Optimal strategies for mitigating gastrointestinal bleeding in patients receiving antiplatelet therapy: Real-world study

Table 1 Baseline characteristics for all antiplatelet ± anticoagulant/non-steroidal anti-inflammatory drug patients across different designs, n (%)

Variables	Cohort dataset (n = 98404)	SCCS dataset (n = 1137)	Matched landmark dataset (n = 6029)
Age, median (IQR)	62 (53-70)	64 (56-71)	61 (54-69)
Sex
Male	54789 (55.7)	703 (61.8)	2934 (48.7)
Female	43615 (44.3)	434 (38.2)	3095 (51.3)
Mucosal DAs
Aspirin	90766 (92.2)	977 (85.9)	5510 (91.4)
Clopidogrel	34921 (35.5)	465 (40.9)	3316 (55)
Warfarin	6869 (7.0)	151 (13.3)	487 (8.1)
NSAIDs	3994 (4.0)	66 (5.8)	469 (7.8)
DOAC	3003 (3.1)	70 (6.2)	274 (4.5)
PAs co-administered with DAs
PPI	13337 (12.3)	476 (41.9)	1366 (22.7)
Rebamipide	5890 (54.4)	196 (17.2)	1068 (17.7)
H2RA	19919 (18.4)	594 (52.2)	1352 (22.4)
Others	3647 (34.7)	103 (9.1)

SCCS: Self-controlled case series; IQR: Interquartile range; DA: Damaging agent; NSAID: Non-steroidal anti-inflammatory drug; DOAC: Direct oral anticoagulant; PA: Protective agent; H2RA: H2-receptor antagonist; PPI: Proton pump inhibitor; Others: Agents such as sodium alginate, ecabet sodium hydrate, polaprezinc, and stillen (an ethanol extract of Artemisiae Argyi herba).

Table 2 Baseline characteristics for aspirin or clopidogrel alone users, n (%)

Variables	Aspirin-alone users (n = 55295)	Clopidogrel-alone users (n = 6882)	Concurrent users of aspirin & clopidogrel (n = 7080)	Concomitant users of aspirin & clopidogrel (n = 22452)
Age, median (IQR)	61 (52-69)	65 (56-73)	65 (57-73)	63 (54-70)
Sex
Male	28344 (51.3)	3465 (50.3)	5081 (71.8)	15176 (67.6)
Female	26951 (48.7)	3417 (49.7)	1999 (28.2)	7276 (32.4)
Mucosal DAs
Aspirin	55295 (100)	0 (0)	7080 (100)	22452 (100)
Clopidogrel	0 (0)	6882 (100)	7080 (100)	22452 (100)
PAs co-administered with DAs
PPI	5737 (31.8)	715 (31.9)	742 (23.1)	3745 (30.3)
Rebamipide	2143 (11.9)	450 (20.1)	224 (7.0)	1484 (12.0)
H2RA	8065 (44.7)	927 (41.4)	2187 (68.0)	6503 (52.5)
Others	2085 (11.6)	147 (6.6)	63 (1.9)	643 (5.2)

IQR: Interquartile range; DA: Damaging agent; PA: Protective agent; H2RA: H2-receptor antagonist; PPI: Proton pump inhibitor; Others: Agents such as sodium alginate, ecabet sodium hydrate, polaprezinc, and stillen (an ethanol extract of Artemisiae Argyi herba).

Table 3 Effect of protective agent uses on significant hemoglobin drop incidences by risk groups for all antiplatelet ± anticoagulant/non-steroidal anti-inflammatory drug patients in self-controlled case series analyses

Exposure period	Total (n = 1137)			High-risk group (n = 1028)			Low-risk group (n = 109)
	Number of SHD incidence	IRR (95%CI)	P value	Number of SHD incidence	IRR (95%CI)	P value	Number of SHD incidence	IRR (95%CI)	P value
All SHD events
Mucosal DA alone	939	Reference		845	Reference		94	Reference
PPI	233	0.42 (0.34-0.53)	< 0.001	222	0.42 (0.33-0.53)	< 0.001	11	0.46 (0.18-1.20)	0.114
PPI & rebamipide	2	0.07 (0.02-0.30)	< 0.001	2	0.07 (0.02-0.29)	< 0.001	0
PPI & H2RA	8	0.27 (0.11-0.65)	0.003	8	0.28 (0.12-0.68)	0.005	0
PPI & others	4	0.09 (0.02-0.52)	0.007	4	0.09 (0.01-0.51)	0.007	0
Rebamipide	122	0.68 (0.50-0.93)	0.017	110	0.66 (0.47-0.92)	0.014	12	0.92 (0.39-2.15)	0.840
Rebamipide & H2RA	6	0.23 (0.09-0.59)	0.002	6	0.25 (0.10-0.64)	0.004	0
H2RA	356	0.75 (0.63-0.90)	0.002	333	0.77 (0.64-0.93)	0.006	23	0.59 (0.31-1.13)	0.113
H2RA & others	2	0.24 (0.05-1.18)	0.078	2	0.34 (0.07-1.74)	0.196	0
Others	29	0.37 (0.22-0.60)	< 0.001	23	0.31 (0.17-0.53)	< 0.001	6	1.01 (0.27-3.79)	0.985
First SHD event only
Mucosal DA alone	938	Reference		844	Reference		94	Reference
PPI	219	0.43 (0.34-0.53)	< 0.001	208	0.42 (0.34-0.54)	< 0.001	11	0.43 (0.16-1.13)	0.087
PPI & rebamipide	2	0.07 (0.02-0.29)	< 0.001	2	0.07 (0.02-0.28)	< 0.001	0
PPI & H2RA	8	0.32 (0.13-0.78)	0.0120	8	0.34 (0.14-0.83)	0.017	0
PPI & others	4	0.09 (0.02-0.53)	0.0080	4	0.09 (0.02-0.53)	0.008	0
Rebamipide	118	0.68 (0.49-0.94)	0.0200	106	0.65 (0.46-0.92)	0.015	12	0.96 (0.40-2.28)	0.923
Rebamipide & H2RA	4	0.19 (0.06-0.55)	0.0020	4	0.20 (0.07-0.61)	0.005	0
H2RA	331	0.76 (0.63-0.91)	0.0030	309	0.78 (0.64-0.94)	0.010	22	0.60 (0.32-1.15)	0.122
H2RA & others	2	0.29 (0.06-1.45)	0.1300	2	0.43 (0.08-2.31)	0.328	0
Others	29	0.39 (0.24-0.65)	< 0.001	23	0.33 (0.19-0.58)	< 0.001	6	0.92 (0.24-3.49)	0.898

Adjusted incidence rate ratios were estimated after adjusting prescription period for protective agents and damaging agents. SHD: Significant hemoglobin drop; CI: Confidence interval; DA: Damaging agent; PPI: Proton pump inhibitor; H2RA: H2-receptor antagonist; IRR: Incidence rate ratio; Others: Agents such as sodium alginate, ecabet sodium hydrate, polaprezinc, and stillen (an ethanol extract of Artemisiae Argyi herba).

Table 4 Effect of protective agent uses on significant hemoglobin drop incidences for aspirin or clopidogrel alone users in self-controlled case series analyses

Exposure period	Aspirin-alone users (n = 351)		Clopidogrel-alone users (n = 35)		Concurrent users of aspirin & clopidogrel (n = 30)		Concomitant users of aspirin & clopidogrel (n = 348)
	IRR (95%CI)	P value	IRR (95%CI)	P value	IRR (95%CI)	P value	IRR (95%CI)	P value
All SHD events
Mucosal DA alone	Reference		Reference
PPI	0.33 (0.21-0.52)	< 0.001	0.43 (0.09-2.13)	0.301	0.39 (0.10-1.60)	0.191	0.43 (0.30-0.62)	< 0.001
PPI & rebamipide	0.35 (0.06-1.90)	0.223
PPI & H2RA							0.54 (0.18-1.64)	0.281
PPI & others							0.14 (0.02-1.02)	0.052
Rebamipide	0.69 (0.36-1.34)	0.276	0.25 (0.02-2.87)	0.263			1.49 (0.87-2.57)	0.148
Rebamipide & H2RA	0.61 (0.12-3.17)	0.553					0.27 (0.05-1.35)	0.111
H2RA	0.60 (0.43-0.83)	0.002	1.85 (0.55-6.23)	0.322	1.02 (0.42-2.53)	0.958	0.93 (0.67-1.29)	0.661
H2RA & others	0.46 (0.07-2.95)	0.411
Others	0.47 (0.20-1.10)	0.081	2.34 (0.32-17.19)	0.403			0.40 (0.15-1.07)	0.068
First SHD event only
Mucosal DA alone	Reference		Reference
PPI	0.33 (0.21-0.51)	< 0.001	0.42 (0.08-2.08)	0.286	0.39 (0.10-1.60)	0.191	0.45 (0.31-0.65)	< 0.001
PPI & rebamipide	0.35 (0.06-1.91)	0.224
PPI & H2RA							0.81 (0.26-2.50)	0.708
PPI & others							0.15 (0.02-1.04)	0.055
Rebamipide	0.74 (0.38-1.44)	0.380	0.26 (0.02-3.07)	0.285			1.46 (0.85-2.52)	0.173
Rebamipide & H2RA	0.60 (0.12-3.15)	0.549
H2RA	0.62 (0.44-0.86)	< 0.001	2.22 (0.59-8.33)	0.239	1.02 (0.42-2.53)	0.958	0.96 (0.69-1.34)	0.814
H2RA & others	0.45 (0.07-2.89)	0.401
Others	0.48 (0.20-1.12)	0.090	2.30 (0.31-16.93)	0.413

SHD: Significant hemoglobin drop; IRR: Incidence rate ratio; CI: Confidence interval; DA: Damaging agent; PPI: Proton pump inhibitor; H2RA: H2-receptor antagonist; Others: Agents such as sodium alginate, ecabet sodium hydrate, polaprezinc, and stillen (an ethanol extract of Artemisiae Argyi herba).