Assessment of delayed bleeding after endoscopic submucosal dissection of early-stage gastrointestinal tumors in patients receiving direct oral anticoagulants

Table 1 Possible methods for monitoring the anticoagulant ability of direct oral anticoagulants[49,71,87]

	Qualitative methods			Quantitative methods					Other
	aPTT	TT	PT	Anti-FIIa levels	Anti-Fxa levels	Plasma level	dTT	ECT/ECA	CBC	CMP
Dabigatran	2	2	2	1		1	2	2	2	2
Apixaban			2		1	1			2	2
Edoxaban			2		1	1			2	2
Rivaroxaban			2		1	1			2	2

¹Possible excellent markers.

²Possible sensitive markers.

APTT: Activated partial thromboplastin time; CBC: Complete blood count; CMP: Comprehensive metabolic panel; dTT: Dilute thrombin time; ECA: Ecarin chromogenic assay: ECT: Ecarin clotting time; FXa: Activated factor X; PT: Prothrombin time; TT: Thrombin time.

Table 2 Pharmacological characteristics of direct oral anticoagulant[71,87]

	Dabigatran	Apixaban	Edoxaban	Rivaroxaban
Target factor	Thrombin (Factor IIa)	Factor Xa	Factor Xa	Factor Xa
Half-time (h)	10.7-11.8	6.12-8.11	6.21-6.70	5.7-12.6
Time to peak effect (h)	4	3.0-3.5	1-1.5	1.4-3.3
Distribution volume (L)	50-70	21	107	50
Renal excretion (%)	85	27	35.4-50	50
Fecal excretion (%)	6	25	62.2	50
Hepatic metabolism	No	CYP3A4/5	CYP3A4	CYP3A4 and CYP2J2
Transporter	P-gP	P-gP/BCRP	P-gP	P-gP/BCRP
Protein binding (%)	28.2-31.5	87	40.0-58.9	92-95
Dialyzable	Yes	No	No	No
Prodrug	Yes	No	No	No
Bioavailability (%)	6.5	50	61.8	66-112
Dose for AF (in Japan)	150 mg	5 mg	60 mg	15 mg
Dosing time	Twice daily	Twice daily	Once daily	Once daily
Reversal agent	Idarucizumab	Andexanet alfa	Andexanet alfa	Andexanet alfa
FDA-approved indications	Nonvalvular AF, VTE (T, SP, P)	Nonvalvular AF, VTE (T, SP, P)	Nonvalvular AF, VTE (T)	Nonvalvular AF, VTE (T, SP, P)
Japanese insurance system-approved indications	Nonvalvular AF (P)	Nonvalvular AF (P), VTE (T, SP)	Nonvalvular AF (P), VTE (T, SP)	Nonvalvular AF (P), VTE (T, SP)
Non-pharmacologic interactions	Age, reduced GFR	Age, reduced body weight, reduced GFR, probable severe liver damage	Reduced GFR, probable severe liver damage	Age, reduced GFR, probable severe liver damage
Drug interactions	Dose reduction: Concomitant P-gp inhibitor, gastric acid inhibitory drug	Avoid: Concomitant P-gp and CYP3A4 inhibitors	Avoid: Concomitant rifampin	Avoid: Rivaroxaban with concomitant dual P-gp and CYP3A4 inhibitors
Contraindications	Ccr: < 30mL/min	Nonvalvular AF: Ccr: < 15mL/min, VTE:	Nonvalvular AF: Ccr: < 15mL/min, VTE:	Nonvalvular AF: Ccr: < 15mL/min, VTE:
		Ccr: < 30mL/min	Ccr: < 30mL/min	Ccr: < 30mL/min

AF: Atrial fibrillation; P: Prophylaxis; SP: Secondary prevention; T: Treatment; VTE: Venous thromboembolism; FDA: Food and Drug Administration; Ccr: Creatinine clearance.

Table 3 Comparison of clinical trials on patients receiving direct oral anticoagulant: Major bleeding

	Dabigatran	Apixaban	Edoxaban	Rivaroxaban
Trial name	RE-LY[4]	ARISTOTLE[5]	ENGAGE AF TIMI48[6]	ROCKET AF[7]/J-ROCKET AF
Number of patients	18113	18201	21105	14264
Method	PROBE	RCT	RCT	RCT
Primary endpoints	Stroke or systemic embolism	Ischemic or hemorrhagic stroke or systemic embolism	Stroke or systemic embolism	Stroke or systemic embolism
Period (years)	2.0	1.8	2.8	1.9
CHADS2 score (mean)	2.2	2.1	2.8	3.48 (J-ROCKET: 3.25)
Dosing dose	150 mg/10 mg bid	5 mg bid	60 mg/30 mg qd	20 mg od (J-ROCKET: 15 mg od)
Evaluation
Thrombus/embolism (vs warfarin)	110 mg: Non-inferior, 150 mg: Superior	Superior	60 mg: Similar, 30 mg: Similar	On treatment: Superior, Intention-to-treat: Non-inferior
Outcomes: Stroke or systemic embolism	War: 1.69%/yr, D (110): 1.51%/yr, D (150): 1.11%/yr	War: 1.50%/yr, A: 1.27%/yr	War: 1.81%/yr, E (30): 2.06%/yr, E (60): 1.57%/yr	War: 2.2%/yr, R: 1.7%/yr
Major bleeding (vs warfarin)	110 mg: Superior, 150 mg: Similar	Superior	Superior	Similar
Bleeding rate	War: 3.36%/yr, D (110): 2.71%/yr, D (150): 3.11%/yr	War: 3.09%/yr, A: 2.13%/yr	War: 3.43%/yr, E (30): 1.61%/yr, E (60): 2.75%/yr	War: 3.4%/yr, R: 3.6%/yr
Intracranial bleeding	War: 0.74%/yr, D (110): 0.23%/yr, D (150): 0.30%/yr	War: 2.27%/yr, A: 1.79%/yr	War: 0.85%/yr, E (30): 0.26%/yr, E (60): 0.39%/yr	War: 0.7%/yr, R: 0.5%/yr
Gastrointestinal bleeding	War: 1.02%/yr, D (110): 1.12%/yr, D (150): 1.51%/yr	War: 0.86%/yr, A: 0.76%/yr	War: 1.23%/yr, E (30): 0.82%/yr, E (60): 1.51%/yr	War: 2.2%/yr, R: 3.2%/yr1
Minor bleeding (vs warfarin)	War: 16.37%/yr, D (110): 13.16%/yr, D (150): 14.84%/yr	War: 6.01%/yr, A: 4.07%/yr	War: 4.89%/yr, E (30): 3.52%/yr, E (60): 4.12%/yr	War: 11.4%/yr, R: 11.8%/yr
Mortality rate	War: 4.13%/yr, D (110): 3.75%/yr, D (150): 3.64%/yr	War: 3.94%/yr, A: 3.52%/yr	War: 4.35%/yr, E (30): 3.80%/yr, E (60): 3.99%/yr	War: 2.2%/yr, R: 1.9%/yr

A: Apixaban; D: Dabigatran; E: Edoxaban; R: Rivaroxaban; war: Warfarin; RCT: Randomized clinical trial; CHADS: Congestive heart failure, Hypertension, Age > 75 years, Diabetes mellitus, and Stroke; PROBE: Prospective randomized open blinded-endpoint.

Table 4 Summary of international guidelines concerning withdrawal of direct oral anticoagulants during gastroenterological endoscopy

Ref.	Country	Standard endoscopy	Biopsy	Low risk of bleeding	High risk of bleeding, including ESD
[71]	Japan	1	2Avoid peak plasma level	2Avoid peak plasma level	3(1) Withdraw on the day of treatment; and (2) Heparin replacement
[72]	Europe	1	3Withdraw on the day of treatment	3Withdraw on the day of treatment	3(1) Withdraw 3 d before treatment; (2) Withdraw 5 d before treatment for dabigatran patients at Ccr 30–50 mL/min; and (3) No heparin bridging
[73]	United States	1	1	1	3(1) Withdraw; and (2) Bridge therapy required for patients at high risk for thromboembolic events
[74]	Korea	1	1	1	3Withdraw 2 d before treatment
[75]	Asia-Pacific	1	1	1	3Withdraw 2 d before treatment

¹Withdrawal is not required.

²Withdrawal is not required but possible.

³Withdrawal is required.

ESD: Endoscopic submucosal dissection; Ccr: Creatinine clearance.

Table 5 Delayed bleeding after endoscopic submucosal dissection in patients receiving direct oral anticoagulants

Ref.	Year	Country	Type	Organ	DOAC patients	Bleeding rate	Non-DOAC patients	Bleeding rate
Nagata et al[83]	2018	Japan	Retrospective	Upper GI	275	39.6%	301 (warfarin)	45.8%
Horie et al[85]	2022	Japan	Retrospective	Esophagus	161	13%	8692	0.3%1
Yoshio et al[88]	2017	Japan	Retrospective	Stomach	24	20.8%	73 (warfarin)	24.6%
Sanomura et al[89]	2018	Japan	Retrospective	Stomach	21	19.0%	40 (warfarin)	17.5%
Saito et al[90]	2020	Japan	Retrospective	Stomach	77	19.5%	66 (warfarin)	22.7%
Hatta et al[36]	2021	Japan	Retrospective	Stomach	253	17.0%	10,067	4.4%1
Tomida et al[84]	2021	Japan	Retrospective	Stomach	261	14%	467 (warfarin)	18%
Choi et al[91]	2021	Korea	Retrospective	Stomach	23	8.7%	1499	3.0%
Kagawa et al[37]	2022	Japan	Retrospective	Stomach	39	15.4%	752	4.3%1
Nagata et al[83]	2018	Japan	Retrospective	Lower GI	121	13.2%	111 (warfarin)	25.9%
Yamashita et al[92]	2018	Japan	Retrospective	Colon	9	22.0%	19 (warfarin)	26.3%
Ogiyama et al[93]	2020	Japan	Retrospective	Colon	43	23.3%	44 (warfarin)	11.4%
Harada et al[94]	2020	Japan	Retrospective	Colon	25	16.0%	26 (warfarin)	7.7%

¹Included 2 endoscopic mucosal resection patients.

²Included no antithrombotic drug patients.

DOAC: Direct oral anticoagulants.