Safety of liver resection in patients receiving antithrombotic therapy: A systematic review of the literature

Table 1 Types, specific agents, and acting duration of commonly used antithrombotic drugs

Class of agents	Type	Specific agents	Duration of action
Antiplatelets
	Thienopyridines	Clopidogrel (Plavix), ticlopidine (Panardine), prasugrel (Effient), ticagrelor (Brilinta)	5-7 d1
	Type III PDE inhibitor	Cilostazol (Pretal)	2 d
	Acetylsalicylic acid	Aspirin	7-10 d
	Other NSAIDs	Ibuprofen (Brufen, Advil), loxoprofen (Loxonin), diclofenac (Voltaren) etc.	Varies
Anticoagulants
	Heparin (unfractionated)	Heparin	1-2 h
	Heparin (LMWH)	Dalteparin (Fragmin iv), enoxaparin (Clexane, s.c.), nadroparin (s.c.)	6-12 h2
	Vitamin K antagonist	Warfarin (Coumadin)	5 d
	Factor Xa inhibitor (s.c.)	Fondaparinux (Arixtra)	1-1.5 d
	DOACs
	Direct thrombin inhibitor	Dabigatran (Pradaxa)	1-2 d
	Factor Xa inhibitors	Rivaroxaban (Xarelto), apixaban (Eliquis), edoxaban (Lixiana)	1-2 d

¹In ticlopidine, duration of action is 10-14 d.

²In dalteparin, duration of action is 2-4 h. PDE: Phosphodiesterase; NSAID: Non-steroidal anti-inflammatory drug; DOAC: Direct-acting oral anticoagulant.

Table 2 Reported data concerning bleeding complications of liver resection in patients with antithrombotic therapy

Ref.	Year, type	Surgery type	Drug use and exposure	Bleeding events	TE, mortality
Naito et al[9]	2020, PSM	Liver resection (n = 425)	Patients with continued ASA (n = 63); Patients not on continued APT (control, n = 362); Post-PSM: 63 vs 63 matched cases	BC 4.8% in continued ASA vs 4.8% in control (P = 1.00); SBL was identical (P = 0.54)	TE 1.6% in continued ASA vs 4.8% in control (P = 0.62); Mortality 1.6% vs 1.6% (P = 1.00)
Fujikawa et al[10]	2017, RCS	Liver resection (n = 258) including 77 laparoscopic liver resection	Patients with ATT (n = 100); Patients without ATT (control; n = 158)	BC 3.0% in ATT vs 3.8% in control (P > 0.05); No BC in laparoscopic surgery; SBL was identical	TE 1.0% vs 1.3% (P > 0.05); No TE in laparoscopic surgery; Mortality 1.0% vs 0% (P = 0.350)
Ishida et al[11]	2017, CCS	HBP surgery (n = 886) including 520 liver resection	Patients with ACT (n = 39); Patients with APT (n = 77); Patients without ATT (control, n = 770)	BC 0.0% in ACT vs 1.3% in APT vs 3.4% in control (P = 0.32); SBL was identical (P = 0.99)	TE 0% vs 1.3% vs 0.8% (P = 0.75); Mortality 0% vs 0% vs 1.2% (P = 0.50)
Gelli et al[12]	2018, PSM	Liver resection (n = 1803)	Patients with continued ASA (n = 118); Patients not on continued APT (control, n = 1685); Post-PSM: 108 vs 108 matched cases	Overall BC 10.2% in continued ASA vs 12.0% in control (P > 0.05); Major BC 6.5% vs 5.6% (P > 0.05)	Mortality 5.6% vs 4.6% (P > 0.05)
Monden et al[13]	2017, CCS	Liver resection (n = 378)	Patients with continued ASA (n = 31); Patients not on continued APT (control, n = 347)	Major BC 0% in continued ASA vs 0.3% in control (P > 0.05); SBL 450 mL vs 360 mL (P = 0.735)	TE 3.2% vs 0% (P > 0.05); Mortality 3.2% vs 0.9% (P = 0.291)
Fujikawa et al[14]	2019, CCS	HBP surgery (n = 105) including 37 liver resection	Patients with DOAC (n = 35); Patients with WF (control, n = 80)	BC 2.9% in DOAC vs 0% in WF (P = 0.304); SBL was identical (P = 0.782)	No TE event in both groups; No mortality in both groups

RCS: Retrospective cohort study; mRCS: Multicenter retrospective cohort study; CCS: Case-control study; PSM: Case-control study with propencity-score matching; ATT: Antithrombotic therapy; APT: Antiplatelet therapy; ACT: Anticoagulation therapy; ASA: Aspirin; LAP: Laparoscopic; SBL: Surgical blood loss; BC: Postoperative bleeding complication; TE: Thromboembolism.

Table 3 Reported data concerning the safety of thromboprophylaxis for venous thromboembolism during liver resection

Ref.	Year, type	Surgery type	Drug use and exposure	Bleeding events	TE, mortality
Ainoa et al[15]	2020, RCS	Liver resection (n = 512)	Patients with preop TP (n = 253); Patients with postop TP (control, n = 259)	BC 15.0% in preop TP vs 13.9% in control (P > 0.05)	VTE 1.2% vs 9.7% (P < 0.0001); PE 1.2% vs 9.3% (P < 0.0001)
Ejaz et al[16]	2014, RCS	Liver resection (n = 599)	Patients with TP (n = 454); Patients without TP (control, n = 145)	Not mentioned	VTE 5.1% in TP vs 3.4% in control (P = 0.42)
Nathan et al[17]	2014, RCS	Liver resection (n = 2147)	Patients with early TP (n = 1295); Patients with late or no TP (control, n = 852)	Major BC 1.7% in early TP vs 1.6% in control (P > 0.05)	VTE 2.1% vs 3.3% (P > 0.05); Overall mortality 1.9%
Eguchi et al[18]	2020, mPCS	Major HBP surgery (n = 133) including 74 liver resection	Patients with TP [LMWH (enoxaparin), n = 133, single arm]	Major BC 2.3%; Minor BC 5.2%	No PE event in whole cohort
Hayashi et al[19]	2014, RCS	Major HBP surgery (n = 349) including 138 liver resection	Patients with TP (n = 207); Patients without TP (control, n = 142)	BC 26.6% in TP vs 8.5% in control (P < 0.05); Rate of major BC is identical	VTE 2.9% vs 7.7% (P > 0.05)
Wang et al[20]	2018, CCS	Liver resection (n = 233)	Patients with TP (LMWH, n = 117); Patients without TP (control, n = 116)	Not mentioned	VTE 0.85% in TP vs 13.8% (P < 0.05)
Kim et al[21]	2017, RCS	Liver resection (n = 124)	Patients with extended TP [LMWH (enoxaparin), n = 124, single arm]	BC 1.6% in extended TP	No VTE in whole cohort
Doughtie et al[22]	2014, RCS	Major HBP surgery (n = 223) including 110 liver resection	Patients with preop TP (LMWH, n = 93); Patients without preop TP (control, n = 130)	Major BC 10.9% in preop TP vs 3.1% in control (P = 0.026); SBL was identical	VTE 1.1% vs 6.1% (P = 0.05)
Melloul et al[23]	2012, RCS	Liver resection (n = 410)	Patients with TP (n = 410, single arm)	Not mentioned	PE 6% (24/410) in TP
Reddy et al[24]	2011, RCS	Major liver resection (n = 419)	Patients with TP (n = 275); Patients without TP (control, n = 144)	RBC transfusion rate 35.0% in TP vs 30.6% in control (P = 0.36)	CR-VTE 2.2% in TP vs 6.3% in control (P = 0.03); PE 2.2% vs 4.2% (P = 0.35)

mRCT: Multicenter randamized controlled trial; RCS: Retrospective cohort study; mRCS; multicenter retrospective cohort study; LMWH: Low-molecular-weight heparin; TP: Thromboprophylaxis; LAP: Laparoscopic; CR: Clinically relevant; BC: Postoperative bleeding complication; VTE: Venous thromboembolism; PE: Pulmonary embolism; AOR: Adjusted odds ratio.