Direct oral anticoagulants in the treatment of portal vein thrombosis in patients with portal hypertension

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PVT is a heterogeneous condition with regard to its natural history, disease manifestations, and therapeutic options.¹ PVT results from a combination of abnormal portal blood flow, vascular endothelial injury, and a hypercoagulable state.^2,3 Patients with cirrhosis develop PVT as a result of chronic inflammation and coagulopathy of liver disease.^2,4 In patients without liver disease, PVT develops due to clinical conditions characterized by an underlying hypercoagulable state.^2,3,5 Consultation with hematology is generally advised to screen for work-up of hypercoagulability, including malignancy in patients who do not have cirrhosis.⁶ The objectives of this review article are to categorize and understand the treatment options for PVT, review the literature for direct oral anticoagulants (DOACs) compared with alternative choices, and outline the treatment guidelines of PVT in patients with and without portal hypertension.

PVT is classified based on descriptions of the time course, percent occlusion of the main portal vein, and interval change (Table 1).^1,5,7,8 Time course is split into recent (when present for <6 months) or chronic (when present or persistent for more than 6 months).^1,5 The term recent is preferred to acute as acute implies clinical symptoms with the onset of thrombosis; patients can be asymptomatic with a recent PVT.⁵ Percent occlusion of the main portal vein is divided into completely occlusive (no lumen), partially occlusive (obstructing more than 50% of the vessel lumen), minimally occlusive (obstructing less than 50% of the vessel lumen), and cavernous transformation (if gross portoportal collaterals are seen without the original portal vein).⁵ Furthermore, interval change is separated into progressive (thrombus increases in size or occlusion), stable (no appreciable change), and regressive (thrombus decreases in size or occlusion).^1,5

TABLE 1.

Main classification system for portal vein thrombosis

Time course	Recent	When present for <6 m
	Chronic	When present or persistent for >6 mo
Percent of lumen occluded	Completely occlusive	Obstructing 100% of the lumen
	Partially occlusive	Obstructing >50% of the lumen
	Minimally occlusive	Obstructing less than 50% of the lumen
	Cavernous transformation	Gross portoportal collaterals are seen without the original portal vein
Interval change	Progressive	Thrombus increases in size or occlusion
	Stable	No appreciable change
	Regressive	Thrombus decreases in size or occlusion

The treatment of PVT traditionally has been with vitamin K antagonist (VKA) and low-molecular-weight heparin (LMWH) due to lower costs, more physician experience, and ease of reversibility in the setting of severe bleeding.⁹ Recently, the use of DOACs for the treatment of PVT has become more common despite limited literature evaluating the use of DOACs in the treatment of PVT.^5,9 Although historically large clinical trials of DOACs have excluded patients with PVT, several recent retrospective studies have demonstrated the successful use of DOACs for the treatment of PVT in patients with and without cirrhosis (Table 2).^5,10,12–14

TABLE 2.

Anticoagulation for PVT with DOACs compared with other treatments

References	Study design	Study sample	Conclusion	Drug	Safety
Koh et al1 Efficacy and safety of direct oral anticoagulants vs. vitamin K antagonist for PVT in cirrhosis: a systematic review and meta-analysis	Cirrhosis Systematic review and meta-analysis	Studies (10 observational, 1 randomized trial), 552 patients	DOAC associated with higher pooled rate of PVT recanalization and lower rate of PVT progression	DOAC vs. VKA	Similar risk of major bleeding, variceal bleeding, and death
Ng et al, 202110 A network meta-analysis of direct oral anticoagulants for PVT in cirrhosis	Cirrhosis Network meta-analysis	10 studies (3 randomized trial, 7 cohort), 527 patients	DOAC superior to LMWH, VKA, and no treatment in complete PVT recanalization but not significantly superior for partial recanalization	DOAC vs. LMWH and VKA	No increased risk of bleeding or mortality when comparing DOACs to LMWH and VKA
Naymagon et al11 The efficacy and safety of direct oral anticoagulants in noncirrhotic portal vein thrombosis	Noncirrhosis Retrospective	330 patients	DOACs were associated with recanalization rates similar to LMWH and greater than warfarin	DOAC vs. LMWH and VKA	Less major bleeding when comparing DOACs to VKA

There are currently 5 Food and Drug Administration (FDA)–approved DOACs (Table 3): dabigatran (Pradaxa, direct thrombin inhibitor), rivaroxaban (Xarelto, factor Xa inhibitor), apixaban (Eliquis, factor Xa inhibitor), edoxaban (Savaya, factor Xa inhibitor), and betrixaban (Bevyxxa, factor Xa inhibitor).⁷ DOACs work by directly inhibiting thrombin or Factor Xa without binding to antithrombin or inhibiting carboxylation to prevent the conversion of prothrombin to thrombin in the coagulation cascade.³ Unlike LMWH, DOACs can be administered orally, which may improve compliance over subcutaneous administration.^9,10 Unlike VKA, DOACs have standardized dosage recommendations and do not require routine monitoring in most patients.¹¹ Furthermore, cirrhosis causes hemostatic changes due to impaired liver synthetic functions of clotting factors, which makes its coagulation biomarkers, such as international normalized ratio, inaccurate.^2,4

TABLE 3.

Characteristics of DOACs

	Rivaroxaban	Apixaban	Edoxaban	Betrixabana	Dabigatran
Mechanism of action	Factor Xa inhibition	Factor Xa inhibition	Factor Xa inhibition	Factor Xa inhibition	Thrombin inhibition
Frequency	Once daily	Twice daily	Once daily	Once daily	Twice daily
Half-life (h)	5–9	12	10–14	19–27	12–17
CYP450 metabolism	Yes	Yes	No	No	No
CTP class	A: +	A: +	A: +	NR	A: +
	B: —	B: caution	B: —	NR	B: caution
	C: —	C: —	C: —	NR	C: —
Renal exertion	66	25	35	18	>80
Kidney impairment	Avoid in CrCl < 15 mL/min	Can use in ESRD	Avoid in CrCl < 15 mL/min	Can use in ESRD	Avoid in CrCl < 30 mL/min
Antidote	Yes (andexanet alfa)	Yes (andexanet alfa)	Yes (andexanet alfa)	No	Yes (idarucizumab)

^aDiscontinued in 4/2020 by the manufacturer for business reasons.

Abbreviations: CTP, Child-Turcotte-Pugh; NR, not reported; CrCl, creatinine clearance; ESRD, end-stage renal disease.

Based on data from Weinberg et al,⁷ Huisman and Klok,¹⁵ Qamar et al.¹⁶

Patients with and without cirrhosis, who develop recent PVT, should receive anticoagulation for treatment, provided that there are no contraindications (Figure 1).² The decision to start anticoagulation should always be individualized with a shared discussion of risks and benefits with every patient. Higher rates of PVT recanalization are seen when anticoagulants are started within 6 months of diagnosis.¹⁸ It is common practice to screen for varices and optimize beta-blocker therapy or perform endoscopic variceal ligation before starting anticoagulation in patients with cirrhosis and recent PVT.⁹ Anticoagulation improves the success of complete and partial portal vein recanalization, lowers the risk of thrombus extension, and decreases the risk of hepatic decompensation.^{3,7,9,10,18,19} In patients without cirrhosis, treatment is indicated to prevent mesenteric ischemia and the development of chronic PVT with portal hypertension.^2,3 In patients with cirrhosis, treatment is generally indicated in those with PVT that could lead to the progression of portal hypertension and for liver transplant candidates that have significant clot extension that may exclude them from transplant candidacy and worsen post-transplant outcomes.^2,5,10 Clot burden is associated with higher morbidity and mortality in potential liver transplant candidates, and anticoagulation for these patients is associated with improved post-transplant survival.^2,9 Meanwhile, the decision to treat chronic PVT in cirrhosis is on a case-by-case basis and considers important factors, including liver transplant candidacy and bleeding risk.^4,5,7 Although patients with cirrhosis are at increased risk for gastrointestinal bleeding, anticoagulation can help limit the progression of sequelae from portal hypertension through thrombus reduction in patients with cirrhosis with chronic portal vein thromboses.^7,19,20 However, if a patient with cirrhosis has a chronic complete occlusion from a portal vein thrombus or has cavernous transformation with established collaterals, there is no established benefit for anticoagulation, and instead, treatment should target the management of complications from portal hypertension.^4,5

FIGURE 1.

Approach to the management of PVT. ^aAnticoagulation should be initiated as long as the benefits of treatment outweigh concurrent risks. Duration: 3–6 months if provoked by known event; indefinite if thrombophilia or if active listed liver transplant candidate. ^bFor compensated cirrhosis only as studies excluded patients with more advanced cirrhosis, including MELD > 16 and CTP C. Abbreviations: EGD, esophagogastroduodenoscopy; NSBB, nonselective beta-blocker; EVL, endoscopic variceal ligation. Based on data from Simonetto et al¹⁷ and Galante and De Gottardi.²

Several retrospective studies have demonstrated that DOACs were associated with recanalization rates similar to LMWH and greater than VKA for noncirrhotic PVT.^5,11 A recent meta-analysis by Ng (2021) found that DOACs were superior to LMWH and VKA in achieving complete recanalization in cirrhotic PVT.¹⁰ Furthermore, multiple systematic reviews and meta-analyses comparing DOACs to traditional anticoagulants of LWMH and VKA in the treatment of PVT in patients with and without cirrhosis found similar adverse events for the failure of anticoagulation and similar bleeding events compared with LMWH and less bleeding events compared with VKA (Table 2).^{5,6,9–11,21}

There are important considerations when selecting DOACs (Table 4). DOACs are more expensive than LWMH and VKA, and have more expensive agents that reverse the anticoagulant (idarucizumab for dabigatran andexanet alfa for rivaroxaban and apixaban).² Studies of DOACs for the treatment of PVT in cirrhosis were generally limited to patients with compensated cirrhosis.^1,5,10 Patients with decompensated cirrhosis have greater coagulopathy resulting in differences in anticoagulant potency.^2,4,5,20 As a result, DOACs are generally avoided in Child-Turcotte-Pugh C patients.^17,22 DOACS are also dose-reduced for patients with renal insufficiency and creatinine clearance of 15–30 mL/min and are not indicated for patients with end-stage renal disease and on hemodialysis.⁹

TABLE 4.

Advantages and disadvantages of DOAC, VKA, or LMWH for anticoagulation

	DOAC	LMWH	VKA
Administration	Oral	s.c.	Oral
Costa	$ $ $	$ $	$
Frequency	Once or twice daily	Once or twice daily	Once daily
Monitoring	Not needed	Not needed	PT/INRb
Efficacy	May be more effective than warfarin for PVT resolution	May be more effective than warfarin for PVT resolution
Kidney impairment	See Table 3.	Avoid in renal failure and ESRD	No dose change
Hepatotoxicity	Rates vary (highest with rivaroxaban)	Rare	Rare
Wash out period (d)	~2	~2–3	~5–7
Bleeding events	+ +	+ +	+ + +
Antidote	Yesc	Yes	Yes
Advantage	More convenient for patient	More efficacious in malignancy	More clinical familiarity due to oldest

Note: Symbols ($, +) signify relative change.

^aPrices from GoodRX.

^bINR may not be accurate in some patients with cirrhosis due to coagulopathy.

^cAvailable in select centers.

Abbreviations: DOACs, direct oral anticoagulants; INR, international normalized ratio; LMWH, low-molecular-weight heparin; PT, prothombin time; VKA, vitamin K antagonist.

Based on data from Martens et al,¹⁸ Simonetto et al,¹⁷ and Weinberg 2019.⁷

DOACs are emerging as the preferred treatment for recent PVT in patients without cirrhosis and with compensated cirrhosis. As data for DOACs in patients with decompensated cirrhosis are limited, further studies in this population are necessary to compare the safety and efficacy of DOACs to LMWH and VKA for PVT.