Safety of pancreatic surgery with special reference to 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.)	2-4 h, 6-12 h, 6-12 h
	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. PDE: Phosphodiesterase; NSAID: Non-steroidal anti-inflammatory drug; DOAC: Direct-acting oral anticoagulant.

Table 2 Reported data concerning bleeding complications of pancreatic surgery in patients with antithrombotic therapy

Ref.	Year, Type	Surgery type	Drug use and exposure	Bleeding events	TE, mortality
Nakamura et al[17]	2020 mRCS	Pancreatic surgery	Patients with ATT (n = 144); Patients without ATT (control, n = 1297)	PPH 8.3% in ATT vs 2.0% in control (P < 0.001); SBL was identical (P = 0.338)	TE 1.4% vs 0.4% (P = 0.149); Mortality 2.8% vs 2.1% (P = 0.542)
Fujikawa et al[18]	2020 RCS	Major digestive surgery including pancreatic surgery	Patients with continued use of ASA (n = 421); Patients with discontinuation of APT (n = 542); Patients not on APT (control, n = 2019)	BC 3.8% in continued ASA vs 3.5% in discontinuation vs 1.3% in control (P < 0.001); BC rate comparable after adjusting	TE 0.5% in continued ASA or control vs 2.8% in discontinuation (P < 0.001); Mortality 0.7%/0.6% vs 1.1% (P = 0.340)
Komokata et al[19]	2020 CCS	Pancreaticoduodenectomy	Patients with ATT (n = 30); Patients without ATT (control, n = 47)	PPH 16.7% in ATT vs 6.4% in control (P = 0.250); SBL was identical (P = 0.454)	TE 13.3% vs 0% (P = 0.020); Mortality 6.7% vs 2.1% (P = 0.557)
Fujikawa et al[20]	2019 RCS	Gastroenterological surgery including pancreatic resection	Patients with DOAC w/o HEP (n = 69); Patients with DOAC w/ HEP (n = 34); Patients with WF w/ HEP (control, n = 231)	BC 1.4% in DOAC w/o HEP vs 14.7% in DOAC w/HEP vs 4.8% in control (P = 0.011); SBL was identical (P = 0.772)	TE 0% vs 0% vs 0.9% (P = 0.637); Mortality 0% vs 1% vs 1.3% (P = 0.791)
Ishida et al[21]	2017 PSM	HBP surgery including pancreatic surgery	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)
Fujikawa et al[22]	2019 CCS	HBP surgery including pancreatic surgery	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
Fujikawa et al[23]	2018 RCS	Pancreaticoduodenectomy	Patients with APT (n = 31); Patients without APT (control, n = 69)	PPH 12.9% in APT vs 2.9% in control (P = 0.072); SBL was identical (P = 0.704)	Only one TE (3.2%) in APT group; No mortality in both groups
Mita et al[10]	2016 CCS	Pancreatic surgery	Patients with ATT (n = 34); Patients without ATT (control, n = 124)	PPH 29.4% in ATT vs 6.5% in control (P = 0.039)	Mortality 11.8% vs 2.4% (P = 0.005)
Wolf et al[24]	2014 CCS	Pancreatic surgery	Patients with continued use of ASA (n = 289); Patients without ASA (control, n = 728)	SBL 400 mL in ASA vs 400 mL in control (P = 0.661)	CV complications 10.1% vs 7.0% (P = 0.107)

RCS: Retrospective cohort study; mRCS: Multicenter RCS; CCS: Case-control study; PSM: CCS with propencity-score matching; HBP: Hepatobiliary and pancreatic; ATT: Antithrombotic therapy; APT: Antiplatelet therapy; ACT: Anticoagulation therapy; ASA: Aspirin; DOAC: Direct-acting oral anticoagulant; HEP: Heparin; PPH: Postpancreatectomy hemorrhage; BC: Postoperative bleeding complication; SBL: Surgical blood loss; TE: Thromboembolism; CV: Cardiovascular.

Table 3 Reported data concerning the safety of thromboprophylaxis for venous thromboembolism during pancreatic surgery

Ref.	Year, Type	Surgery type	Drug use and exposure	Bleeding events	TE, mortality
Eguchi et al[25]	2020 PCS	Major HBP surgery including pancreatic surgery	Patients with TP [LMWH (enoxaparin), n = 133, single arm]	Major BC 2.3%; Minor BC 5.2%	No TE event in whole cohort
Hashimoto et al[26]	2017 PCS	Pancreatic surgery	Patients with TP [LMWH (enoxaparin), n = 103, single arm]	Major PPH 2.9%	Asymptomatic VTE 1.9%; No symptomatic VTE; No motality
Imamura et al[27]	2017 PCS	Pancreatic surgery	Patients with TP [LMWH (enoxaparin), n = 151, single arm]	Major PPH 3.3%; Minor PPH 3.3%	No PE event in whole cohort
Hanna-Sawires et al[28]	2019 RCS	Pancreatic surgery	Patients with single LMWH (nadroparin) (n = 80); Patients with double dose LMWH (n = 80); Patients with split dose LMWH (n = 80)	CR-PPH 16.0% in double LMWH vs 3.8% in others (P = 0.015)	VTE was identical among groups
Fong et al[29]	2020 RCS	Pancreatic surgery	Patients with TP (preop heparin, n = 1062); Patients without TP (control, n = 386)	(Not mentioned)	VTE 2.6% in TP vs 1.3% in control (P = 0.079), increased AOR in TP (AOR 2.93, P = 0.031)
Doughtie et al[30]	2014 RCS	Major HBP surgery including pancreatic surgery	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)
Hayashi et al[31]	2014 RCS	Major HBP surgery including 211 pancreatic surgery	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)
Skertich et al[32]	2019 RCS	Surgery for NETs including pancreatic surgery	Patients with abdominal NETs (n = 7226, single arm)	(not mentioned)	VTE 2.0% in whole cohort; VTE 3.4% in malignant PNETs
Rashid et al[33]	2019 RCS	Pancreatic surgery for malignant diseases	Patients with extended DOAC [dabigatran] until POD28 (n = 134, single arm)	Major PPH 2.0% and minor PPH 2.0%	Post-discharge VTE 2.0%
Beal et al[34]	2018 RCS	Major HBP surgery including pancreatic surgery	Patients with hepatectomy or pancreatectomy (n = 48860, single arm)	(not mentioned)	VTE 3.2% after hepatectomy; VTE 1.1% after pancreatectomy; Post-discharge VTE 1.1% in all

PCS: Prospective cohort study; RCS: Retrospective cohort study; TP: Thromboprophylaxis; LMWH: Low-molecular-weight heparin; NET: Neuroendocrine tumor; DOAC: Direct-acting oral anticoagulant; PPH: Postpancreatectomy hemorrhage; CR: Clinically relevant; SBL: Surgical blood loss; BC: Postoperative bleeding complication; VTE: Venous thromboembolism; PE: Pulmonary embolism; AOR: Adjusted odds ratio; PNET: Pancreatic NET.