Gene polymorphism as a cause of hemorrhagic complications in patients with non-valvular atrial fibrillation treated with oral vitamin K-independent anticoagulants

Abstract

Atrial fibrillation (AF) accounts for 40% of all cardiac arrhythmias and is associated with a high risk of stroke and systemic thromboembolic complications. Dabigatran, rivaroxaban, apixaban, and edoxaban are direct oral anticoagulants (DOACs) that have been proven to prevent stroke in patients with non-valvular AF. This review summarizes the pharmacokinetics, pharmacodynamics, and drug interactions of DOACs, as well as new data from pharmacogenetic studies of these drugs. This review is aimed at analyzing the scientific literature on the gene polymorphisms involved in the metabolism of DOACs. We searched PubMed, Cochrane, Google Scholar, and CyberLeninka (Russian version) databases with keywords: ‘dabigatran’, ‘apixaban’, ‘rivaroxaban’, ‘edoxaban’, ‘gene polymorphism’, ‘pharmacogenetics’, ‘ABCB1’, ‘CES1’, ‘SULT1A’, ‘ABCG2’, and ‘CYP3A4’. The articles referred for this review include (1) full-text articles; (2) study design with meta-analysis, an observational study in patients taking DOAC; and (3) data on the single-nucleotide polymorphisms and kinetic parameters of DOACs (plasma concentration), or a particular clinical outcome, published in English and Russian languages during the last 10 years. The ages of the patients ranged from 18 to 75 years. Out of 114 reviewed works, 24 were found eligible. As per the available pharmacogenomic data, polymorphisms affecting DOACs are different. This may aid in developing individual approaches to optimize DOAC pharmacotherapy to reduce the risk of hemorrhagic complications. However, large-scale population studies are required to determine the dosage of the new oral anticoagulants based on genotyping. Information on the genetic effects is limited owing to the lack of large-scale studies. Uncovering the mechanisms of the genetic basis of sensitivity to DOACs helps in developing personalized therapy based on patient-specific genetic variants and improves the efficacy and safety of DOACs in the general population.

Plain language summary

Keywords

apixaban dabigatran edoxaban gene polymorphism non-valvular atrial fibrillation rivaroxaban

Introduction

Atrial fibrillation (AF), a type of arrhythmia, accounts for 40% of all cardiac arrhythmias and is associated with an increased risk of thromboembolic events, including stroke, resulting in morbidity and mortality.¹ The prevalence of AF is steadily increasing. According to the population-based Framingham study published in 2015, the incidence of AF increased by 4.7 times in men and 3.6 times in women over a 50-year follow-up period.² The percentage incidence of strokes associated with AF has increased by 16 times among patients aged 50–59 (1.5%) and 80–89 years (23.5%).^3,4 In addition to advancing age, co-morbidities such as chronic heart failure, arterial hypertension, and diabetes mellitus also increase the risk of stroke.^3,4

To prevent cardioembolic stroke, patients with non-valvular atrial fibrillation (NVAF) are traditionally prescribed long-term or lifelong oral anticoagulants.^5–8 In recent years, direct oral anticoagulants (DOACs) have quickly gained their place among the mainstay of drugs in the treatment of NVAF, and their use has significantly increased worldwide.^4,9 DOACs include dabigatran (an inhibitor of clotting factor IIa), apixaban, rivaroxaban, and edoxaban (inhibitors of clotting factor Xa).^7,9,10 DOACs share common characteristics: they have a shorter half-life (lasting between 5 and 17 h) compared to warfarin, pose a reduced risk of drug interactions, do not require laboratory monitoring, offer fixed dosages, and have a broad ‘therapeutic window’.^1,7,11 When the efficacy of DOACs was compared with that of another representative of long-acting vitamin K antagonists, phenprocoumon, the risks of thromboembolic complications were significantly higher; however, the risk of bleeding was lower than that of phenprocoumon.^12,13 DOACs have a wide therapeutic index, fast onset and cessation of action, and relatively low potential for interactions with other drugs and food. There are standard dosing schemes, and international normalized ratio monitoring is neither necessary nor meaningful. Some disadvantages of using DOACs include inter-individual variability in plasma levels and interactions with some commonly used AF drugs, which may increase the risk of side effects such as hemorrhagic complications.⁴ The uncontrolled effects of DOACs due to gene polymorphism can cause both hemorrhagic and thrombotic complications. Several cases of hemorrhagic complications associated with the long-term use of rivaroxaban have been described.^14,15

Objective: To conduct a systematic search and generation of scientific knowledge on the influence of genetic factors on the pharmacokinetic parameters of DOAC treatment in a cohort.

Materials and methods

Search strategy

Inclusion criteria: This systematic review included studies that met the following criteria: (1) full-text articles; (2) study designs, meta-analyses, and observational studies among patients taking DOACs; (3) information on single-nucleotide polymorphisms (SNPs) and kinetic parameters of DOACs (concentration in plasma), or a specific clinical outcome. The ages of the patients ranged from 18 to 75 years. Articles published in English and Russian languages during the last 10 years were included. Exclusion criteria: (1) study design not described; (2) no detailed genotyping; (3) no information for data extraction; (4) meta-analysis included less than two studies; (5) non-systematic reviews, case-controls.

All reviewed articles have been published and are available in databases. All information resources were divided by drugs and shown in the results of the study. Original scientific studies and articles on the association between genetic variants (polymorphisms) and the pharmacokinetics of DOACs were searched on PubMed, Cochrane, and Google Scholar databases, and the Russian scientific electronic library, CyberLeninka using the keywords: ‘dabigatran’, ‘apixaban’, ‘rivaroxaban’, ‘edoxaban’, ‘gene polymorphism’, ‘pharmacogenetics’, ‘ABCB1’, ‘CES1’, ‘SULT1A’, ‘ABCG2’, and ‘CYP3A4’. Publications were searched independently by two investigators using inclusion criteria.

In the initial stage, the identification of articles based on their titles allowed for the exclusion of search results that did not align with the primary objective of the review. At this stage, two researchers (KG and SA) independently identified articles/abstracts published in English and Russian based on their titles. In case of disagreement on the inclusion of publications in the further screening process, a consensus was reached through discussion. At the screening stage, 129 articles were selected (56 from PubMed, 6 from Cochrane, 38 from Google Scholar, and 29 from CyberLeninka). Of the 129 articles, 15 were duplicated and were therefore excluded from the review, resulting in a final selection of 114 relevant studies on the topic of the review at the identification stage (Figure 1). Furthermore, 67 studies were excluded owing to inconsistencies between their abstracts and the main topic of the review. Only 47 full-text studies were selected. After excluding studies that were not available in full-text versions and their results, we assessed 45 studies for acceptability. Of these, 21 articles were excluded from the review because they were non-systematic literature reviews and did not meet the inclusion criteria. In total, 24 studies met all the inclusion criteria and were assessed as acceptable for analysis and generalization in the subsequent writing of the review.

Figure 1.

Flowchart depicting the study design.

Results

Out of the 114 papers selected, 15 duplicate records were omitted, 67 records were excluded, and 45 were assessed for eligibility. However, the number of relevant literature included in the study was 24 (Figure 1).

All the information gathered on four DOACs has been categorized into individual drugs describing their pharmacokinetics, pharmacodynamics, and pharmacogenetics.

Risk of biases: There can be a confirmation bias, which is the tendency to search, interpret, and recall information in a way that aligns with our pre-existing values, opinions, or beliefs. The following section summarizes the information gathered on the four DOACs.

Dabigatran

Pharmacokinetics and pharmacodynamics

Dabigatran etexilate is the precursor to the active form of dabigatran. Dabigatran inhibits the coagulation factor IIa, thrombin, via competitive inhibition upon direct binding.^16–18 Etexilate of dabigatran is a prodrug and, upon oral administration, is biotransformed into the active metabolite, dabigatran. In the intestine, the intermediate metabolite of dabigatran, ethyl ester, is converted to the active form by the sequential action of intestinal carboxylesterase enzyme (CES2) and the liver carboxylesterase enzyme (CES1).^16–18 The human carboxyesterase 1 (CES1) gene encodes a hepatic esterase responsible for the hydrolysis of drugs containing multiple ester and amide bonds.^8,19 CES1 plays a greater role in the conversion of dabigatran etexilate to dabigatran than CES2.¹⁷ After 0.5–2 h, dabigatran reaches its maximum plasma concentration (Cmax).²⁰ The half-life of dabigatran is 12–14 h; the unchanged drug has two routes of excretion: the main route through the kidneys (85%) and, to a lesser extent, through the liver (15%).^21,22 Therefore, the half-life of dabigatran may be extended to 15–35 h in renal failure.²³

According to Dimatteo et al.¹⁹ in the RE-LY study, significant factors affecting the plasma concentration of dabigatran were age, creatinine clearance, body weight, and sex. The bioavailability of dabigatran is only 3–7%^24,25 and is affected by the ATP-dependent drug efflux transporter p-glycoprotein (P-gp), which transports chemicals out of cells and is encoded by the ABCB1 gene.²⁶ Therefore, drug interactions should be considered when prescribing this drug with P-gp inducers and their inhibitors. Bernier et al.²⁷ reported the development of bleeding among 30.4% of patients taking P-gp inhibitors along with dabigatran. P-gp inhibitors (e.g. verapamil, nicardipine, and carvedilol) affect the concentration of P-gp substrate drugs, causing their increase in plasma, which can lead to adverse drug reactions such as bleeding. When P-gp inducers (e.g. rifampicin, morphine, and dexamethasone) are simultaneously administered with dabigatran, there is a decrease in the concentration of the P-gp substrate drug and its efficacy.²⁸

Pharmacogenetics of dabigatran

ABCB1 polymorphism

Among more than 1200 polymorphisms known in the ABCB1 gene, rs1128503, rs2032582, rs1045642, and rs4148738 are the most studied. In the RE-LY study,²⁹ dabigatran genotyping and concentration determinations were performed on 1490 patients diagnosed with AF. In this study, a relationship between an SNP in the minor allele of the ABCB1 rs4148738 and a 12% increase in the peak concentration of dabigatran was observed. Based on a study on 92 Caucasian patients with AF, Dimatteo et al.¹⁹ reported that the rs4148738 polymorphism did not affect the peak and minimum concentrations of dabigatran. Sychev et al.¹⁶ assessed the effect of SNPs ABCB1 rs1045642 and rs4148738 on the peak and trough concentrations of dabigatran among 60 patients with total knee arthroplasty and found that the TT genotype of ABCB1 rs1045642 was associated with a higher peak of dabigatran concentration, and hence, a higher risk of bleeding than the CC genotype, which is the polymorphism rs4148738; no significant association with changes in the peak and minimum concentrations of dabigatran was found. This was confirmed in a study by Ji et al.,²⁵ where no significant differences were observed in the pharmacokinetics of dabigatran among SNP ABCB1 rs4148738 and rs1045642 genotype variants. The frequency of bleeding in carriers of the minor allele SNP ABCB1 rs1045642 was 15.3%, and it was 13.8% in non-carriers.²⁵ Cosmi et al.³⁰ examined the effect of the ABCB1 SNP rs4148738 on plasma DOAC concentrations and found a decline in peak dabigatran concentrations without any clinically significant effect. Gouin-Thibault et al.³¹ studied the effect of clarithromycin on the pharmacokinetics of dabigatran among 60 healthy Caucasian volunteers with rs1045642 and rs2032582 polymorphisms of the ABCB1 gene and found that the ABCB1 genotype did not affect the pharmacokinetics of dabigatran, but co-administration of clarithromycin resulted in a twofold increase in dabigatran area under the curve (AUC). Another study conducted among 218 Caucasian patients found that among those who experienced bleeding following the administration of dabigatran, 75% were carriers of the rs4148738 genotype variant (GA + AA), and 75% were carriers of the rs1045642 (CT + TT) variant genotype. Similar results were confirmed in the study by Sychev et al., in which the rs1045642 (C > T) genotype variant was more frequently detected in patients with bleeding episodes.^4,16 Lähteenmäki et al.³² studied the ABCB1 polymorphisms rs1045642, rs2032582, rs4148738, and rs1128503 among 1806 patients treated with dabigatran, rivaroxaban, and apixaban. This study conducted on 340 patients taking dabigatran found no significant association between the above polymorphisms and the development of thromboembolism and bleeding.³² Liu et al.³³ found no relationship between the ABCB1 polymorphisms rs2032582, rs4148738, and rs1045642 and the pharmacokinetics of dabigatran in healthy volunteers.

CES1 genetic polymorphisms

Currently, more than 2000 different polymorphisms for CES1 are known. The most studied are the CES1 SNPs rs2244613 and rs8192935.⁹ According to the RE-LY study, 32.8% of patients were carriers of the CES1 rs2244613 polymorphism (of which 29.4% were heterozygous, and 3.4% were homozygous), and this polymorphism was associated with a low plasma concentration of dabigatran.²⁹ In heterozygotes, for the minor allele C rs2244613, the peak equilibrium concentration (Cssmax) was 15% lower, while in homozygotes (CC), it was 28% lower compared to non-carriers. Carriers of the rs8192935 polymorphism showed a decrease (Cssmax) in the active metabolite of dabigatran by 12%, but no such effect was found in Cssmin carriers. Based on these data, the authors concluded that the carriage of the CES1 rs8192935 polymorphism does not lead to the development of bleeding, while CES1 rs2244613 can reduce the risk of bleeding.²⁹ In the study of Sychev et al.,¹⁶ equilibrium peak concentrations of dabigatran showed no significant differences in relation to the polymorphism rs 2244613 of the CES1 gene. A similar study found that the CES1 polymorphisms rs2244613 and rs8192935 altered the pharmacokinetics of dabigatran and that the AA or CA rs2244613 genotype was associated with a higher risk of minor bleeding. The percentage of carriers of the AA CES1 rs2244613 genotype was 39.4% among the Chinese population and 58.6% among Caucasians.²⁵

An in vitro study by Shi et al.¹⁷ showed that rs71647871 polymorphism was associated with a decreased rate of dabigatran conversion into the active metabolite of the drug. Moreover, no relationship was found between rs2244613 and rs8192935 and the metabolic activity of dabigatran etexilate.¹⁷ In the work of Dimatteo et al.,¹⁹ the effect of rs2244613 and rs8192935 polymorphisms of the CES1 gene of dabigatran etexilate in 92 Caucasian patients with AF was studied, and a 3% and 11% decrease in Cssmin of dabigatran were found in heterozygotes (CT) (p = 0.055) and homozygotes for rs8192935 polymorphism respectively; there was no association of SNP CES1 rs8192935 with peak concentrations of dabigatran. In addition, the rs2244613 polymorphism revealed a decrease in Cssmin by 2% and 3% in heterozygotes and homozygotes, respectively.¹⁹

In a 2017 study conducted among 72 patients by Meshcheryakov et al., no relationship was established between the rs2244613 CES1 polymorphism and the development of ischemic and hemorrhagic complications while taking the drug. It was possibly owing to a relatively small sample size and a short follow-up period.³⁴

Another study,³³ conducted on 106 healthy volunteers, found that the frequencies of the CES1 rs2244613 and CES1 rs8192935 genotypes differed significantly between the Chinese population and Caucasians. CES1 rs8192935 was associated with peak dabigatran levels. In addition, the study noted that food significantly slowed the absorption of dabigatran.³³ Table 1 summarizes the authors’ conclusions based on the reviewed literature on dabigatran.

Table 1.

Conclusions of the authors of the literature used for dabigatran.

Name of DOAC	Authors	Number and characteristics of participants in the study	Authors’ conclusions
Dabigatran etexilate	Li et al.³⁵ (a systematic review and meta-analysis)	The relationship between the pharmacokinetics of dabigatran and the CES1 rs2244613 was studied. Ten studies (n = 2777) were included.	A meta-analysis showed an association between the CES1 rs2244613 genotype and the pharmacokinetics of dabigatran. Carriers of the T allele had high concentrations of dabigatran; therefore, such patients have a high risk of bleeding.
	Abdullaev et al.³⁶ (meta-analysis)	Five works were selected, 2030 patients.	The carriage of the C allele rs2246613 was statistically significantly associated with a decrease in the risk of any bleeding while taking dabigatran, but no statistically significant association with a decrease in the plasma concentration of dabigatran was found.
	Zhu et al.³⁷	86 patients who received 110 mg of the drug twice a day.	An association was found between the rs8192935 SNP of the CES1 gene and minimal plasma concentrations of dabigatran. The rs4148738 and rs1045642 ABCB1 polymorphisms have been associated with an increased risk of major bleeding in the Chinese population.
	Liu et al.³³	106 healthy volunteers	CES1 rs8192935 was associated with a maximum concentration of dabigatran.
	Ji et al.²⁵	198 patients with atrial fibrillation received dabigatran etexilate at a dose of 110 mg twice a day.	The ABCB1 polymorphisms rs4148738 and rs1045642 were not associated with the pharmacokinetics of dabigatran.The minor allele C of the rs8192935 CES1 polymorphism led to an increase in Cssmin. Carriers of the minor allele (A) CES1 rs2244613 had a higher level of minimal (plasma dabigatran etexilate cincentrationts) than non-carriers.
	Sychev et al.³⁸	The study included 96 patients with atrial fibrillation and stage 3 CKD (chronic kidney disease) treated with dabigatran etexilate.	Patients with the rs2244613 CC genotype had low C/D values compared with the AA genotype. There was no effect of rs1045642 and rs4148738 ABCB1 on trough plasma concentrations of dabigatran and C/D.
	Roşian et al.⁴	The study included Caucasian patients with AF, of which 104 patients were taking dabigatran, and 114 patients were taking apixaban.	The study found no association between ABCB1 rs1045642 (C > T) and ABCB1 rs4148738 (G > A) and risk of minor bleeding in patients treated with anticoagulants.
	Sychev et al.¹⁶	The study included 60 patients who underwent knee arthroplasty and received dabigatran etexilate at a dose of 220 mg once a day.	The TT genotype of the rs1045642 ABCB1 polymorphism was associated with a higher risk of bleeding compared to the CC genotype (p < 0.008). There was no statistically significant genotype-dependent difference in the minimum concentrations between rs1045642 and rs4148738 of the ABCB1 gene and rs2244613 of the CES1 gene.
	Gouin-Thibault et al.³¹	Sixty participants were enrolled to evaluate the influence of ABCB1 polymorphisms on the pharmacokinetics of dabigatran and rivaroxaban.	The ABCB1 genotype did not affect the effects of the drugs.
	Dimatteo et al.³⁹	The study included 92 patients with atrial fibrillation who received anticoagulant prophylaxis dabigatran etexilate.	There was no significant association between genotypes and peak concentrations of dabigatran. The CES1 SNP rs8192935 was associated with minimal plasma concentrations of dabigatran. No significant effect was found for SNP ABCB1 rs4148738. The CES1 SNP rs8192935 significantly influenced the dabigatran trough concentrations and carriers of the T allele showed lower concentrations than did carriers of the CC genotype.
	Pare et al.²⁹	2944 participants receiving long-term anticoagulant therapy	Carriage of the CES1 rs2244613 minor allele was associated with lower risk of bleeding.

AF, atrial fibrillation; SNP, single-nucleotide polymorphism.

Apixaban

Apixaban reversibly inhibits factor Xa of the coagulation cascade and was approved by the FDA in 2012 as a preventive treatment for stroke in patients with NVAF and the treatment of pulmonary embolism and deep vein thrombosis.^9–11 It is preferably used in patients with risk factors (previous history of stroke, hypertension, diabetes mellitus, heart failure, or age ⩾75 years).⁷ The evidence base for apixaban to prevent thromboembolic events in such patients is presented in two studies – AVERROES and ARISTOTLE.¹¹ In the ARISTOTLE clinical study, the administration of apixaban (5 mg twice a day) reduced the risk of stroke by 21%, major bleeding by 31%, and death by 11% compared to warfarin.⁴⁰

Pharmacokinetics and pharmacodynamics

The drug has a bioavailability of approximately 50%, a half-life ranging between 8 and 15 h, and reaches its peak plasma concentration within 3 or 4 h after ingestion.^7,9–11,24 Food has no clinically significant effect on the bioavailability of apixaban.²⁸ Frost et al. studied the effect of sex on the plasma concentration of apixaban and found that the effect of apixaban in women was 18% longer than in men. The age of the patient (over 65 years) leads to an increase in the plasma concentration of the drug, and a body weight of more than 120 kg negatively correlated with the plasma concentration.⁴¹

Apixaban is metabolized to a greater extent by CYP3A4/5 isoenzyme and to a lesser extent by CYP1A2, CYP2C8, CYP2C9, CYP2C19, and CYP2J2 isoenzymes (many authors), and SULT1A1 and SULT1A2 sulfotransferases (resulting in O-desmethyl apixaban sulfate), mainly SULT1A1. Given the fact that apixaban is a substrate for P-gp and breast cancer resistance protein (BCRP/genome-encoded ABCG2),^3,9,24 care should be taken when using strong inducers and inhibitors of both metabolic pathways simultaneously.⁹ Rifampicin, carbamazepine, phenobarbital, etc., being inducers of CYP3A4 and P-gp, can cause an insufficient therapeutic effect of apixaban by reducing its plasma level. The opposite happens with simultaneous use with strong inhibitors of CYP3A4 and P-gp (ketoconazole, ritonavir, and clarithromycin), which leads to an increase in the level of apixaban on average by two times, potentially resulting in excessive bleeding.^9,24 Apixaban is excreted through various pathways: 75% as unchanged metabolites through bile and direct intestinal excretion, while the remaining 25% is excreted by the kidneys.^3,9,28

Pharmacogenetics of apixaban

The study by Dimatteo et al.³⁹ included 80 patients with AF who took apixaban. Upon analyzing the effect of rs4148738 polymorphism of the ABCB1 gene on the pharmacokinetics of apixaban of 80 patients, 18 had the AA genotype (22.5%; 95% CI: 13.9–33.2), 39 had the AG genotype (48.8%; 95% CI: 37.4–60.2), and 23 patients had the GG genotype (28.7%; 95% CI: 19.2–40.0).³⁹ In particular, patients with the genotype AA rs4148738 were found to have relatively higher peak levels of apixaban than patients with G allele carriers. Consequently, the authors concluded that ABCB1 rs4148738 was significantly associated with the variability of peak levels of apixaban compared to trough levels.³⁹ A pharmacokinetic study involving 44 Japanese patients treated with apixaban for non-valvular AF revealed an association of ABCG2 rs2231142 and CYP3A5 rs776746 with elevated plasma concentrations of apixaban. However, ABCB1 rs1128503, rs2032582, or rs1045642 did not show any association with trough apixaban concentration.^28,42 Moreover, the carriage of the T allele (rs77674) of the CYP3A5 gene can increase the clearance of apixaban.⁴² Among 17 patients with non-valvular AF and cardiometabolic stroke, no significant association was found between specific genetic variations in the ABCB1 gene (rs1045642 and rs4148738) and CYP3A5*3 (rs776746) and apixaban metabolism. These patients exhibited diverse polymorphisms of the ABCB1 gene, including five with the CC genotype, nine with the CT genotype, three with the TT genotype for rs1045642, four with the CC genotype, seven with the CT genotype, and six with the TT genotype for rs4148738.¹⁰

The frequency of carriage of the SNV CYP3A5 gene is higher in people of African descent than in Europeans, proving the dependence on patients’ ethnicity.²⁸ In patients not expressing CYP3A5, caution is required in titrating apixaban and monitoring for adverse events, as higher plasma concentrations of the apixaban have been identified.²⁸ In a recent study⁴³ conducted among 53 patients with NVAF, no significant differences were found between the ABCB1 rs1045642 and rs4148738 genotypic groups with minimal or peak plasma concentrations of apixaban. In a large genome-wide association study, Attelind et al.,⁴⁴ using data from 1325 participants in a pivotal phase III study of apixaban, found a polymorphism in the ABCG2 drug transporter gene associated with the pharmacokinetics of apixaban. Analysis of candidate genes showed a statistically significant association of the ABCG2 gene (c.421G>T, rs2231142) with a high concentration of apixaban. Heterozygotes showed a 5% increase in AUC, while homozygotes showed a 17% increase compared to the wild-type allele. However, ABCG2 rs2231142 was not associated with thromboembolic events or bleeding.⁴⁴

Rivaroxaban

Pharmacokinetics and pharmacodynamics

Rivaroxaban is a widely used oral anticoagulant that prevents the formation of fibrin clots by selective, reversible inhibition of factor Xa.^9,24,28,45 After oral administration, the drug is rapidly absorbed, and the maximum plasma concentration is reached within 2–4 h. The bioavailability of rivaroxaban is high but varies depending on the dosage: for example, when taking 10 mg of rivaroxaban, the absolute bioavailability ranges from 80% to 100%; however, if 20 mg of the drug is taken on an empty stomach, the bioavailability decreases to 66% and significantly increases during meals.⁴⁶ The degree of the drug binding to blood plasma proteins is approximately 92–95%.²⁴ Rivaroxaban has several routes of elimination. Inactive metabolites, formed mainly as a result of metabolism by the cytochrome P450 (CYP450) 3A4, 3A5, and 2J2 system, are excreted in the urine and feces, and the remaining third of the drug is excreted unchanged by the kidneys. This is due to the active transport secretion of P-gp and by the breast cancer resistance protein BCRP.^9,24 Age, renal pathology, and concomitant drug therapy may affect the individual variability of rivaroxaban concentration.⁴⁵ In patients with renal insufficiency, the concentration of the drug increases, which leads to the prolongation of the prothrombin time.⁴⁶

Drug interactions of rivaroxaban are mediated by CYP450 and P-gp. Strong inhibitors of CYP450 and P-gp enzymes (e.g. ketoconazole and ritonavir) can increase the concentration of rivaroxaban in the blood plasma (by 2.6 times), leading to an increased risk of bleeding. On the contrary, co-administration of strong CYP3A4 inducers with rivaroxaban leads to its insufficient pharmacological effect.^9,24

Pharmacogenetics

Polymorphism of the ABCB1, ABCG2, and CYP3A4 genes can lead to changes in the pharmacokinetics of rivaroxaban and the risk of bleeding while taking this drug. Previously published studies have described four SNPs of the ABCB1 gene (rs2032582, rs1045642, rs4148738, and rs1128503), which may be associated (mainly within the haplotype) with higher plasma concentrations of rivaroxaban and a higher risk of hemorrhagic complications.^14,15,31

In a recent study by Lorenzini et al.,¹⁴ a patient with gastrointestinal bleeding following rivaroxaban administration was found to be a carrier of homozygous mutant genotype TT rs2032582 and rs1045642 of the ABCB1 gene. Similar results were reported in a systematic review and meta-analysis by Xie et al.,⁴⁷ where increased peak concentrations were found in carriers of homozygous variants (ABCB1 rs1045642 TT and rs2032582 TT). Another study in 2018 also reported three cases of major bleeding associated with elevated rivaroxaban residual concentrations; all patients were heterozygous for rs1128503, rs2032582, and rs4148738; two were heterozygous, and one was a homozygous TT mutant for ABCB1 rs1045642.¹⁵

According to Gouin-Thibault et al.,³¹ ABCB1 polymorphisms rs2032582 and rs1045642 did not significantly affect the pharmacokinetics of rivaroxaban among healthy volunteers, and the combined use of the P-gp/CYP3A4 inhibitor clarithromycin with rivaroxaban may require caution in patients at risk of overdose, as this leads to a twofold increase in the AUC of the ABCB1 genotype.³¹ Sychev et al.⁴⁸ found no significant differences in peak steady-state concentrations of rivaroxaban between mutant haplotypes and wild haplotypes of the ABCB1 gene. Similar results were published by Sennesael et al.,¹⁵ who found that SNV 1236 C>T, α2677 G>T-3435, C>T, and 1199 G>A of the ABCB1 gene had no significant effect on the intracellular accumulation of rivaroxaban compared to wild-type protein.¹⁵ It has been suggested that ABCB1 single-nucleotide variants (SNVs) are unlikely to contribute to individual variability in rivaroxaban plasma concentrations.¹⁵ Moreover, the maximum and minimum concentrations of rivaroxaban depended on the activity of CYP3A4.⁴⁸

Zhao et al. recently published a systematic evaluation of the involvement of CYP isoforms in the metabolism of rivaroxaban and demonstrated, for the first time, the major role of CYP2J2 in the metabolism of rivaroxaban (41.1%). The contribution of CYP3A4 in this study was much lower (27.3%).⁴⁹ Nakagawa et al. studied the effect of SNPs CYP3A5*3, ABCB1 c.3435C>T, c.2677G>A/T, c.1236C>T, ABCG2 c.421C>A, and CYP2J2*7 on plasma concentrations of rivaroxaban in Japanese patients with non-valvular AF. In this study, ABCB1 genotypes c.2677G>A/T, c.3435C>T, and c.1236C>T did not affect the trough plasma concentration of rivaroxaban.⁵⁰ A recent retrospective cohort study found no association between the same eight pharmacogenetic variants studied with bleeding risk.⁵¹

Edoxaban

As a direct inhibitor of factor Xa, edoxaban was approved in 2015, confirming its effectiveness in various cardiovascular complications.⁵² Similar to other drugs of the same group, edoxaban is rapidly absorbed and reaches its maximum plasma concentration in 1–2 h. The bioavailability of edoxaban is 62%, the plasma half-life is 10–14 h, and approximately 50% is excreted by the kidneys. Unlike rivaroxaban and apixaban, the hepatic clearance by the cytochrome P450 type CYP3A4 system does not play a major role in the elimination of edoxaban. Thus, drug–drug interactions with inducers and inhibitors of cytochrome P450 enzymes are considered to be minimal.⁵³ Edoxaban is a substrate for P-gp. The urinary excretion of edoxaban is 35% of the remaining unchanged fraction, and metabolites are excreted in the feces. Powerful inhibitors of P-gp enzymes increase the bioavailability of edoxaban by 1.5–2 times, thereby enhancing the effect of the drug.⁵⁴

Pharmacogenetics

Edoxaban is metabolized primarily by CES1 and, to a lesser extent, by CYP3A4/3A5 and is transported by P-gp. Changes in systemic exposure may be associated with CES1, ABCB1, and SLCO1B1 polymorphisms.^28,54 Edoxaban and its active metabolite M4 serves as substrates for an organic anion carrier protein, OATP1B1, encoded by SLCO1B1. Rs1045642 (3435 C>T) ABCB1 and rs4149056 (521 T>C) SLCO1B1 variants do not affect the pharmacokinetics of edoxaban; however, a slight increase in M4 exposure was observed in carriers of the minor C* allele of the SLCO1B1 gene.⁵⁵ Studies on the effect of carriage of the studied SNVs of the CES1 gene on the pharmacokinetics of edoxaban could not be found. Larger randomized trials using data from the pharmacogenetics of edoxaban also have not been found.

Tables 1 and 2 summarize the conclusions of the authors on the literature used for dabigatran and X-factor inhibitors. These conclusions include studies in humans, which cover patients with diseases as well as healthy volunteers.

Table 2.

Conclusions of the authors based on literature used for X-factor inhibitors.

Name of DOAC	Authors	Number and characteristics of participants in the study	Authors’ conclusions
Apixaban	Attelind et al.⁴⁴	Data from 1325 participants in a pivotal phase III study of apixaban were used to identify genetic factors influencing the pharmacokinetics of apixaban.	The study demonstrated an association with the drug transporter gene ABCG2 (c.421G>T, rs2231142).
	Gulilat et al.⁵⁶	The study included 358 Caucasian patients with non-valvular AF. In this study, drug interactions and pharmacogenetic variability of apixaban were evaluated.	The results indicated that amiodarone and the ABCG2 genotype contribute to the apixaban variability.
	Roşian et al.⁴³	53 NVAF patients were treated with 5 mg apixaban twice/day; peak plasma concentrations of apixaban were determined.	In this study, no significant differences in statistics were found between the ABCB1 rs1045642 and ABCB1 rs4148738 genotypic groups in trough or peak plasma concentrations of apixaban.
	Kryukov et al.¹⁰	17 patients with cardioembolic stroke who received apixaban at a dose of 5 mg were included.	ABCB1 (rs1045642 and rs4148738) and CYP3A5 (rs776746) gene polymorphisms did not influence the pharmacokinetics of apixaban.
	Ueshima et al.⁴²	The study included 44 Japanese patients taking apixaban.	Apixaban’s trough plasma C/D ratio was higher in patients with genotype ABCG2 421A/A and CYP3A51/3 or 3/3 (p < 0.05).
Rivaroxaban	Lähteenmäki et al.³²	1806 patients on apixaban, dabigatran, or rivaroxaban were studied.	SNV ABCB1 c.3435C>T (p.Ile1145=, rs1045642) and 1236T-2677T-3435T (rs1128503-rs2032582 - rs1045642) led to a decrease in thromboembolic complications. Patients with SNV ABCB1 c.2482-2236G>A (rs4148738) who took apixaban had a low risk of bleeding.
	Sychev et al.⁵⁷	Study participants were 128 patients aged 80 years or older with NVAF taking rivaroxaban.	ABCB1 gene polymorphisms (rs1045642 and rs4148738) did not affect the pharmacokinetics of rivaroxaban.
	Fedina et al.⁵⁸	50 patients on apixaban and 42 patients on rivaroxaban	In carriers of the genotype CT+TT ABCB1 (rs4148738) C>T, the concentration of rivaroxaban in blood plasma was statistically significantly higher. While taking apixaban together with a CYP3A4/P-gp inhibitor, hemorrhagic complications were 3.5 times more common.
	Wang et al.⁶	155 patients of Mongolian origin	The SNP of the ABCB1 gene rs1128503 was statistically associated with the concentration of rivaroxaban; there was no significant correlation between the ABCB1 gene variation loci rs1045642, rs1128503, rs4148738, and bleeding events.
	Wu et al.⁵⁹	95 patients	Polymorphisms of the ABCB1 rs4148738 and rs4728709 genes have a significant effect on Ctrough/D of rivaroxaban in patients with NVAF. Polymorphisms of the CYP3A4/5, ABCB1, and ABCG2 genes have not been associated with the risk of bleeding with rivaroxaban.
Edoxaban	Vandell Alexander et al.⁵⁵	The study involved 458 healthy volunteers taking edoxaban.	Polymorphisms rs1045642 (3435 C>T) of the ABCB1 gene and rs4149056 (521 T>C) of the SLCO1B1 gene did not affect the pharmacokinetics of the drug.

DOAC, direct oral anticoagulant; NVAF, non-valvular atrial fibrillation.

Risk of bias: Evidence selection bias can occur when a systematic review does not identify all available data on a topic. This can arise from publication bias, where data from statistically significant studies are more likely to be published than those that are not statistically significant.

Furthermore, reporting bias can refer to the selective dissemination of research findings based on the nature of the results.

Discussion

Considering the widespread use of dabigatran, rivaroxaban, apixaban, and edoxaban, it is necessary to study new possibilities for the use of DOACs and predict their dosage when used as monotherapy or in combination with other drugs.

Currently, only a few genes associated with DOACs have been studied. Previous studies have shown that variability in plasma levels of dabigatran is associated with polymorphisms in the CES1 and ABCB1 genes, in apixaban with the SULTA1A, ABCB1, ABCG2, CYP3A5 genes, in rivaroxaban ABCB1, ABCG2, CYP3A4, in edoxaban CES1, ABCB1, SLCO1B1.

The scientific and practical effect is to obtain new knowledge on the effects of DOACs in the development of cardiovascular pathology with respect to genetic polymorphisms. The socio-economic effect is due to the cumulative genetic risk of the cohort of people, the transition of time to the adoption of DOACs, and the proposed measures to reduce health hazards. In addition, the review can be used to prepare fundamental and applied works and educational and methodological materials on genetic and medical profiles of these drugs globally. There is a lack of information on the pharmacokinetics of these drugs in different ethnic groups, including Kazakh population. The authors are interested in addressing this particular problem. Additionally, further studies are needed to compare DOACs with phenprocoumone.

The pharmacogenomic database Pharmacogenomics (http://www.pharmgkb.org), which provides information about the association of drugs with certain polymorphisms, has been created. Based on the latest data from this pharmacogenomics database, the determination of rs2244613 and rs8192935 CES1 polymorphisms, as well as rs1045642, rs2032582, and rs4148738 ABCB1 polymorphisms in patients taking dabigatran has a low level (3) of evidence, which prevents us from recommending the determination of these CES1 and ABCB1 genetic polymorphisms in the routine clinical practice.^28,60

Moreover, studies in various ethnic groups demonstrate interracial, interethnic differences in sensitivity to drugs, which can also be reflected in the personalization of drug dosing regimens since the frequency of alleles and genotypes for one population may not be applicable to another.

Limitations

The authors have not included any study whose results are negative or are not statistically significant. The outcomes may not be of relevance to the publisher but may have serious clinical implications. The already known important genetic variants affecting the pharmacokinetics of dabigatran, rivaroxaban, apixaban, and edoxaban need further consideration due to the absence of large-scale studies. There is a need for more extensive studies in the future so that it is possible to develop algorithms for dosing DOAC based on the genotype. However, additional clinical studies on the relationship between the levels of DOAC in plasma and clinical outcomes (bleeding and thromboembolic complications) are required. The question of additional genetic variants that could influence the pharmacokinetics and pharmacodynamics of these drugs remains open.

Conclusion

Uncovering the mechanisms of genetic determination of sensitivity to DOACs may provide keys to personalize therapies based on patient-specific genetic variants and improve the efficacy and safety of direct oral anticoagulants in the general population. There is a need to design and conduct large studies in different ethnic groups, including sufficient numbers of patients for genetic association studies. The pharmacogenetic testing results can be a valuable tool for doctors in selecting appropriate dosages of DOACs, particularly in cases requiring long-term pharmacotherapy with these drugs.

Footnotes

Acknowledgements

We would like to thank Editage () and SAGE Author Services for English language editing.

Declarations

ORCID iDs

Ayan Abdrakhmanov

Aizhana Shaimerdinova

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