio (n=3), platelet inhibition rate (PIR) or platelet reactivity units (PRUs; n=1), thromboembolic
events (n=1)], and safety (n=5) [including major bleeding (n=2), CRNMB (n=2), any hemorrhage (n=1)]. For ABCB1
gene polymorphism, the relationship between PT and ABCB1 rs1045642 was inconsistent across studies, however there was
no pharmacogenetic relationship with other efficacy outcomes. Safety associations were found in ABCB1 rs4148738 and
major bleeding, ABCB1 rs4148738 and CRNMB, ABCB1 rs1045642 and CRNMB, and ABCB1 rs2032582 and hemorrhage.
Pharmacokinetic results were inconsistent among studies. For ABCG2 gene polymorphism, no correlation was observed
between ABCG2 rs2231142 and dose-adjusted trough concentration (Cmin/D). For CYP gene polymorphisms, PIR or PRUs
have a relationship with CYP2C19 rs12248560, however bleeding or pharmacokinetic effects did not show similar results.
Conclusions Currently available data are insufficient to confirm the relationship between clinical or pharmacokinetic out-
comes of rivaroxaban and gene polymorphisms. Proactive strategies are advised as a priority in clinical practice rather than
detection of SNP genotyping.
Clinical Trials Registration PROSPERO registration number CRD42022347907.
1 Introduction
The introduction of direct oral anticoagulants (DOACs)
represents a major medical breakthrough, of which rivar-
oxaban is an example [1]. As the first oral direct inhibitor of
factor Xa (FXa), rivaroxaban is approved for the treatment
and prophylaxis of deep vein thrombosis (DVT) and pulmo-
nary embolism (PE), as well as for the reduction of the risk
of stroke and embolism in non-valvular atrial fibrillation
(NVAF) [2, 3]. Due to several good reasons, the last decade
has witnessed a great increase in the clinical use of rivaroxa-
ban in the field of anticoagulation care.
It is acknowledged that compared with warfarin, rivar-
oxaban has a more predictable anticoagulant effect due to
its precise target, well-studied pharmacokinetic (PK) data,
and low potential for drug–drug interactions (DDIs) [4, 5].
Consequently, rivaroxaban is usually administered in a fixed
dosing regimen and does not require routine monitoring in
most cases [6]. However, after using rivaroxaban outside of
the closely supervised conditions of clinical trials, effec-
tiveness and safety concerns as well as considerable inter-
individual differences in dose-concentration response have
Yi Ma and Zaiwei Song contributed equally to this work.
Extended author information available on the last page of the article

Y.Ma et al.
Key Points
1. Individualized anticoagulant therapy of rivaroxaban
still presents a challenge for clinical practitioners, and
thus this study provides the inaugural comprehensive
examination and presentation of the relationship between
genetic polymorphisms and rivaroxaban outcomes.
2. Currently available data are insufficient to confirm
the relationship between clinical or pharmacokinetic
outcomes of rivaroxaban and gene polymorphisms.
3. Taking into account available evidence and health
resources, additional proactive strategies are advised as
a priority rather than the detection of SNP genotyping in
clinical settings.
been noted in real-world settings [7]. The striking data from
published studies have shown an up to 15-fold variation in
rivaroxaban plasma concentration [8, 9]. Moreover, a sub-
stantial proportion (17.24%) of patients had bleeding events
after rivaroxaban therapy [10].
Although several factors such as the patient’s age, liver
and kidney function, and DDI may contribute to the inter-
individual variability of rivaroxaban, these factors are not
enough to completely explain the current clinical confusion.
Within the framework of anticoagulation therapy, pharma-
cogenetics and personalized approach come into play [11].
Polymorphisms of genes that encode transporters and bio-
transformation enzymes, especially ABCB1, ABCG2, and
cytochrome P450 (CYP) isoforms 3A4, 3A5, 2C19, and 2J2,
are thought to potentially contribute to the wide interindi-
vidual variability seen in rivaroxaban responses [11, 12].
At present, investigations into the rivaroxaban response
from the perspective of genetic variation have been relatively
recent and wide in scope [13–15]; however, regarding the
functional effect of these polymorphisms in the rivaroxaban
pathway, no consensus has been reached. Furthermore, to a
certain extent, genetic testing is costly and time-consuming
for patients and clinical staff. Individualized anticoagulant
therapy of rivaroxaban still presents a challenge for clinical
practitioners. What is covered by current available pharma-
cogenetic research on rivaroxaban? What part does genetic
polymorphism play in the PK and clinical outcomes of rivar-
oxaban? What kind of genetic testing should be undertaken
in patients taking rivaroxaban?
Based on the above considerations, we carried out a sys-
tematic review to examine the relationship between genetic
polymorphisms within the rivaroxaban pathway and the PK
or clinical outcomes of rivaroxaban. We aimed to clarify the
necessity of genetic testing of rivaroxaban and fill the gap
between knowledge and clinical practice.
2 Methods
This study was performed according to the Preferred Report-
ing Items for Systematic Reviews and Meta-Analyses
(PRISMA) statement and the reporting guideline for Syn-
thesis Without Meta-Analysis (SWiM) in systematic reviews
[16, 17]. The PRISMA checklist is included in Online
Resource I. The protocol for this systematic review has
been registered in the International Prospective Register of
Systematic Reviews (PROSPERO; no. CRD42022347907).
2.1 Eligibility Criteria
Studies were considered eligible if they satisfied all the
following inclusion criteria: (1) type of studies: cohort
studies; (2) type of subject: patients undergoing treat-
ment with rivaroxaban who are of any race, sex or age;
(3) types of exposure/comparison: patients categorized by
wild or mutant genotype of included genes in the rivar-
oxaban pathway (Table1); a total of 11 single nucleotide
polymorphisms (SNPs) were considered, including, but
not limited to, genes involved in the Pharmacogenomics
Knowledge Base (PharmGKB; https:// www. pharm gkb.
org/ guide lineA nnota tions), which contains recommenda-
tions from the Clinical Pharmacogenetics Implementa-
tion Consortium (CPIC) and other national association of
pharmacogenomics; and (4) types of outcomes measured:
rivaroxaban-related efficacy or safety outcomes (primary
outcomes) and PK outcomes (secondary outcomes).
All-cause mortality, any thromboembolic events,
prothrombin time (PT), international normalized ratio
(INR), platelet inhibition rate (PIR), platelet reactivity
units (PRUs), and other coagulation-related tests were
among the efficacy outcomes. We included PIR and PRUs
Table 1 Genetic polymorphisms within the rivaroxaban pathway
Gene SNP Polymorphisms
Transporters
ABCB1 rs1045642 c.3435C>T
ABCB1 rs2032582 c.2677T>G/A
ABCB1 rs1128503 c.1236T>C
ABCB1 rs4148738 c.2482-2236G>A
g.87163049C>T
ABCB1 rs4728709 c.-330-3208G>A
ABCG2 rs2231142 c.421C>A
Drug-metabolizing
enzymes
CYP3A4*22 rs35599367 c.522-191C>T
CYP3A5*3 rs776746 c.-253-1A>G
CYP2J2*7 rs890293 c.-76G>T
CYP2C19*2 rs4244285 c.681G>A
CYP2C19*17 rs12248560 c.-806C>T

Genetic Polymorphism and Rivaroxaban
because some studies have suggested that rivaroxaban
inhibits FXa to exert its anticoagulant effects and also
has an effect on platelets [18, 19], and also because one of
the primary studies included in our analysis used PIR and
PRUs as outcome measures. Considering the limited num-
ber of included studies, we elected to include all reported
coagulation tests in this systematic review.
The rate of major bleeding, clinically relevant non-
major bleeding (CRNMB), and any hemorrhage events
(with no restriction on severity) were included in the
safety outcomes. The plasma concentration (C) [including
trough concentration (Cmin), peak concentration (Cmax),
concentration after 2h of administration (C2h)], dose-
adjusted concentration (C/Dose), and area under the drug-
time curve (AUC) were included in the PK outcomes. The
exclusion criteria were duplicate publications, literature
published in languages other than English or Chinese,
abstracts without essential details, unqualified data, and
studies that did not adhere to the Hardy–Weinberg equi-
librium (HWE) [20].
2.2 Search Strategy
The PubMed, Embase, Cochrane Central Register of Con-
trolled Trials (CENTRAL), and Chinese databases were
searched for potentially relevant studies from inception to
23 October 2022. Specific search strategies were developed
for each database (Online Resource II). Keywords were
collected through experts’ opinions, literature review, con-
trolled vocabulary and review of the primary search results.
No restrictions were placed on study design or language. The
search strategy was confirmed by an experienced informa-
tion library specialist. The reference list of previous system-
atic reviews and included literature was searched manually.
2.3 Study Selection
After carefully examining the study title, abstract, and full
text in turn, two authors (YM and ZWS) independently eval-
uated the eligibility of all studies based on the inclusion and
exclusion criteria mentioned above. Studies were included
in the systematic review only (but not the meta-analysis) if
their findings were relevant to the research question but data
were not available for quantitative analysis. The correspond-
ing authors (RSZ and ZMY) discussed and resolved any
disagreements among the authors.
2.4 Data Extraction
Based on a predesigned standardized extraction form, two
authors (YM and ZWS) independently extracted data,
including publication year, first author, country, ethnicity,
diagnosis, number of patients, sex, age, rivaroxaban dose,
calculated p-value for HWE, outcomes, and individual
results of the single study. Study authors were contacted for
missing data. Two authors extracted the data, documented it
in Microsoft Excel (Microsoft Corporation, Redmond, WA,
USA), and then had a third author double-check it.
2.5 Quality Assessment/Risk ofBias
Two authors (YM and ZWS) independently assessed the
quality of studies under the Newcastle–Ottawa Scale (NOS)
[21]. The NOS attributes a maximum of 9 points to stud-
ies based on methodological design and formal reporting,
involving ‘selection of cohorts’, ‘comparability of cohorts’,
and ‘assessment of outcome’. An NOS score between 7 and
9 points indicates high quality, a score between 5 and 6 indi-
cates medium quality, and a score between 0 and 4 indicates
low quality [22]. Agreement regarding data extraction and
quality assessment was reached by consensus or, if neces-
sary, by consulting the corresponding authors (RSZ and
ZMY).
2.6 Statistical Analyses
A Chi-square test was performed to verify genotype distribu-
tions using SPSS version 25.0 (IBM Corporation, Armonk,
NY, USA). A p-value >0.05 would indicate accordance
with the HWE. Clinical heterogeneity was estimated by
comparing the population, exposure/comparison, outcome
definition, and other clinical features among studies. If meta-
analysis is feasible, the statistical heterogeneity across the
studies was further assessed using a Chi-square-based Q-test
and I2 statistics [23]. Initially, this review was intended
as a meta-analysis if valid data assessing the association
between genetic polymorphisms with rivaroxaban-related
efficacy, safety and PK outcomes were available from suf-
ficiently homogeneous studies. However, a narrative syn-
thesis rather than a meta-analysis was carried out due to
the significant clinical heterogeneity and data deficit among
various investigations.
3 Results
3.1 Electronic Searches andStudy Selection
A total of 855 candidate references were identified in elec-
tronic database searches. After removing duplicate refer-
ences and carefully reviewing the titles and abstracts, 25
references were recognized as relevant, and all full texts
were then assessed. Of the 25 references, four were not
cohort studies, two did not focus on rivaroxaban, three
did not report the targeted SNPs, two were abstracts and
full-text duplicates, one was published in Russian, and

Y.Ma et al.
one was a trial without results. Finally, according to the
aforementioned inclusion and exclusion criteria, 12 studies
[13–15, 24–32] were included in this systematic review
(Fig.1). The 12 studies were included in the descriptive
analysis since the meta-analysis was infeasible.
3.2 Study Characteristics andQuality Assessment
In total, 12 studies involving 1364 patients were included.
The main characteristics and quality assessment of the
included studies are summarized in Table2. All included
studies were published between 2019 and 2022, and
one was published as a meeting abstract. Seven stud-
ies included Caucasian patients, while the remainder of
the studies included Asian patients. Most of the studies
followed the HWE, except for one abstract that did not
provide the genotype distribution. The common daily
dose of rivaroxaban is 10, 15, or 20mg. PK outcomes
accounted for the majority of the outcomes reported
(n=11), followed by efficacy (n=5) [including PT or
INR, PIR or PRUs, thromboembolic events], and safety
(n=5) [including major bleeding, CRNMB, any hemor-
rhage]. The quality of the cohort studies as determined
by the NOS was ≥7, indicating a low risk of bias. The
quality of one abstract could not be evaluated since there
were insufficient details on the study design [31]. The
detailed results of the quality assessment of cohort studies
included are shown in Online Resource III.
3.3 Overall Findings
The overall findings are summarized in Table3. The
effect of genetic polymorphisms on rivaroxaban out-
come measures with statistical significance is presented
in Table4. Regarding the transporter pathway, ABCB1
Fig. 1 The PRISMA 2020 flow
diagram of study selection.
PRISMA Preferred Reporting
Items for Systematic Reviews
and Meta-Analyses, SNP single
nucleotide polymorphisms

Genetic Polymorphism and Rivaroxaban
Table 2 Main characteristics and quality assessment of the included studies
Study ID Country Ethnicity Diagnosis No. of
patients Male/
Female Age, years
Mean (SD)
Median
[range]
Rivaroxaban
dose (mg) SNPsaHWE Efficacy
outcomes Safety
outcomes Pharmacokinetic
outcomes NOS
Sychev
etal.
(2022)
[13]
Russia Caucasian AF 86 42/44 67.24 (1.01) 20mg qd ①④⑦⑧ Yes PT NR √ 9
Sychev
etal.
(2022)
[14]
Russia Caucasian AF 128 NR 87.5 [83.0–
90.0] 15, 20mg qd ①④ Yes PT CRNMB √ 8
Zhang etal.
(2022)
[24]
China Asian AF 216 102/114 72.65
(12.91)
71.81
(12.81)
2.5–20mg
qd ①②④⑧⑨⑩⑪ Yes NR Hemorrhage √ 9
Lenoir etal.
(2022)
[15]
Switzerland Caucasian AF, VTE 135 89/46 71.1 (12.1) 10, 15,
20mg qd
15mg bid
①②③ Yes NR NR √ 8
Zhang etal.
(2022)
[25]
China Asian AF 150 95/55 68 (12.6) No limit ⑤ Yes NR NR √ 7
Rytkin etal.
(2022)
[26]
Russia Caucasian AF 57 NR NR 15, 20mg qd ⑦ Yes PT, INR NR NR 7
Nakagawa
etal.
(2021[27]
Japan Asian AF 86 73/13 62.4 (10.6) 10, 15mg qd ①②③⑥⑧⑨ Yes NR NR √ 8
Wang etal.
(2021)
[28]
China Asian AF 155 81/74 71.98
(10.72) 15, 20mg qd ①②④ Yes NR Hemorrhage √ 9
Sychev
etal.
(2020)
[29]
Russia Caucasian AF 103 56/47 73 (9.8) NR ①④⑧⑩⑪ Yes PIR, PRUs NR √ 8
Xiang
(2020)
[30]
China Asian AF 28 8/20 68.4 (8.3) NR ①②③④ Yes NR CRNMB √ 8
Cosmi etal.
(2020)
[31]
Italy Caucasian AF, VTE 142 NR NR 20mg qd ④ NR Thromboem-
boliccomplica-
tions
Major bleed-
ing √NA

Y.Ma et al.
rs1045642 and rs4148738 are the two most widely
investigated SNPs. In terms of efficacy, the association
between PT and ABCB1 rs1045642 was inconsistent
between studies, and the pharmacogenetic association
was not observed in other SNPs or efficacy outcomes.
In terms of safety, the pharmacogenetic association was
found in ABCB1 rs4148738 and major bleeding [31],
ABCB1 rs4148738 and CRNMB [13], ABCB1 rs1045642
and CRNMB [13], and ABCB1 rs2032582 and hemor-
rhage [24]. In terms of PK, some studies have revealed
that SNPs of ABCB1 may have an impact on Cmin or Cmax,
whereas the results were inconsistent among studies.
Regarding the drug-metabolizing enzyme pathway, in
terms of efficacy, the association between PIR or PRUs
and CYP2C19 rs12248560 was observed in a single study
[29]. In terms of safety, the pharmacogenetic association
between hemorrhage and CYP-related SNPs was not
observed. In terms of PK, just one study [24] identified a
link between Cmax/Dose and CYP2C19 rs4244285; how-
ever, no pharmacogenetic relationship was revealed in
other SNPs and PK outcomes.
3.4 Genetic Polymorphisms ofTransporters
3.4.1 The Effect ofABCB1 rs1045642
Nine studies reported the influence of ABCB1 rs1045642 on
rivaroxaban outcomes, of which three, four, and nine stud-
ies reported the efficacy, safety, and PK outcomes, respec-
tively. Regarding the efficacy outcomes, one study reported
that the PT level of the TT genotype of ABCB1 rs1045642
was higher than in CC genotype carriers [median (quartile
ranges): TT vs. CC = 14.2 (13.0–16.1) vs. 13.3 (12.4–14.5);
p=0.049] [14] (Table4), whereas results from a multi-
variate analysis of variance (ANOVA) indicated that there
was no correlation between PT level and ABCB1 rs1045642
[13]. According to another study, there was no correlation
between ABCB1 rs1045642 and either PIR {mean (standard
deviation [SD]): CC vs. CT/CT = 29.8% (28.2) vs. 30.9%
(27.9); p=0.839} or PRUs [mean (SD): CC vs. CT/CT =
136.8 (61.3) vs. 135.5 (32.8); p=0.910] [29].
Regarding the safety outcomes, one study found that TT
genotype carriers had a greater incidence of CRNMB than
CC genotype carriers [TT vs. CC: 12/41 (29.3%) vs. 1/22
(4.5%); p=0.021] [14] (Table4). In contrast, no correlation
was observed between ABCB1 rs1045642 and hemorrhage
events [24, 28] or CRNMB [30].
Regarding the PK outcomes, included studies [13–15, 24,
27–30, 32] reported the lack of association between ABCB1
rs1045642 and Cmin, Cmin/Dose, the ratio of Cmin > 87 ng/
mL, C2h, Cmax/Dose, and AUC
6.
a SNP: ①ABCB1 rs1045642; ②ABCB1 rs2032582; ③ABCB1 rs2032582; ④ABCB1 rs4148738; ⑤ABCB1 rs4728709; ⑥ABCG2 rs2231142; ⑦CYP3A4*22 rs35599367; ⑧CYP3A5*3 rs776746;
⑨CYP2J2*7 rs890293; ⑩CYP2C19*2 rs4244285; ⑪CYP2C19*17 rs12248560
AF atrial fibrillation, bid twice daily, CRNMB clinically relevant non-major bleeding, HWE Hardy–Weinberg equilibrium, INR international normalized ratio, NA not applicable, NOS New-
castle–Ottawa Scale, NR not reported, qd once daily, PIR platelet inhibition rate, PRUs platelet reactivity units, PT prothrombin time, SD standard deviation, SNPs single nucleotide polymor-
phisms, THR total hip replacement surgery TKR total knee replacement surgery; VTE venous thromboembolism, √ indicates the outcomes were reported
Table 2 (continued)
Study ID Country Ethnicity Diagnosis No. of
patients Male/
Female Age, years
Mean (SD)
Median
[range]
Rivaroxaban
dose (mg) SNPsaHWE Efficacy
outcomes Safety
outcomes Pharmacokinetic
outcomes NOS
Sychev
etal.
(2019)
[32]
Russia Caucasian THR, TKR 78 22/56 59 (11) 15mg qd ①④⑦⑧ Yes NR NR √ 8

Genetic Polymorphism and Rivaroxaban
3.4.2 The Effect ofABCB1 rs2032582
Four studies reported the impact of ABCB1 rs2032582 on
rivaroxaban outcomes, of which the safety and PK out-
comes were reported by two and four studies, respectively.
Regarding the safety outcomes, one study reported that
the ABCB1 rs2032582 polymorphism was associated with
the risk of hemorrhage events {AA vs. GA/GG: odds ratio
[OR] (95% confidence interval [CI]) = 0.442 (0.232–0.842);
p=0.013} (Table4), indicating that patients carrying GG
and GA genotypes had a higher risk of bleeding than the AA
carriers [24]. However, the lack of an association between
ABCB1 rs2032582 and CRNMB was revealed in another
study (p=0.257) [30].
Regarding the PK outcomes, one study reported that
patients carrying the ABCB1 2677G allele exhibited sig-
nificantly higher Cmax/Dose than non‐carriers [mean (SD):
GG vs. GA vs. AA: 28.18 (14.29) vs. 19.1 (12.28) vs. 18.83
(8.9); p=0.025] [24] (Table4), whereas another study
found no association between ABCB1 rs2032582 and Cmax
(p=0.44) [30]. In addition, included studies [15, 24, 27, 30]
revealed the lack of association between ABCB1 rs2032582
and Cmin, Cmin/Dose, C2h and AUC
6.
3.4.3 The Effect ofABCB1 rs1128503
Four studies reported the effect of ABCB1 rs1128503 on
rivaroxaban outcomes, of which the safety and PK outcomes
were reported by two and four studies, respectively. Regard-
ing the safety outcomes, included studies reported the lack
of association between ABCB1 rs1128503 and hemorrhage
events (p=0.806) [28] and CRNMB (p=0.61) [30].
Regarding the PK outcomes, one study observed a rela-
tionship between ABCB1 rs1128503 and Cmin [median (quar-
tile ranges): AA/GA vs. GG = 20.93 (10.77–26.84) vs. 51.72
(30.36–61.45); p=0.023] [30] (Table4). Additionally, one
study found that the patients carrying TT genotypes had a
higher Cmin than the CC carriers [median (quartile ranges):
TT vs. CC = 34.66 (18.00–74.00) vs. 20.23 (13.64–51.70);
p=0.042] [28]. However, another study reported a lack
of association between ABCB1 rs1128503 and Cmin/Dose
(p=0.85) [27]. Moreover, included studies [15, 30] reported
the lack of association between ABCB1 rs1128503 and C2h,
Cmax and AUC
6.
3.4.4 The Effect ofABCB1 rs4148738
Eight studies reported the effect of ABCB1 rs4148738 on
rivaroxaban outcomes, with four, five and eight studies
reporting on efficacy, safety and PK outcomes, respectively.
Regarding the efficacy outcomes, included studies reported
the lack of association between ABCB1 rs4148738 and PT
level [13, 14]. Another study reported the lack of association
Table 3 Evidence table for the pharmacogenetic association of rivaroxaban outcomes
AUC
6 area under the drug-time curve from time zero to 6h, Cmin trough concentration, Cmax peak concentration, C/Dose dose-adjusted concentration, CRNMB clinically relevant non-major
bleeding, INR international normalized ratio, PIR platelet inhibition rate, PRUs platelet reactivity units, PT prothrombin time, ▲ indicates a significant association was reported, △ indicates no
significant association was reported, – indicates not reported by available evidence
Outcomes classification Outcomes ABCB1 ABCB1 ABCB1 ABCB1 ABCB1 ABCG2 CYP3A4 CYP3A5 CYP2J2 CYP2C19 CYP2C19
rs1045642 rs2032582 rs1128503 rs4148738 rs4728709 rs2231142 rs35599367 rs776746 rs890293 rs4244285 rs12248560
Efficacy outcomes Thromboembolic – – – △– – – – – – –
PT, INR ▲△––△––△ △ – – –
PIR, PRUs △––△––– △–△▲
Safety outcomes Major bleeding – – – ▲– – – – – – –
CRNMB ▲––▲– – – – – – –
Hemorrhage △▲△△––– △ △ △ △
Pharmacokinetic outcomes Cmin, Cmin/Dose △△▲△ △ ▲△ △ △ △ △ △
Cmax, Cmax/Dose △▲△ △ ▲△––△ △△▲△
AUC
6△△△– – – – – – – –

Y.Ma et al.
Table 4 Effect of genetic polymorphisms on rivaroxaban outcome measures with statistically significant
CI confidence interval, Cmin trough concentration, Cmax peak concentration, C/Dose dose-adjusted concentration, CRNMB clinically relevant non-major bleeding, OR odds ratio, PIR platelet
inhibition rate, PRUs platelet reactivity units, PT prothrombin time
* p<0.05, ** p<0.01
a Median (quartile ranges)
b Mean (SD)
c Incidence
Study ID Outcome Exposure group Comparison group p-Value Effect
Genotype No. of patients Results Genotype No. of patients Results
Genetic polymorphisms of transporters
The effect of ABCB1 rs1045642
Sychev etal.
(2022) [14]PT level TT 41 14.2 (13.0–16.1)aCC 22 13.3 (12.4–14.5)a0.049* TT vs. CC:↑
Sychev etal.
(2022) [14]CRNMB TT 41 12/41 (29.3%)cCC 22 1/22 (4.5%)c0.021* TT vs. CC:↑
The effect of ABCB1 rs2032582
Zhang etal.
(2022) [24]Hemorrhage AA vs. GA/GG: OR 0.442, 95% CI 0.232–0.842 0.013* G allele:↑
Zhang etal.
(2022) [24]Cmax/Dose GG 26 28.18 (14.29)bGA 88 19.1 (12.28)b0.003** GG vs. GA:↑
Zhang etal.
(2022) [24]Cmax/Dose GG 26 28.18 (14.29)bAA 102 18.83 (8.91)b0.001** GG vs. AA:↑
The effect of ABCB1 rs1128503
Xiang (2020)
[30]Cmin AA/GA 21 20.93 (10.77–26.84)aGG 7 51.72 (30.36–
61.45)a0.023* AA/GA vs. GG:↓
Wang etal.
(2021) [28]Cmin TT 65 34.66 (18.00–74.00)aCC 27 20.23 (13.64–
51.70)a0.042* TT vs. CC:↑
The effect of ABCB1 rs4148738
Sychev etal.
(2022) [14]CRNMB TT 28 11/28 (39.3%)cCC 37 3/37 (8.1%)c0.002** TT vs. CC:↑
Sychev etal.
(2022) [14]CRNMB TT 28 11/28 (39.3%)cCT 63 9/63 (14.3%)c0.008** TT vs. CT:↑
Genetic polymorphisms of drug-metabolizing enzymes
The effect of CYP2C19*2 (rs4244285)
Zhang etal.
(2022) [24]Cmax/Dose GG 100 25.18 (15.64)bAA 12 9.36 (4.42)b<0.00001** GG vs. AA:↑
Zhang etal.
(2022) [24]Cmax/Dose GA 104 21.65 (13.12)bAA 12 9.36 (4.42)b<0.00001** GA vs. AA:↑
The effect of CYP2C19*17 (rs12248560)
Sychev etal.
(2020) [29]PIR (%) CC 58 25.0 (25.9)bCT/TT 45 37.8 (28.9)b0.013* CC vs. CT/TT:↓
Sychev etal.
(2020) [29]PRUs CC 58 147.1 (59.0)bCT/TT 45 121.4 (63.5)b0.044* CC vs. CT/TT:↑

Genetic Polymorphism and Rivaroxaban
between ABCB1 rs4148738 and either PIR [mean (SD): CC
vs. CT/CT: 34.5% (28.5) vs. 29.7% (7.8); p=0.416] or
PRUs [mean (SD): CC vs. CT/CT = 113.8 (57.1) vs. 141.0
(62.3), p=0.053] [29]. Additionally, the incidence of throm-
boembolic events was comparable among ABCB1 rs4148738
genotypes [31].
Regarding the safety outcomes, one study reported that
the incidence of CRNMB in TT genotype carriers was sig-
nificantly higher than in CC genotype carriers [TT vs. CC:
11/28 (39.3%) vs. 3/37 (8.1%); p=0.002] and CT geno-
type carriers [TT vs. CT: 11/28 (39.3%) vs. 9/63 (14.3%);
p=0.008] [14] (Table4). Additionally, a study indicated
that those with the AA allele had a lower cumulative rate
of major bleeding than individuals with the GA/GG allele
(AA vs. GA/GG: 8% vs. 17%) [31]. However, no correlation
between ABCB1 rs4148738 and hemorrhage events [24, 28]
or CRNMB [30] was found.
Regarding the PK outcomes, included studies [13, 14, 24,
28–30, 32] reported the lack of association between ABCB1
rs4148738 and Cmin, Cmin/Dose, and the ratio of Cmin >87
ng/mL. The results of Cmax-related PK outcomes varied
between investigations. Some studies found no correlation
between the ABCB1 rs4148738 and Cmax or Cmax/Dose [24,
30, 32], whereas one study found that the Cmax of carriers
with AA is lower, but detailed data were not provided [31].
3.4.5 The Effect ofABCB1 rs4728709
Only one study reported the impact of ABCB1 rs4728709 on
rivaroxaban outcomes, and focused on PK outcomes [24].
For patients with the ABCB1 rs4728709 mutation, the Cmin
in the 10, 15, and 20 mg once-daily dosage regimens were,
accordingly, below the target range. Additionally, a popula-
tion PK study revealed that the ABCB1 rs4728709 consider-
ably affected the apparent clearance (CL/F) [p<0.01] [25].
3.4.6 The Effect ofABCG2 rs2231142
Only one study reported the effect of ABCG2 rs2231142 on
rivaroxaban outcomes, and focused on PK outcomes [27].
No correlation was observed between ABCG2 rs2231142
and Cmin/Dose [median (quartile ranges): CC vs. CA vs. AA
= 3.35 (2.25–5.14) vs. 3.47 (1.88–5.39) vs. 1.89 (0.99–3.49);
p=0.315].
3.5 Genetic Polymorphisms ofDrug‑Metabolizing
Enzymes
3.5.1 The Effect ofCYP3A4*22 (rs35599367)
Three studies reported the effect of CYP3A4*22
(rs35599367) on rivaroxaban outcomes, with two reporting
on efficacy and two reporting on PK outcomes. Regarding
the efficacy outcomes, included studies revealed the lack of
association between CYP3A4*22 (rs35599367) and PT or
INR level [13, 14]. In investigations that looked at the PK
outcomes, it was noted that there was no correlation between
CYP3A4*22 (rs35599367) and Cmin or Cmax [26, 32].
3.5.2 The Effect ofCYP3A5*3 (rs776746)
Five studies reported the effect of CYP3A5*3 (rs776746) on
rivaroxaban outcomes, of which the efficacy, safety, and PK
outcomes were reported by two, one, and five studies, respec-
tively. Regarding the efficacy outcomes, one study reported
a lack of association between CYP3A5*3 (rs776746) and
PT level [13]. Moreover, another study reported the lack
of association between CYP3A5*3 (rs776746) and either
PIR [mean (SD): AA vs. GA/AA: 30.6% (28.0) vs. 30.4%
(28.2); p=0.993] or PRUs [mean (SD): AA vs. GA/AA:
135.0% (62.9) vs. 139.8% (60.0); p=0.75] [29]. Regarding
the safety outcomes, no correlation was observed between
CYP3A5*3 (rs776746) and hemorrhage events [24]. Regard-
ing the PK outcomes, included studies reported the lack of
association between CYP3A4*22 (rs35599367) and Cmin,
Cmin/Dose, Cmax, and Cmax/Dose [13, 24, 27, 29, 32].
3.5.3 The Effect ofCYP2J2*7 (rs890293)
Two studies reported the effect of CYP2J2*7 (rs890293)
on rivaroxaban outcomes, of which the safety and PK out-
comes were reported by one and two studies, respectively.
Regarding the safety outcomes, no correlation was observed
between CYP2J2*7 (rs890293) and hemorrhage events [24].
In studies that investigated PK outcomes, it was noted that
there was no correlation between CYP2J2*7 (rs890293) and
Cmin/Dose or Cmax/Dose [24, 27].
3.5.4 The Effect ofCYP2C19*2 (rs4244285)
Two studies reported the effect of CYP2C19*2 (rs4244285)
on rivaroxaban outcomes, of which the efficacy, safety, and
PK outcomes were reported by one, one, and two studies,
respectively. Regarding the efficacy outcomes, one study
reported the lack of association between CYP2C19*2
(rs4244285) and either PIR [mean (SD): GG vs. GA/AA =
31.4% (26.3) vs. 28.6% (31.6); p=0.275] or PRUs [mean
(SD): GG vs. GA/AA = 131.9 (57.8) vs. 145.2 (71.0);
p=0.276] [29]. Regarding the safety outcomes, no cor-
relation was observed between CYP2C19*2 (rs4244285)
and hemorrhage events [AA vs. GA/GG: OR (95% CI) =
1.443 (0.692–3.010); p=0.328] [24]. Regarding the PK
outcomes, one study found patients with one or two copies
of the variant allele had a statistically significant rivaroxaban

Y.Ma et al.
Cmax/Dose [mean (SD): GG vs. GA vs. AA: 25.18 (15.64)
vs. 21.65 (13.12) vs. 9.36 (4.42); p=0.022] [24] (Table4),
whereas other studies reported the lack of association
between CYP2C19*2 (rs4244285) and Cmin and Cmin/Dose
[24, 29].
3.5.5 The Effect ofCYP2C19*17 (rs12248560)
Two studies reported the effect of CYP2C19*17
(rs12248560) on rivaroxaban outcomes, of which the
efficacy, safety, and PK outcomes were reported by one,
one, and two studies, respectively. Regarding the efficacy
outcomes, one study reported the presence of an associa-
tion between CYP2C19*17 (rs12248560) and either PIR
[mean (SD): CC vs. CT/TT = 25.0% (25.9) vs. 37.8%
(28.9); p=0.013] or PRUs [mean (SD): CC vs. CT/TT =
147.1 (59.0) vs. 121.4 (63.5); p=0.044] [29] (Table4).
Regarding the safety outcomes, no correlation was
observed between CYP2C19*17 (rs12248560) and hem-
orrhage events [AA vs. GA/GG: OR (95% CI) = 3.333
(0.446–24.936); p=0.241] [24]. Regarding the PK out-
comes, included studies reported the lack of association
between CYP2C19*17 (rs12248560) and Cmin, Cmin/Dose,
and Cmax/Dose [24, 29].
4 Discussion
In real-world settings, selecting the suitable initial dose
of rivaroxaban is a complex process with different factors
involved, which remains an unmet clinical need [22]. It
has been proposed that the interindividual diversity in
the response to rivaroxaban can be partially explained
by genetic variations involved in the metabolism pathway
[11]. However, data on the influence of genetic varia-
tions on drug responses are controversial. Therefore, we
conducted a systematic review aiming to identify and
summarize present evidence evaluating the relation-
ship between genetic polymorphisms with rivaroxaban
outcomes, to address the necessity for genetic testing of
rivaroxaban.
4.1 Overall Findings andTrends
This review pinpointed a few salient points of current
pharmacogenetic research on rivaroxaban. First, all
included studies were published in recent years. With the
ongoing interest in this topic, we have witnessed a dra-
matic increase since 2022. Second, the majority of stud-
ies focus on ABCB1-related SNPs (particularly rs1045642
and rs4148738) and PK outcomes, with a relatively small
number of studies examining other SNPs and clinical
outcomes. Third, a definite correlation between ABCB1-
related SNPs and rivaroxaban efficacy, safety, and PK
outcomes cannot be drawn in this review. However, there
exists suggestive evidence of a pharmacogenetic asso-
ciation between safety outcomes and ABCB1 rs4148738,
ABCB1 rs1045642 or ABCB1 rs2032582. Finally, a defi-
nite correlation between CYP-related SNPs and rivaroxa-
ban efficacy, safety, and PK outcomes cannot be drawn
in this review. However, a pharmacogenetic association
between PIR or PRUs and CYP2C19 rs12248560 was sug-
gestive by limited evidence [29].
4.2 Biological Mechanisms
Currently, the biological mechanisms linking genetic poly-
morphisms to rivaroxaban outcomes remain incompletely
understood. Theoretically, genetic polymorphisms may
primarily alter the activity and/or function of drug-metab-
olizing enzymes or transporters along the rivaroxaban
route, further affect rivaroxaban exposure in the body, and
ultimately affect the treatment outcomes of rivaroxaban.
But what is interesting, in one study [28], although ABCB1
rs1128503 was correlated with the serum concentration
of rivaroxaban, a genetic association with bleeding events
was not obtained, which reminds us that other clinical and
genetic factors may play a role together.
Elimination of rivaroxaban exists via a dual pathway.
Around two-thirds of the rivaroxaban dose is metabolized
in the liver and one-third is eliminated in an unchanged form
in the urine [3]. Regarding the main part metabolized by the
liver, it was metabolized into inactive metabolite by both
CYP-dependent and -independent mechanisms, and half of
the drug was then excreted through urine and the other half
through feces. About 50% of the above metabolic processes
are involved in CYP450 subtypes, of which CYP3A4/5
accounts for about 18% of the elimination of rivaroxaban,
and CYP2J2 accounts for about 14% [33]. There are a lot
of polymorphisms in the genes that encode CYP enzymes,
and these polymorphisms are associated with changes in
enzyme activity levels [34]. For example, the CYP3A4*22
(rs35599367) allele mutation is associated with decreased
CYP3A4 activity, while the SNP*7 (rs890293) allele muta-
tion in the CYP2J2 promoter region can reduce epoxide
hydrolase activity.
With regard to the remaining part excreted renally as
an unchanged form, active renal secretion accounts for the
vast majority of renal excretion [35]. P-glycoprotein (P-gp)
encoded by the ABCB1 gene, and breast cancer resistance
protein (BCRP) encoded by the ABCG2 gene are two trans-
porters that play a major role in active renal rivaroxaban

Genetic Polymorphism and Rivaroxaban
secretion [36, 37]. Multiple SNPs that were identified in
the ABCB1 and ABCG2 genes can be associated with P-gp
and BCRP expression and activity variations according to
invitro studies [38, 39]. However, in terms of human studies,
further clinical studies are still needed to better understand
the synergistic effects of ABCB1 and ABCG2 in regulating
rivaroxaban plasma concentration, anticoagulant efficacy,
and bleeding complications [40].
4.3 Limitations
Our findings must be interpreted with caution considering sev-
eral limitations. First, the data were derived from studies with
different statistical methods, outcome definitions, and meas-
urements. The heterogeneity among studies was still largely
unexplained, which could explain why some findings remained
inconsistent. Additionally, methodological flaws in primary
research may systematically affect how the genetic polymor-
phisms relate to outcomes. Second, the number and sample
size of the included primary studies were somehow limited.
For example, only one study focused on ABCB1 rs4728709
[25] and one study focused on ABCG2 rs2231142 [27], respec-
tively. Therefore, quantitative meta-analyses could not be per-
formed to draw more definitive conclusions. Third, one meet-
ing abstract [31] focusing on ABCB1 rs4148738 was included
for descriptive analysis, although it did not provide enough
details on the study design, gene distribution, and exact sta-
tistical results; however, it is unlikely that this would alter our
conclusions. The aforementioned limitations warrant future
larger validation studies of the association between genetic
polymorphisms and treatment outcomes in patients receiving
rivaroxaban therapy.
4.4 Recommendation forClinical Practice
To the best of our knowledge, this is the first systematic review
that provides a full summary of the current pharmacogenetic
research on rivaroxaban, describes their characteristics and
findings, and summarizes the accessible evidence to clarify
the necessity of genetic testing of rivaroxaban. In light of the
findings in this review, the association between genetic poly-
morphisms and clinical outcomes cannot be well established.
From a pharmacist’s point of view, we propose some sugges-
tions for the clinical management of patients receiving rivar-
oxaban therapy.
First, taking into account available evidence and health
resources, conducting genetic testing before rivaroxaban
medication is not yet recommended as a priority in current
practice. We would like to encourage clinicians or pharma-
cists to accumulate more evidence of the clinical or economic
benefit of genetic testing of rivaroxaban. Second, an optimal
dose should be provided prudently from the initiation of
rivaroxaban therapy, based on a full evaluation of the patient’s
condition, including age, liver and kidney function, co-medica-
tions, etc. [1]. Third, we would encourage practitioners to pay
adequate attention to DDI management [41]. In terms of PK,
drugs of interest include those affecting the activity of drug
transporters (ABCB1, P-gp) and CYP (CYP3A4, CYP3A5,
CYP2J9, CYP2C19), while in terms of pharmacodynamics
(PD), drugs of interest include those causing an increased risk
of bleeding, such as antithrombotic drugs. Last but not least,
for patients with high-risk bleeding, such as elderly patients,
low-weight patients, patients with impaired liver and kidney
function, those with high scores of bleeding risk, and those
taking multiple drugs, PD monitoring-guided individualized
therapy of rivaroxaban may be an option. When conditions
permit, testing of FXa activity can be performed to monitor the
drug concentration of rivaroxaban [42]. Notably, the impact
of rivaroxaban on hemostasis testing may cause false-positive
or false-negative results; however, these can be minimized by
using specific assays and collecting blood samples at trough
concentrations [6].
5 Conclusion
Currently available evidence is insufficient to demonstrate a
definitive link between rivaroxaban clinical or PK outcomes
and gene polymorphisms. To manage the efficacy and safety
of rivaroxaban medication, additional proactive strategies
are advised as a priority in current daily practice rather
than clinical detection of SNP genotyping, particularly for
patients with high-risk bleeding.
Supplementary Information The online version contains supplemen-
tary material available at https:// doi. org/ 10. 1007/ s40262- 024- 01358-3.
Declarations
Funding This work was supported by the National Key R&D Program
of China (2020YFC2008305) and the National Natural Science Foun-
dation of China (NSFC) [72074005, 72104003].
Conflicts of Interest Yi Ma, Zaiwei Song, Xinya Li, Dan Jiang, Ron-
gsheng Zhao, and Zhanmiao Yi declare they have no potential conflicts
of interest that might be relevant to the contents of this manuscript.
Ethics Approval Not applicable.
Consent to Participate Not applicable.
Consent for Publication Not applicable.
Code Availability Not applicable.
Data Availability Statement All data generated and/or analyzed during
this study are included in this published article (and its supplementary
information files).

Y.Ma et al.
Authors’ Contributions ZMY and RSZ conceived and designed the
study. YM and ZWS collected and analyzed the data and performed
the statistical analysis. YM and ZWS wrote the article. XYL and DJ
prepared the pictures and tables. ZMY and RSZ provided suggestions
and participated in the revision of the article. All authors read and
approved the final manuscript.
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Authors and Aliations
YiMa1,2,3· ZaiweiSong1,2,3· XinyaLi1,2,3,4· DanJiang1,2,3,4· RongshengZhao1,2,3· ZhanmiaoYi1,2,3
* Rongsheng Zhao
zhaorongsheng@bjmu.edu.cn
* Zhanmiao Yi
yzm@bjmu.edu.cn
1 Department ofPharmacy, Peking University Third Hospital,
Beijing100191, China
2 Institute forDrug Evaluation, Peking University Health
Science Center, Beijing100191, China
3 Therapeutic Drug Monitoring andClinical Toxicology
Center, Peking University, Beijing100191, China
4 Department ofPharmacy Administration andClinical
Pharmacy, School ofPharmaceutical Sciences, Peking
University, Beijing100191, China