ABCG2 Gene Polymorphisms May Affect the Bleeding Risk in Patients on Apixaban and Rivaroxaban

Figures & data

Figure 1 Flowchart of patient selection.

Table 1 Baseline Characteristics of the Study Patients

Characteristics	Controls n=229 (%)	Cases n=64 (%)	P
Sex
Male	146 (63.8)	37 (57.8)	0.385
Female	83 (36.2)	27 (42.2)
Age (y)
<65	72 (31.4)	19 (29.7)	0.789
≥65	157 (68.6)	45 (70.3)
Mean ± SD	68.3 ± 10.1	70.8 ± 9.8	0.076
Body weight (kg)
<65	103 (46.2)	32 (50.0)	0.590
≥65	120 (53.8)	32 (50.0)
Mean ± SD	68.3 ± 12.4	66.0 ± 13.8	0.208
Creatinine clearance (mL min^−1)
<50	41 (18.6)	14 (22.6)	0.489
≥50	179 (81.4)	48 (77.4)
Mean ± SD	68.4 ± 24.6	65.1 ± 24.2	0.345
Systolic blood pressure (mmHg)	130.4 ± 21.5	128.7 ± 20.9	0.580
Diastolic blood pressure (mmHg)	76.3 ± 14.6	76.1 ± 12.6	0.919
Modified HAS-BLED^a
Mean ± SD	1.9 ± 1.1	2.3 ± 1.0	0.008
Dose of DOAC^b
Under & Standard dose	225 (98.3)	61 (95.3)	0.179^c
Overdose	4 (1.7)	3 (4.7)
Alcohol	73 (34.0)	17 (27.9)	0.371
Smoking	35 (16.5)	8 (12.7)	0.465
Comorbidity
Hypertension	162 (70.7)	48 (75.0)	0.504
Diabetes mellitus	62 (27.1)	21 (32.8)	0.368
Chronic heart failure	49 (21.4)	7 (10.9)	0.060
Dyslipidemia	67 (29.3)	18 (28.1)	0.860
Hepatic abnormality	4 (1.7)	2 (3.1)	0.615^c
Renal abnormality	6 (2.6)	2 (3.1)	0.688^c
Malignancy	27 (11.8)	3 (4.7)	0.098
Previous history
Stroke/TIA/thromboembolism	82 (35.8)	33 (51.6)	0.022
Bleeding	7 (3.1)	11 (17.2)	<0.001^c
Co-medication
ACEI/ARB	97 (42.4)	26 (41.3)	0.877
Antiplatelet drugs	26 (11.4)	6 (9.5)	0.681
Beta-blocker	174 (76.0)	44 (69.8)	0.321
Calcium channel blocker	58 (25.3)	15 (23.8)	0.805
Diuretics	63 (27.5)	17 (27.0)	0.934
Statins	121 (52.8)	38 (60.3)	0.291
PPI	24 (10.5)	13 (20.6)	0.032

Notes: ^aModified HAS-BLED (hypertension, abnormal renal or liver function, stroke, bleeding history or predisposition, elderly (age≥65), concomitant drug and alcohol use; range 0–8) score was calculated without the factor of liable international normalized ratio compared to HAS-BLED. ^bStandard dose was defined according to the FDA-approved labeling ^cP-value using the Fisher’s exact test.

Abbreviations: ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker; DOAC, direct oral anticoagulant; PPI, proton pump inhibitor; TIA, transient ischemic attack.

Table 2 Genetic Factors Associated with Bleeding Complications in Patients Treated with Apixaban and Rivaroxaban

Gene Polymorphism	Minor Allele Frequency (Allele)	Grouped Genotypes	Controls n=229 (%)	Cases n=64 (%)	p
ABCG2
rs2231142	0.27 (T)	GG	116 (50.9)	38 (59.4)	0.229
		GT, TT	112 (49.1)	26 (40.6)
rs2231137	0.29 (T)	CC	117 (51.5)	24 (38.1)	0.059
		CT, TT	110 (48.5)	39 (61.9)
rs2622604	0.16 (T)	TT, TC	62 (27.1)	28 (43.8)	0.011
		CC	167 (72.9)	36 (56.2)
rs3114018	0.32 (A)	AA, AC	115 (50.2)	42 (66.7)	0.020
		CC	114 (49.8)	21 (33.3)
rs1481012	0.26 (G)	AA	121 (53.1)	39 (60.9)	0.264
		AG, GG	107 (46.9)	25 (39.1)
ABCB1
rs1045642	0.33 (A)	AA	19 (8.3)	12 (18.8)	0.017
		AG, GG	209 (91.7)	52 (81.2)
rs2032582	0.49 (C)	AA, AC	176 (77.2)	45 (70.3)	0.257
		CC	52 (22.8)	19 (29.7)
rs1128503	0.41 (G)	AA	77 (33.6)	25 (39.7)	0.372
		AG, GG	152 (66.4)	38 (60.3)
rs3789243	0.42 (A)	AA, AG	154 (67.2)	39 (60.9)	0.346
		GG	75 (32.8)	25 (39.1)
rs3213619	0.07 (G)	AA	201 (87.8)	55 (85.9)	0.696
		AG, GG	28 (12.2)	9 (14.1)
CYP3A4
rs2242480	0.24 (T)	CC	129 (56.8)	37 (58.7)	0.787
		CT, TT	98 (43.2)	26 (41.3)
rs4646437	0.07 (A)	GG	195 (86.3)	56 (88.9)	0.588
		GA, AA	31 (13.7)	7 (11.1)
rs12333983	0.28 (A)	TT, TA	213 (93.0)	57 (89.1)	0.299
		AA	16 (7.0)	7 (10.9)
CYP3A5
rs776746	0.26 (T)	CT, TT	103 (45.4)	31 (49.2)	0.589
		CC	124 (54.6)	32 (50.8)
rs15524	0.29 (G)	AA	118 (51.8)	31 (48.4)	0.639
		AG, GG	110 (48.2)	33 (51.6)
rs4646450	0.27 (A)	GG	122 (53.3)	31 (49.2)	0.567
		GA, AA	107 (46.7)	32 (50.8)

Notes: There were 1 missing data for rs2231142, rs3114018, rs1481012, rs1045642, rs2032582, rs1128503, rs15524, and rs4646450, 3 missing data for rs2231142, rs2231137, rs2242480, and rs776746, and 4 missing data for rs2231142 and rs4646437.

Table 3 The Results of Logistic Regression Analysis for Bleeding Complications in Patients Treated with Apixaban and Rivaroxaban

Variables	Unadjusted OR (95% CI)	Model I	Model II
		Adjusted OR (95% CI)	Adjusted OR (95% CI)
Female	1.284 (0.730–2.257)
Age ≥ 65 (years)	1.086 (0.593–1.988)
Weight < 65 (kg)	1.165 (0.668–2.032)
Creatinine clearance < 50 (mL min^−1)	1.273 (0.642–2.527)
Modified HAS-BLED score^a	1.425 (1.092–1.859)**		1.347 (1.018–1.782)*
History of stroke/TIA/thromboembolism	1.908 (1.090–3.340)*
History of bleeding	6.582 (2.436–17.783)***	6.209 (2.210–17.442)***
Concurrent use of PPI	2.221 (1.057–4.666)*	2.385 (1.064–5.349)*	2.359 (1.079–5.156)*
ABCG2 rs2622604 T allele carrier	2.095 (1.181–3.717)*
ABCG2 rs3114018 A allele carrier	1.983 (1.105–3.557)*	2.188 (1.156–4.142)*	2.335 (1.250–4.360)**
ABCB1 rs1045642 AA genotype carrier	2.538 (1.159–5.559)*	3.243 (1.371–7.671)**	3.167 (1.349–7.436)**

Notes: ^aModified HAS-BLED (hypertension, abnormal renal or liver function, stroke, bleeding history or predisposition, elderly (age≥65), concomitant drug and alcohol use; range 0–8) score was calculated without the factor of labile international normalized ratio compared to HAS-BLED. Model I included variables of female, age, weight, creatinine clearance, history of stroke/TIA/thromboembolism, history of bleeding, concurrent use of PPI, ABCG2 rs2622604, ABCG2 rs3114018, and ABCB1 rs1045642. Model II included variables of female, weight, history modified HAS-BLED score, concurrent use of PPI, ABCG2 rs2622604, ABCG2 rs3114018, and ABCB1 rs1045642. *p < 0.05 **p<0.01 ***p<0.001.

Abbreviations: CI, confidence interval; PPI, proton pump inhibitor; OR, odds ratio; TIA, transient ischemic attack.