Direct oral anticoagulants for the treatment of splanchnic vein thrombosis: A state of art

Table 1 Characteristics of studies on non-cirrhotic patients with portal vein thrombosis treated with direct oral anticoagulants

Study	Population	Outcomes	Adverse events	Ref.
Prospective	Non-cirrhotic, atypical sites (including PVT); Riva and Api for PVT (n = 16) vs enoxa for PVT (n = 13)	Riva and Apixaban are effective and safe in patients with venous thrombosis of atypical locations	No major difference in bleeding rate	Janczak et al[40], 2018
Retrospective	Non-malignant PVT, both cirrhotic and non-cirrhotic; Edo (n = 4), Api (n = 3), Riva (n = 2), Dabi (n = 1) vs traditional AC (n = 12), no AC (n = 39)	Favourable outcomes with DOACs with regression/resolution of thrombus in 20% of patients and stability or nonprogression in 80%	One bleeding episode in DOACs	Scheiner et al[41], 2018
Retrospective	Non-cirrhotic PVT; Riva (n = 65), Api (n = 20), Dabi (n = 8) vs Warf (n = 108), Enoxa (n = 70), Fondap (n = 2)	Resolution rate: Dabi (75%), Api (65%), Riva (65%), Enoxa (57%), Warf (31%); Recanalization rates are higher in DOACs compared to Warf but similar to Enoxa	Less major bleeding incidence in DOACs	Naymagon et al[42], 2020
Retrospective	IBD-associated PVT; DOACs (n = 23) vs Warf (n = 22), Enoxa (n = 13)	Resolution rate: DOACs (96%), Warf (55%); DOACs group needed a shorter course of anticoagulation (median 3.9 vs 8.5)	N/A	Naymagon et al[43] 2021
Retrospective	Intraabdominal surgery < 3 mo prior to PVT diagnosis; DOACs (n = 35) vs Warf (n = 31), Enoxa (n = 29), no AC (n = 12)	Complete resolution rate: DOACs (77%), Enoxa (69%), Warf (45%), no AC (17%)	N/A	Naymagon et al[44], 2021
Retrospective	PVT with/without cirrhosis; DOACs (n = 13; 8 non-cirrhotic) vs Warf (n = 20; 15 non cirrotic)	Treatment failure: DOACs (n = 0); Warf (n = 4)	Major bleedings: DOACs: n=0; VKA: n=1	Ilcewicz et al[45], 2021
Prospective	SVT without cirrhosis; Riva 15 BID for 3 wk + Riva 20 mg OD for 3 mo (n = 100)	Recanalization > 80% at 3 mo (47% complete)	2 major bleeding; 2 SVT recurrence	Ageno et al[46], 2022

AC: Anticoagulation; Api: Apixaban; BID: Twice daily; Dabi: Dabigatran; DOACs: Direct oral anticoagulants; Edo: Edoxaban; Enoxa: Enoxaparin; Fondap: Fondaparinux; IBD: Inflammatory bowel disease; OD: Once daily; PVT: Portal vein thrombosis; Riva: Rivaroxaban; SVT: Splanchnic vein thrombosis; VKA: Vitamin K antagonists; Warf: Warfarin.

Table 2 Comparison of main clinical practice guidelines for the management of portal vein thrombosis in non-cirrhotic patients

	EASL 2016[30]	AASLD 2020[38]	ACG 2020[52]	Baveno VII 2022[35]
Classification	Acute; Chronic	Recent: < 6 mo; Chronic: > 6 mo	Acute; Chronic	Recent: < 6 mo; Chronic: > 6 mo
Treatment	Acute: AC; Chronic: Not specified	Recent PVT: AC; Chronic complete PVT or cavernous transformation: No benefit from AC	Acute PVT: AC; Chronic: thrombophilia, progression of thrombus into mesenteric veins, current or previous evidence of bowel ischemia	Recent PVT: At diagnosis; Chronic PVT: After prophylaxis for portal hypertensive bleeding in high-risk varices
Choice of anticoagulation	LMWH, VKA	LMWH, VKA, DOACs	UFH, LMWH for initiation; LMWH or VKA for maintenance (DOACs absorption limited in the presence of intestinal oedema)	LMWH, VKA, DOACs
Duration of treatment	At least 6 mo in presence of transient risk factor; long term for persistent risk factor or in case of chronic PVT with history of intestinal ischemia or recurrent thrombosis	AC for 3 mo	At least 6 mo for acute without thrombophilia; long term with thrombophilia	Recent PVT: At least 6 mo; Chronic: Long term for patient with permanent prothrombotic state
Notes				EVL can be performed safely without withdrawing VKA

AASLD: American Association for the Study of Liver Diseases; AC: Anticoagulation; ACG: American College of Gastroenterology; DOACs: Direct oral anticoagulants; EASL: European Association for the Study of the Liver; EVL: Endoscopic variceal ligation; LMWH: Low molecular weight heparin; PVT: Portal vein thrombosis; UFH: Unfractioned heparin; VKA: Vitamin K antagonists.

Table 3 Characteristics of studies on cirrhotic patients with portal vein thrombosis treated with direct oral anticoagulants

Study	Population	Aim of study	Doses and duration	Outcomes	Adverse events	Ref.
Retrospective	Cirrhotic, CP A/B/C; any indication (incl. PVT); subgroup with PVT: Riva or Api (n = 4) vs Enoxa or VKA (n = 3)	Efficacy and safety of DOACs vs traditional AC in cirrhosis	Riva 15 mg OD +/- 20 mg OD load; Api 5 mg BID +/- 10 mg BID load 10.6 mo (mean)	Recurrent thrombosis: DOACs (n = 1); Trad AC (n = 1)	Total bleeding events were similar in the two groups (with lesser major bleeding in the DOACs group)	Hum et al[87], 2017
Retrospective	Cirrhotic, CP A/BAny indication (incl. PVT); subgroup with PVT: Riva or Api (n = 12) vs LMWH or Warf (n = 6)	Compare the bleeding rates in cirrhotic patients	Riva 20 mg OD; Api 5 mg BID 10.6 mo (mean)	No statistical difference between therapeutic and prophylactic dosing between groups	Similar rates of major and minor bleeding in the two groups	Intagliata et al[89], 2016
Retrospective	Both cirrhotic and non, CP A/B; any indication (incl. PVT); subgroup with cirrhosis and PVT: Riva, Api or Dabi (n = 22)	Indication for starting or switching to DOACs and report short-term efficacy and safety	Cirrhotic: Different doses 9.6 mo (mean)	Cirrhotic: recurrent PVT (n = 1, 4.5%)	Cirrhotic group any indication: Major bleeding (n = 1), minor bleeding (n = 4)	De Gottardi et al[88], 2017
Retrospective	Both cirrhotic and non, CP A/B/C; non-malignant PVT; Edo (n = 4), Api (n = 3), Riva (n = 2), Dabi (n = 1) vs traditional AC (n = 12), no AC (n = 39)	Efficacy and safety of AC in non-malignant PVT	Edo 30/60 mg OD, Api 5 mg BID, Riva 10 mg OD, Dabi 110 mg BID 9.2 mo (median)	Favourable outcomes with DOACs: Regression/resolution 20%; stability/non-progression 80%	Portal hypertensive gastropathy bleeding	Scheiner et al[41], 2018
Retrospective	Cirrhotic, CP A/B; non-malignant PVT; Edo (n = 20) vs Warf (n = 30) (following 2 wk Danaparoid)	Compare the efficacy and safety of Edo and Warf for treatment of chronic PVT in cirrhotic patients	Edo 60 mg OD, (if CrCl > 50; n = 4) or Edo 30 mg OD (if CrCl < 50; n = 16) 6 mo (max)	Edo group had more complete resolution and less PVT progression than Warf group	Major GI bleeding: Edo (n = 3; 7%); Warf (n = 2; 15%)	Nagaoki et al[91], 2018
Prospective	Cirrhotic, CP A; chronic PTV; Riva (n = 26), Dabi (n = 14) vs no AC (n = 40)	Compare the efficacy and safety of DOACs and no AC in chronic PVT in cirrhotic patients	Riva 20 mg OD; Dabi 150 mg BID; 6 mo (max)	Recanalization rate with DOACs 28.2% (statistically higher) and improvement of liver function	No statistically significant difference between the DOACs and the control group in bleeding events	Ai et al[92], 2020
Prospective	Cirrhotic, CP A/B/C; non-malignant PVT; TIPS + AC (n = 197, 18 Riva) vs AC only (n = 63, 4 Riva) vs TIPS only (n = 88) vs nothing (n = 48)	Compare the management using a wait-and-see strategy, AC, and TIPS to treat PVT in cirrhosis	Riva 10 mg OD; 21.0 mo (median)	Recanalization: 0% with Riva only (all with PVT and SMV thrombosis), 100% with Riva + TIPS	Major bleeding events: AC only (n = 14); TIPS+AC (n = 30)	Lv et al[93], 2021

AC: Anticoagulation; Api: Apixaban; VKA: Vitamin K antagonists; BID: Twice daily; CP: Child-Pugh score; Dabi: Dabigatran; DOACs: Direct oral anticoagulants; Edo: Edoxaban; GI: Gastrointestinal; Enoxa: Enoxaparin; LMWH: Low molecular weight heparin; OD: Once daily; PVT: Portal vein thrombosis; Riva: Rivaroxaban; SMV: Superior mesenteric vein; TIPS: Transjugular intrahepatic portosystemic shunt; Warf: Warfarin.