Behandeling buikvenetrombose

Beoordeeld: 23-09-2025

Uitgangsvraag

Wat is de optimale antistollingsbehandeling voor patiënten met acute buikvenetrombose?

Aanbeveling

Behandel patiënten met een buikvenetrombose (inclusief patiënten met Budd-Chiari syndroom (BCS)) in de acute fase met therapeutisch gedoseerde laagmoleculairgewicht heparine (LMWH).

Overweeg patiënten met een buikvenetrombose na de acute fase te behandelen met een vitamine K antagonist (VKA). Behandeling met een directe orale anticoagulantia (DOAC, Factor Xa-remmer) is ook een optie.

Overweeg behandeling met een DOAC alleen als er geen sprake is van BCS, Child-Pugh C levercirrose, veneuze darmischemie of ernstige nierfunctiestoornissen.
Indien gekozen wordt voor behandeling met een DOAC: kies voor een Factor Xa-remmer bij patiënten met buikvenetrombose zonder levercirrose.

Overwegingen

Voor- en nadelen van de interventie en de kwaliteit van het bewijs

Op basis van de geïncludeerde studies zijn we onzeker over het effect van direct orale anticoagulantia (DOACs) op de cruciale uitkomstmaten majeure bloeding, progressie van buikvenetrombose, (partiële) resolutie van buikvenetrombose en mortaliteit, vergeleken met conventionele antistollingsmedicatie (vitamine K antagonisten (VKA) en laagmoleculairgewicht heparine (LMWH)) in patiënten met een acute buikvenetrombose. Dit geldt voor de totale groep patiënten, alsook voor de patiënten met levercirrose en patiënten zonder levercirrose. De bewijskracht van de gevonden resultaten is erg beperkt, met name vanwege het risico op bias en imprecisie. Ook zijn we onzeker over het effect van DOACs op de belangrijke uitkomstmaten recidief veneuze trombo-embolie (VTE, inclusief buikvenetrombose) en noodzaak voor chirurgische of radiologische ingreep. Geen van de geïncludeerde studies rapporteerde gegevens over de uitkomstmaten leverfalen en levertransplantatie. De overall bewijskracht voor deze module is dan ook zeer laag en er is duidelijk sprake van een kennislacune.

De literatuur is niet eenduidig over de toepassing van DOACs bij de diverse types buikvenetrombose. In de geïncludeerde studies zijn voornamelijk patiënten met portatrombose en in mindere mate met v. mesenterica, v. lienalis trombose en trombose van meerdere buikvenen tegelijkertijd. Patiënten met een Budd-Chiari syndroom (BCS) ontbraken in de geïncludeerde studies. Het is daarom ook niet zeker of de gevonden effecten van DOACs op de cruciale uitkomstmaten van toepassing zijn op de diverse types buikvenetrombose, en in het bijzonder bij patiënten met BCS. Ook varieerde het gebruikte type DOAC tussen de studies, waarbij de meerderheid van de patiënten een Factor Xa-remmer (FXa-remmers) kreeg en een kleine minderheid dabigatran. Helaas zijn er ook geen RCT’s waarin behandeling met DOACs vergeleken worden met VKA/LMWH bij patiënten met een acute SVT. Resultaten uit een niet-vergelijkende cohortstudie waarin patiënten met non-cirrotische acute buikvenetrombose werden behandeld met een DOAC (rivaroxaban), suggereren dat behandeling met rivaroxaban een alternatief zou kunnen zijn voor de standaard antistollingsbehandeling (Ageno, 2022).

De standaardbehandeling van patiënten met een acute buikvenetrombose die een indicatie hebben voor behandeling met antistolling, is therapeutisch LMWH en voor de langere termijn meestal gevolgd door VKA met een streef International Normalized Ratio (INR) tussen 2,0 en 3,0. Hierbij wordt veelal gekozen voor LMWH en niet voor ongefractioneerde heparine (UFH), tenzij er sprake is van een contra-indicatie voor LMWH. Het doel van deze module was te onderzoeken of behandeling met DOACs een plaats heeft bij deze patiënten. Ondanks het feit dat we onzeker zijn over het effect van DOACs op de cruciale uitkomstmaten, suggereren de gevonden resultaten dat DOACs, waarbij met name de FXa-remmers zijn onderzocht en in mindere mate dabigatran, in ieder geval niet meer bloedingen of meer recidief trombose gaven, maar minstens vergelijkbare bloedingsrisico’s en effectiviteit hadden als LMWH of VKA. Daarnaast is het in de klinische praktijk vaak lastig of niet goed mogelijk om bij het stellen van de diagnose buikvenetrombose te weten hoe lang deze al aanwezig is, en daarmee of het om een acute of een chronische buikvenetrombose gaat. Ook is onbekend welke invloed dergelijke kennis heeft op de kansen op een bloeding of trombose en daarmee ook op de veiligheid en de effectiviteit van de behandeling.

Een buikvenetrombose kent meerdere mogelijke oorzaken of omstandigheden waarin deze kan ontstaan. Een bekende setting is bij een infectieuze of inflammatoire ziekte in de buikholte, zoals pancreatitis of inflammatoire darmziekten (IBD). In de studie van Naymagon (2021-B) zijn patiënten met IBD geïncludeerd. Het aantal events voor de uitkomstmaten majeure bloeding en mortaliteit was te laag om uitspraken te kunnen doen over het effect van DOACs vergeleken met conventionele antistolling. Een andere risicogroep zijn patiënten met een maligniteit, in het bijzonder patiënten met een hepatocellulair carcinoom. Zij waren wisselend vertegenwoordigd in de studies en de resultaten en aantallen zijn te beperkt om hier conclusies uit te trekken. Tenslotte is er ook een verschil in patiënten met en zonder levercirrose. Het is mogelijk dat DOACs bij patiënten met gevorderde levercirrose een ander risicoprofiel hebben. In het BAVENO-consensus document wordt aangegeven dat het daarom niet mogelijk is een aanbeveling te doen over de inzet van DOACs bij deze groep patiënten (de Franchis, 2022). In de recente ISTH-richtlijn over antistolling bij een vena porta trombose en levercirrose is de aanbeveling voor patiënten met Child-Pugh A of B levercirrose om te behandelen met een DOAC of LMWH, eventueel gevolgd door VKA. Bij patiënten met Child-Pugh C levercirrose heeft LMWH, eventueel gevolgd door VKA, de voorkeur (Carlin, 2024). Het behandelen van patiënten met een verminderde leverfunctie en een daarbij verlengde INR, kan de behandeling met VKA bemoeilijken. Dit geldt ook voor de interpretatie van de zogenaamde MELD-score, die gebruikt wordt voor de urgentiebepaling bij patiënten op de levertransplantatie-wachtlijst. LMWH blijft dan de antistolling van voorkeur, al kent dit middel voor chronisch gebruik ook beperkingen.

Er is onvoldoende bewijs om het gebruik van DOACs bij patiënten met BSC te adviseren. Er is wel ervaring vanuit de klinische praktijk om dit in individuele gevallen voor te schrijven door voorschrijvers die ervaren zijn met de behandeling van patiënten met BSC.

In het BAVENO-consensus document worden verschillende uitspraken gedaan over het gebruik van DOACs bij patiënten met een buikvenetrombose (de Franchis, 2022). Zo geven zij aan dat er bij patiënten met een verhoogd risico op bloedingen, zoals in het geval van trombocytopenie bij splenomegalie, een individuele afweging gemaakt moet worden. Een ander bloedingsrisico is het hebben van slokdarmvarices, zoals kan ontstaan door portale hypertensie ten gevolge van buikvenetrombose. Derhalve wordt in het BAVENO-consensus document aangegeven dat het raadzaam is om patiënten te screenen op slokdarmvarices en deze te behandelen, indien mogelijk voor de start van antistolling (de Franchis, 2022). De werkgroep is van mening dat het gebruik van antistolling bij patiënten met slokdarmvarices op individuele basis afgewogen moet worden. Als er een indicatie is voor antistollingsmedicatie, heeft de aanwezigheid van slokdarmvarices geen consequenties voor de keuze van het antistollingsmiddel.

De voordelen van parenterale - boven orale - behandeling van een buikvenetrombose zijn theoretisch, tenzij er sprake is van darmischemie. In dat geval is orale therapie niet mogelijk door het kritisch ziek zijn van de patiënt. Ook is de absorptie van orale medicatie in die setting redelijkerwijs verstoord. Het ontbreken van een streefwaarde maakt monitoring van het therapeutische effect van DOACs in deze setting onmogelijk. Het is onbekend wat het effect is van buikvenetrombose die niet gepaard gaat met fulminante darmischemie, maar wel met macro- of microscopisch oedeem van de darmwand, op de absorptie.

Kortom, realiserend dat gerandomiseerde studies ontbreken, de kwaliteit van het bewijs erg laag is en de geïncludeerde studies onvoldoende antwoord geven op de gestelde vragen, is het voorstelbaar dat er, na stabilisatie van het ziektebeeld, toch gekozen wordt voor het gebruik van een DOAC (FXa-remmer) als behandeling van een acute buikvenetrombose, tenzij er sprake is van BCS en cruciale comorbiditeit zoals Child-Pugh C levercirrose, darmischemie of ernstige nierfunctiestoornissen. Bij patiënten met matige levercirrose of Child-Pugh B, is voorzichtigheid geboden (de Franchis, 2022). Bij patiënten met Child-Pugh A kunnen DOACs worden voorgeschreven. De duur van de behandeling moet op individuele basis bepaald worden. Daarbij kunnen de volgende factoren meegewogen worden: locatie van de buikvenetrombose, aanwezigheid van slokdarmvarices of andere risicofactoren voor een bloeding, aanwezigheid van persisterende risicofactoren, andere relevante comorbiditeiten en de voorkeuren van de patiënt.

Waarden en voorkeuren van patiënten (en evt. hun verzorgers)

Naast een mogelijk verschillend risico op bloedingen of recidief trombose, waar de huidige studies onvoldoende uitsluitsel over geven, is voor patiënten het verschil in gebruiks(on)gemak tussen de verschillende anticoagulantia van belang. Waar DOACs een een- of tweemaal daagse inname vereisen, is bij een behandeling met VKA een eenmaal daagse dosering voldoende. Daarnaast is het meten van de INR nodig bij behandeling met VKA, meestal eens per twee tot zes weken, waar bij chronisch gebruik zelfmeten wordt gestimuleerd. In 2020 publiceerde het Zorginstituut Nederland het rapport ‘Evaluatie van de ervaringen en kosten van antistollingszorg (van Dijk, 2020). In dit rapport komt naar voren dat DOAC-gebruikers meer vrijheid ervaren door het overbodig worden van bezoeken aan de trombosedienst. Tegelijkertijd ervaren VKA-gebruikers die zelf meten en doseren ook een grote regie over hun leven.

Het grootste nadeel van DOACs (FXa-remmer) is het ontbreken of beperkte ervaring met een adequaat en direct antidotum wat het gebruik bij een hoog bloedingsrisico of in de setting van een levertransplantatie-wachtlijst onpraktischer maakt. Daarnaast is de klaring van de DOACs grotendeels afhankelijk van de nier- en leverfunctie, wat bij deze patiëntengroep relevant kan zijn.

Het grootste nadeel van de VKA-behandeling is de potentiële ontregeling van de INR door diverse factoren, zoals infecties, koorts, interacterende medicatie maar ook stress of veranderde voeding. Indien door een onderliggende leveraandoening de INR al spontaan verlengd is, kan deze de (stabiliteit van de) behandeling met VKA bemoeilijken. Ook kan het de zogenaamde MELD-score beïnvloeden, die gebruikt wordt voor patiënten op de levertransplantatie-wachtlijst.

Naast een behandeling met tabletten is behandeling met subcutane injecties (LMWH) mogelijk, die een- of tweemaal daags geprikt moeten worden. De meeste patiënten vinden injecties meer belastend dan tabletten en niet iedere patiënt kan zichzelf die injecties toedienen. Hierdoor zijn mantelzorgers of thuiszorg voor deze behandeling noodzakelijk.

Onderzoek naar voorkeuren van patiënten is schaars, maar in het algemeen wordt gevonden dat orale behandeling de voorkeur heeft boven injecties, mits deze even effectief en veilig is (Hutchinson, 2019). Het is van belang om bovenstaande afwegingen met de patiënt te bespreken, om zo samen tot een passende behandeling te komen.

Kosten (middelenbeslag)

In het rapport ‘Evaluatie van de ervaringen en kosten van antistollingszorg’ wordt ook aandacht gegeven aan de kosten. Hierbij was de conclusie dat de kosten voor antistollingszorg gestegen waren, met name door de hogere kosten van DOAC ten opzichte van VKA. LMWH is daarentegen bij de hoogste therapeutische dosering iets duurder dan een DOAC (Farmacotherapeutisch kompas). Tenslotte zijn de meeste DOACs inmiddels (2024) uit patent en zijn de kosten van deze medicatie daardoor ook lager geworden.

Aanvaardbaarheid, haalbaarheid en implementatie

Alle drie de vormen van antistolling, dus LMWH, VKA en DOAC zijn gebruikelijk en gekend in de zorg voor patiënten met trombose. De verwachting is daarom dat de aanbevelingen haalbaar zijn in de klinische praktijk.

Rationale van de aanbeveling: weging van argumenten voor en tegen de interventies

Er is geen literatuur van goede kwaliteit over de voorkeursbehandeling met antistolling bij patiënten met een acute buikvenetrombose. De behandeling met LWMH in de acute fase en vervolgens LMWH of VKA in de post-acute fase is de huidige standaard en kan nog steeds worden aanbevolen. In overleg met de patiënt kan een DOAC als alternatief worden voorgeschreven voor de post-acute fase, mits in afwezigheid van BCS en cruciale comorbiditeit zoals Child-Pugh C levercirrose, darmischemie of ernstige nierfunctiestoornissen.

Met de acute fase wordt het moment van diagnose bedoeld, waarin sommige patiënten klinisch worden behandeld. Het post-acute moment kenmerkt zich door belangrijk herstel van klachten en de ambulante setting waarbij orale intake geen probleem (meer) is. Daarnaast is het belangrijk bij de start van antistollingsbehandeling, of binnen enkele weken na start, de aanwezigheid van slokdarmvarices te beoordelen en indien aanwezig te behandelen. Dit met het risico op potentieel levensbedreigende bloedingen.

Gezien het ontbreken van voldoende bewijs over de veiligheid en effectiviteit van DOACs in vergelijking met de huidige behandeling met LMWH of VKA zijn de aanbevelingen zwak geformuleerd. Deze onzekerheid maakt dat de behandeling met LMWH of VKA ook in de post-acute fase de keuze van voorkeur blijft, waarbij het niet zeker is of een DOAC een verstandig(er) alternatief is.

Onderbouwing

Achtergrond

Patients with acute symptoms of splanchnic vein thrombosis (SVT, thrombosis of mesenteric vein, portal vein, splenic vein, and/or hepatic veins) are treated with anticoagulants. Treatment with anticoagulants seems beneficial for prevention of recurrent thrombosis, bleeding and development of portal hypertension (Candeloro, 2022; Valeriani, 2021 and Valeriani, 2021). Traditionally vitamin K antagonists (VKA) or low molecular weight heparins (LMWH) have been described for this type of venous thromboembolism (VTE). The large direct oral anticoagulants (DOAC) RCTs were performed in patients with deep vein thrombosis or pulmonary embolism and patients with SVT were not included. The question is whether DOACs can be recommended for the treatment of patients with SVT having an indication for anticoagulants. Since many patients with SVT may have comorbidities/ bleeding risk factors, including portal hypertension and oesophageal varices, that are of clinical relevance for the use of anticoagulation and particularly DOACs, the lack of (experience in) a widely available antidote, can have clinical implications and part of decision making. Here we reviewed the present literature on the use of DOACs in patients with SVT.

Conclusies / Summary of Findings

General remarks

In selection of the studies, it seemed difficult to select the studies that only included patients with an acute SVT. In part of the studies, it was not specified whether patients with acute and/or chronic SVT were included (Nagaoki, 2018 and Zhang, 2023). The working group decided to include those studies in the literature analysis, as in clinical practice it is also often not known if a SVT is recent or of older age. Besides, in most of the studies patients with PVT were included and it is therefore not sure whether results are also applicable to patients with other SVT. It is important to take this into account in interpreting the results.

Major bleeding

Total group and patients with cirrhosis (all comparisons)

Very low GRADE

The evidence is very uncertain about the effect of DOACs on the outcome measure major bleeding when compared with LMWH/VKA in adult patients with SVT/in adult patients with SVT and cirrhosis.

Sources: Valeriani, 2021; Ilcewicz (2021); Naymagon (2021); Kawata (2021) and Zhang (2023)

Patients without cirrhosis (all comparisons)

GRADE

None of the included studies reported on the outcome measure major bleeding (according to ISTH criteria) for patients without cirrhosis. Therefore no conclusion can be drawn on the effect of DOAC on the outcome measure major bleeding in patients with SVT without cirrhosis, compared to LMWH/VKA.

Progression of SVT

Total group and patients with cirrhosis (all comparisons)

Very low GRADE

The evidence is very uncertain about the effect of DOACs on the outcome measure progression of SVT when compared with LMWH/VKA in adult patients with SVT/in adult patients with SVT and cirrhosis.

Source: Valeriani, 2021; Ilcewicz, 2021; Kawata, 2021 and Naymagon, 2021

Patients without cirrhosis (all comparisons)

GRADE

None of the included studies reported on the outcome measure progression of SVT for patients without cirrhosis. Therefore no conclusion can be drawn on the effect of DOAC on the outcome measure progression of SVT in patients with SVT without cirrhosis, compared to LMWH/VKA.

(Partial) Resolution of SVT

Total group and patients with cirrhosis and without cirrhosis (all comparisons)

Very low GRADE

The evidence is very uncertain about the effect of DOACs on the outcome measure (partial) resolution of SVT when compared with LMWH/VKA in adult patients with SVT.

Sources: Valeriani, 2021; Kawata, 2021; Naymagon, 2020; Naymagon, 2021, Naymagon, 2021_B and Zhang, 2023

Mortality

Total group and patients with cirrhosis (all comparisons)

Very low GRADE

The evidence is very uncertain about the effect of DOACs on the outcome measure mortality when compared with LMWH/VKA in adult patients with SVT/in adult patients with SVT and cirrhosis.

Source: Naymagon, 2021

Patients without cirrhosis (all comparisons)

GRADE

Data is too limited. Therefore no conclusion can be drawn on the effect of DOAC on the outcome measure mortality in patients with SVT without cirrhosis, compared to LMWH/VKA.

Source: Naymagon (2020)

Clinically relevant non major bleeding

Total group (DOAC vs VKA or LMWH)

Very low GRADE

The evidence is very uncertain about the effect of DOACs on the outcome measure CRNMB (according to ISTH criteria) when compared with LMWH/VKA in adult patients with SVT.

Source: Kawata,2021

Patients with cirrhosis and patients without cirrhosis (all comparisons)

GRADE

None of the included studies reported on the outcome measure CRNMB (according to ISTH criteria) for patients with cirrhosis and patients without cirrhosis. Therefore no conclusion can be drawn on the effect of DOAC on the outcome measure CRNMB in patients with SVT with cirrhosis and patients with SVT without cirrhosis, compared to LMWH/VKA.

Recurrent VTE

Total group (DOAC vs VKA)

Very low GRADE

The evidence is very uncertain about the effect of DOACs on the outcome measure recurrent VTE when compared with VKA in adult patients with SVT.

Source: Ilcewicz, 2021

Total group (DOAC vs LMWH)

GRADE

None of the included studies reported on the outcome measure recurrent VTE for patients without cirrhosis. Therefore no conclusion can be drawn on the effect of DOAC on the outcome measure recurrent VTE in patients with SVT nor on patients with SVT with cirrhosis, compared to LMWH.

Patients with cirrhosis and patients without cirrhosis (all comparisons)

GRADE

Data is too limited. Therefore no conclusion can be drawn on the effect of DOAC on the outcome measure mortality in patients with SVT without cirrhosis, compared to LMWH/VKA.

Sources: Naymagon, 2020 and Ilcewicz, 2021

Liver failure

GRADE

None of the included studies reported on the outcome measure liver failure. Therefore, no conclusion can be drawn on the effect of DOACs on the outcome measure liver failure in adults with acute SVT compared to LMWH/VKA.

Liver transplantation

GRADE

None of the included studies reported on the outcome measure liver transplantation. Therefore, no conclusion can be drawn on the effect of DOACs on the outcome measure liver transplantation in adults with SVT compared to LMWH/VKA.

Need for surgical or radiological intervention

GRADE

Data was too limited. Therefore, no conclusion can be drawn on the effect of DOACs on the outcome measure need for surgical or radiological intervention in adults with acute SVT compared to LMWH/VKA.

Sources: Naymagon, 2020 and Naymagon, 2021_B

Samenvatting literatuur

Description of studies

Valeriani (2021) performed a systematic review to evaluate the effect of anticoagulation treatments in adults with splanchnic vein thrombosis. Several databases were searched up to December 2019, including Medline and Embase. They included 97 studies (N=7969), of which four studies reported data on the effect of treatment with direct oral anticoagulants (DOAC) (Hanafy, 2019; Nagaoki, 2018; Wille, 2019 and Sharma, 2020). However, only the study of Nagaoki (2018) was included in our literature analysis, since the publication of Hanafy (2019) was retracted, Sharma (2020) included also patients in the DOAC-group, when they switched from treatment with VKA to treatment with DOAC and the number of patients using DOAC was too limited in Wille (2018). Quality of the observational studies was assessed using the ROBINS-I tool.

Naymagon (2020) performed a retrospective cohort study to evaluate the efficacy and safety of DOACs in patients with non-cirrhotic acute portal vein thrombosis (PVT), compared to treatment with VKA, LMWH or no anticoagulation. They included 330 patients in a large urban tertiary center in the USA. In total, 108 patients received warfarin, 70 patients received enoxaparin and 93 patients received DOACs. Results on the no anticoagulation group are not considered in our literature analysis. Results on the outcome bleeding events and mortality were reported for the different anticoagulation groups, which was the case for other outcome measures.

Ilcewicz (2021) performed a retrospective cohort study to evaluate the effectiveness and safety of DOACs in patients with new PVT, compared to treatment with warfarin. They included 33 patients admitted to a large academic medical center in the USA. In total, 20 patients received DOACs and 13 patients received warfarin. Patients with cirrhosis were also included (N=10). Important outcome measures were bleeding events and recurrence of thrombo-embolic events.

Kawata (2021) performed a retrospective cohort study to evaluate the management and outcomes of patients with SVT. They included 155 patients with a newly diagnosed episode of SVT at the Thrombosis Clinic in a tertiary care hospital in Canada, of which 47 received DOAC and 98 received LWMH or VKA. SVT should have been objectively documented by imaging. Patients with cirrhosis were also included. Progression of SVT, major bleeding and clinically relevant non major bleeding (CRNMB) were important outcome measures.

Naymagon (2021) performed a retrospective cohort study to share their experiences with the anticoagulation treatment of patients with PVT and liver cirrhosis. They included 214 patients with an acute PVT and cirrhosis which were seen in a tertiary care hospital in the USA and primarily focused on the comparison between patients treated with anticoagulation (DOAC (N=18), warfarin (N=26) and enoxaparin (N=42)), and patients not treated with anticoagulation. Patients not receiving any anticoagulant were not included in our analysis. They also reported outcomes by the different anticoagulants, namely major bleeding, mortality and extension of the PVT.

Naymagon (2021-B) performed a retrospective cohort study to compare anticoagulants in the treatment of patients with acute PVT and inflammatory bowel disease (IBD). They included 63 patients which were seen in a tertiary care hospital in the USA. Patients received DOAC (N=23), warfarin (N=22) or enoxaparin (N=13). Five patients did not receive any anticoagulation, but were not included in our analysis. They reported on amongst others mortality, major bleeding and need for an additional intervention.

Zhang (2023) performed a retrospective cohort study to evaluate the safety and efficacy of anticoagulants in the treatment of PVT in patients with cirrhosis. They included 77 patients who were admitted to the liver disease center of a tertiary hospital in China. Their study focused primarily on the comparison between anticoagulation (DOAC, N=18; warfarin, N=6, heparin, N=1 and nadroparin, N=2)) and no-anticoagulation (N=50). They only compared the safety of DOAC versus warfarin. Therefore only data on the outcome measure major bleeding is included in our analysis.

Table 1 lists more details on the included studies.

Author, year (design)

Participants

Characteristics of PVT

Liver cirrhosis and malignancy (%)

Intervention

Comparison

Follow-up

Nagaoki (2018), retrospective

N=50 (I: 20, C: 30)

Age:

I: 69 (53-74), C: 67 (24-83)

Sex (M):

I: 35, C: 57

PVT, not reported whether it was acute or chronic

Cirrhosis:

100

Malignancy:

HCC

I: 30; C: 63

Edoxaban*

mean duration: 6 months

VKA*

mean duration: 6 months

6 months

Naymagon (2020), retrospective

N=330, of which N=57 not using AC (I 93, C1 108, C2 70)

Age:

I: 47.1 (15.2); C1: 50.4 (14.8); C2: 51.4 (16.9)

Sex (M):

I: 50.5; C1: 52.8; C2: 38.6

PVT, acute

Cirrhosis:

Malignancy:

Non-HCC malignancy

I: 5.4; C1: 1.9; C2: 14.3

Apixaban, Dabigatran, Rivaroxaban

At least for 3 months

VKA (C1), LMWH (C2), Fondaparinux**, no AC**

At least for 3 months

I: 28.1 ± 11.3 months

C1: 55.8 ± 27.4 months

C2: 33.0 ± 18.9 months

Ilcewicz (2021), retrospective

N=33 (I:13, C: 20)

Age:

I: 60 ± 18; C: 51 ± 12

Sex (M)

I: 69; C: 75

New PVT

Cirrhosis:

Previous diagnosis of cirrhosis

I:38; C: 25

Malignancy:

Apixaban, rivaroxaban

mean duration: 3 months

VKA

mean duration: 3 months

90 days

Kawata (2021), retrospective

N=136 (I: 43, C: 93)

Age:

I: 59±15; C: 55±15

Sex (M):

I: 64; C: 59

New episode of SVT

Cirrhosis:

19.4

Malignancy:

Abdominal malignancy

Apixaban, edoxaban, rivaroxaban

mean duration: 483 (359 –606) days

VKA/LMWH/no AC**

mean duration: 483 (359 – 606) days

6 (3-10) months for thrombotic outcomes and 9 (4-15) months for bleeding outcomes

Naymagon (2021), retrospective

N=214, of which N=86 using AC

Age:****

60 (54–67)

Sex (M): ****

60.5

Acute PVT

Cirrhosis:

100

Malignancy:

Concurrent HCC:

15.1

Rivaroxaban, apixaban, dabigatran

median duration of AC: 18.8 (10.8–52.8) months

Warfarin/ enoxaparin/no AC**

median duration of AC: 18.8 (10.8–52.8) months

Median of 21 (11–44) months for patients using AC

Naymagon (2021_B)

retrospective

N=63,of which N=58 using AC

Age (median (IQR)):

I: 42 (29-53); C1: 43 (33-54); C2: 44 (32-53)

Sex (M):

I: 73.9; C1: 46.2; C2: 63.6

Acute PVT and IBD

Cirrhosis:

Malignancy:

Rivaroxaban, apixaban, dabigatran

median duration 3.9 (2.7-6.1) months

Warfarin (C1), enoxaparin (C2)/no AC**

median duration of warfarin 8.5 (3.9-NA) months, for enoxaparin not reported

I: 12 (6-35) months

C1: 43 (9-80) months

C2: 23 (10-58) months

Zhang (2023), retrospective

N=77 of which N=27 using AC

Age: 60.4 ± 12.3***

Sex (M): 67***

PVT, not reported whether it was acute or chronic

Cirrhosis:

100

Malignancy:

HCC

DOAC

Median duration of AC: 6 (2-11) months

Warfarin

Median duration of AC: 6 (2-11) months

Median of 28.5 months for patients using AC

*All patients were first treated with danaparoid sodium and Anthrobin P for 3 days at 1500 units/day i.v. in those patients whose antithrombin III activity decreased by less than 70%. ** Not included in our literature analysis. ***Age and sex are not reported by AC used but only for the total group patients receiving anticoagulants.

Results are reported as % (sex, cirrhosis and malignancy) or as mean ± SD/Median (IQR, age). DOAC: direct oral anticoagulants; HCC: hepatocellular carcinoma; IBD: inflammatory bowel disease; LMWH: low-molecular weight heparin; M: Male; NR: not reported; PVT: Portal vein thrombosis; VKA: vitamin K antagonist

Results

Since part of the studies compared data on treatment with DOAC versus VKA, and on DOAC versus LMWH, it was decided to present the data on those comparisons separately.

Major bleeding

Valeriani (2021), Ilcewicz (2021), Kawata (2021), Naymagon (2021) and Zhang (2023) reported on major bleeding, which was defined as a fatal and/or symptomatic bleeding in a critical area or organ, bleeding leading to a reduction of 2 g/dl or more in hemoglobin concentration or necessitating transfusion of two or more blood units (according to ISTH criteria). Valeriani (2021) included only data of Nagaoki (2018).

Besides, Naymagon (2020) and Naymagon (2021_B) reported on major bleeding, which was however defined as GRADE 3 or 4 according to WHO criteria. We decided not to include these data in the pooled data analysis, but report them separately.

Total group

DOAC vs VKA

Nagaoki (2018), Ilcewicz (2021), Naymagon (2021) and Zhang (2023) reported on major bleeding, for the comparison DOAC versus VKA. In total for 7/69 (10.1%) patients a major bleeding was reported in the DOAC group, compared to 8/82 (9.8%) patients in the VKA group (Figure 1). This corresponds to a risk ratio (RR, 95%CI) of 1.13 (0.44 to 2.86), which is in favor of the VKA group. Corresponding risk difference (RD, 95%CI) is 0.01 (-0.09 to 0.10), which is not considered to be clinically relevant.

Figure 1: Forest plot for the effect of DOACs on the outcome measure major bleeding (according to ISTH criteria) in patients with acute splanchnic vein thrombosis, compared to VKA.

Naymagon (2020) and Naymagon (2021_B) reported that in respectively 2/93 (2.2%) and 0/18 (0%) of the patients in the DOAC group major bleeding was reported, compared to 26/108 (24.1) and 3/22 (13.6%) patients in the VKA group. This corresponds to RRs (95%CI) of respectively 0.09 (0.02 to 0.37) and 0.17 (0.01 to 3.14) which are in favor of the DOAC groups. Corresponding RDs (95%CI) are -0.22 (-0.31 to -0.13) and -0.20 (-0.28 to -0.13), which is considered clinically relevant.

DOAC vs LMWH

Naymagon (2021) reported on major bleeding for the comparison DOAC versus LMWH. In the DOAC group, for 3/18 (16.7%) patients major bleeding was reported, compared to 9/42 (21.4%) patients in the LMWH group. This corresponds to a RR (95%CI) of 0.78 (0.24 to 2.54) which is in favor of the DOAC group. Corresponding RD (95%CI) is -0.05 (-0.26 to 0.16), which is considered clinically relevant.

Naymagon (2020) and Naymagon (2021_B) reported that in respectively 2/93 (2.2%) and 0/18 (0%) of the patients in the DOAC group major bleeding was reported, compared to 10/70 (14.3%) and 1/13 (7.7%) patients in the LMWH group. This corresponds to RRs (95%CI) of respectively 0.15 (0.03 to 0.67) and 0.25 (0.01 to 5.59) which are in favor of the DOAC group. Corresponding RDs (95%CI) are -0.26 (-0.37 to -0.15) and -0.08 (-0.25 to 0.10) which are considered clinically relevant.

DOAC vs LMWH/VKA

Kawata (2021) did not differentiate between patients receiving LMWH or VKA. They reported major bleeding in 3/47 (6.4%) patients in the DOAC group, compared to 6/98 (6.1%) patients in the LMWH/VKA group. This corresponds to a RR (95%CI) of 1.04 (0.27 to 3.99), which is in favor of the LMWH/VKA group. The corresponding RD (95%CI) is 0.00 (-0.08 to 0.09), which is not considered to be clinically relevant.

Patients with cirrhosis

DOAC vs VKA

Nagaoki (2018), Naymagon (2021) and Zhang (2023) reported on major bleeding in patients with cirrhosis for the comparison between DOAC versus VKA. In total, for 7/56 (12.5%) patients, major bleeding was reported in the DOAC group, compared to 7/62 (11.3%) patients in the VKA group (Figure 2). This corresponds to a RR (95%CI) of 1.22 (0.46 to 3.24) which is in favor of the VKA group. The corresponding RD (95%CI) is 0.05 (-0.07 to 0.17), which is considered clinically relevant.

Besides, Ilcewicz (2021) reported that for none of the 10 patients with a previous diagnosis of cirrhosis a bleeding event was reported.

Figure 2: Forest plot for the effect of DOACs on the outcome measure major bleeding (according to ISTH criteria) in patients with acute splanchnic vein thrombosis and cirrhosis, compared to VKA.

DOAC vs LMWH

Naymagon (2021) reported on the outcome measure major bleeding in patients with cirrhosis for the comparison between DOAC versus LMWH – see also the results for the total group: in the DOAC group, for 3/18 (16.7%) patients a major bleeding was reported, compared to 9/42 (21.4%) patients in the LMWH group. This corresponds to a RR (95%CI) of 0.78 (0.24 to 2.54) which is in favor of the DOAC group. Corresponding RD (95%CI) is -0.05 (-0.26 to 0.16), which is considered clinically relevant.

Patients without cirrhosis

Naymagon (2020) reported on major bleeding in patients without cirrhosis, which was defined as GRADE 3 or 4 according to the WHO criteria. Data are reported here, but not used to draw conclusions on the effect of DOAC on the outcome measure major bleeding in patients without cirrhosis, compared to either VKA or LMWH.

DOAC vs VKA

Naymagon (2020) reported on major bleeding in patients without cirrhosis for the comparison DOAC versus VKA. For 2/93 (2.2%) of the patients in the DOAC group major bleeding was reported, compared to 26/108 (24.1%) patients in the VKA group. This corresponds to a RR (95%CI) of 0.09 (0.02 to 0.37), which is in favor of the DOAC group. Corresponding RD (95%CI) is -0.22 (-0.31 to -0.13), which is considered clinically relevant.

DOAC vs LMWH

Naymagon (2020) reported on major bleeding in patients without cirrhosis for the comparison DOAC versus LMWH. For 2/93 (2.2%) in the DOAC group major bleeding was reported, compared to 10/70 (14.3%) patients in the LMWH group. This corresponds to a RR (95%CI) of 0.15 (0.03 to 0.67) which is in favor of the DOAC group. Corresponding RD (95%CI) is -0.12 (-0.21 to -0.03), which is considered clinically relevant.

Progression of SVT

Valeriani (2021), Ilcewicz (2021), Kawata (2021) and Naymagon (2021) reported on progression of SVT which was respectively defined as progression of SVT at follow-up imaging (Valeriani, 2021), extension into previously uninvolved vessels or increase in the length/volume of the clot in the same vessel on imaging at 3, 6, and between 6 and 24 months, with a minimum observation period of 6 months (Kawata, 2021), PVT extension (Naymagon, 2021) or not defined (Ilcewicz, 2021). Valeriani (2021) included data of Nagaoki (2018).

Total group

DOAC vs VKA

Nagaoki (2018), Ilcewicz (2021) and Naymagon (2021) reported on progression SVT for the comparison DOAC vs VKA. In total, for 2/51 (3.9%) of the patients in the DOAC group was progression of SVT reported, compared to 19/76 (25%) patients in the VKA-group (Figure 4). This corresponds to a RR (95%CI) of 0.22 (0.06 to 0.82), which is in favor of the DOAC group. Corresponding RD (95%CI) is -0.18 (-0.41 to 0.05), which is considered clinically relevant.

Figure 3: Forest plot for the effect of DOACs on the outcome measure progression of SVT in patients with acute splanchnic vein thrombosis, compared to VKA.

DOAC vs LMWH

Naymagon (2021) reported on progression of SVT for the comparison DOAC vs LMWH. For one of the patients in the DOAC group (N=18) progression of SVT was reported, compared to 8/42 (19.0%) patients in the LMWH group. The corresponding RR (95%CI) is 0.29 (0.04 to 2.16), which is in favor of the DOAC group. The corresponding RD (95%CI) is -0.13 (-0.29 to 0.02), which is considered clinically relevant.

DOAC vs LMWH/VKA

Kawata (2021) did not differentiate between patients receiving LMWH or VKA. In total for 3/43 (7.0%) patients, progression of SVT was reported in the DOAC group, compared to 5/93 (5.4%) patients in the LMWH/VKA group. This corresponds to a RR (95%CI) of 1.16 (0.29 to 4.62), which is in favor of the LMWH/VKA group. The corresponding RD (95%CI) is 0.01 (-0.08 to 0.10), which is not considered clinically relevant.

Patients with cirrhosis

DOAC vs VKA

Nagaoki (2018), Ilcewicz (2021) and Naymagon (2021) reported on progression of SVT for the comparison DOAC versus VKA in patients with cirrhosis. As is depicted in Figure 3, RDs (95%CI) based on data of Nagaoki (2018) and Naymagon (2021) are respectively -0.42 (-0.62 to -0.21) and -0.10 (-0.27 to 0.08), which are in favor of the DOAC group and are not considered clinically relevant. Finally, Ilcewicz (2021) reported that in none of the 10 patients with previous diagnosis of cirrhosis progression of SVT was found.

DOAC vs LMWH

Naymagon (2021) reported on progression of SVT for the comparison DOAC vs LMWH in patients with cirrhosis – see also results for the total group: for one of the patients in the DOAC group (N=18) progression of SVT was reported, compared to 8/42 (19.0%) patients in the LMWH group. The corresponding RR (95%CI) is 0.29 (0.04 to 2.16), which is in favor of the DOAC group. The corresponding RD (95%CI) is -0.13 (-0.29 to 0.02), which is considered clinically relevant.

Patients without cirrhosis

None of the included studies reported on progression of SVT for patients without cirrhosis.

(partial) Resolution of SVT

Valeriani (2021), Kawata (2021), Naymagon (2020), Naymagon (2021-B), Naymagon (2021) and Zhang (2023) reported on (partial) resolution of SVT which was respectively defined as:

any grade of recanalization (partial or complete) at follow-up imaging (Valeriani, 2021);
either complete resolution (no evidence of thrombus in subsequent imaging) or partial resolution (objective reduction in the number of vessels involved or the length of the clot), on imaging at three, six, and between six and 24 months, with a minimum observation period of six months (Kawata, 2021);
complete radiographic resolution of PVT established on follow-up imaging (Naymagon, 2020; Naymagon, 2021 and Naymagon, 2021_B);
partial (> 50% reduction of the thrombus) or complete (complete disappearance of the thrombus) PVT recanalization (Zhang, 2023).

Valeriani (2021) included data of Nagaoki (2018).

Total group

DOAC vs VKA

Nagaoki (2021), Naymagon (2020), Naymagon (2021), Naymagon (2021_B) and Zhang (2023) reported on (partial) resolution of SVT for the comparison DOAC vs VKA. In total, for 111/154 (72.1%) of the patients in the DOAC-group was complete resolution of SVT reported, compared to 69/186 (37.7%) patients in the VKA-group (Figure 4). This corresponds to a RR (95%CI) of 5.18 (1.49 to 18.09), which is in favor of the DOAC-group. Corresponding RD (95%CI) is 0.35 (0.15 to 0.56), which is considered clinically relevant.

Zhang (2023) reported on partial or complete SVT recanalization. However, number of events was not reported. Therefore, these data could not be included in the pooled analysis. Hazard ratio (95%CI) was 4.05 (0.5 to 37.7), which is in favor of the DOAC-group and is considered clinically relevant.

Figure 4: Forest plot for the effect of DOACs on the outcome measure (partial) resolution of SVT in patients with acute splanchnic vein thrombosis, compared to VKA.

DOAC vs LMWH

Naymagon (2020), Naymagon (2021), Naymagon (2021_B) reported on (partial) resolution of SVT for the comparison DOAC vs LMWH. In total, for 93/134 (69.4%) of the patients in the DOAC group was complete resolution of SVT reported, compared to 66/125 (52.8%) patients in the VKA-group (Figure 5). This corresponds to a RR (95%CI) of 1.21 (1.01 to 1.46), which is in favor of the DOAC-group. Corresponding RD (95%CI) is 0.12 (0.01 to 0.24), which is considered clinically relevant.

Figure 5: Forest plot for the effect of DOACs on the outcome measure (partial) resolution of SVT in patients with acute splanchnic vein thrombosis, compared to LMWH.

DOAC vs LMWH/VKA

Kawata (2021) did not differentiate between patients receiving LMWH or VKA. In total, for 25/43 (58.1%) patients (partial) resolution of SVT was reported in the DOAC-group, compared to 54/83 (65.1%) patients in the LMWH/VKA-group. This corresponds to a RR (95%CI) of 0.89 (0.66 to 1.20), which is in favor of the LMWH/VKA-group. The corresponding RD (95%CI) is -0.07 (-0.25 to 0.11), which is considered clinically relevant.

Patients with cirrhosis

DOAC vs VKA

Nagaoki (2021), Naymagon (2021) and Zhang (2023) reported on (partial) resolution of SVT for the comparison DOAC vs VKA. Zhang (2023) did not report the number of events, so results could not be pooled and are reported in Table 2. Results are inconsistent, since Nagaoki (2021) and Zhang (2023) reported results in favor of the DOAC-group while Naymagon (2021) reported a non-clinically relevant difference in favor of the VKA-group.

Table 2: Results on the effect of DOACs on the outcome measure (partial) resolution of SVT in patients with acute splanchnic vein thrombosis and cirrhosis, compared to VKA.

Study	DOAC-group (n/N (%))	VKA-group (n/N (%))	Effect estimate (95%CI)
Nagaoki (2021)	18/20 (90)	9/30 (30)	RD: 0.60 (0.39 to 0.81) RR: 3.00 (1.70 to 5.28)
Naymagon (2021)	10/18 (55.6)	15/26 (57.7)	RD: -0.02 (-0.32 to 0.28) RR: 0.96 (0.57 to 1.63)
Zhang (2023)	NR	NR	HR: 4.045 (0.52 to 37.67)

RD: Risk difference, RR: risk ratio, HR: Hazard ratio, DOAC: direct oral anticoagulants, NR: not reported, VKA: vitamin K antagonists

DOAC vs LMWH

Naymagon (2021) reported on (partial) resolution of SVT for the comparison DOAC vs LMWH. For 10/18 (55.6%) patients (partial) resolution of SVT was reported in the DOAC-group, compared to 16/42 (0.4%) patients in the LMWH/VKA-group. This corresponds to a RR (95%CI) of 1.46 (0.83 to 2.57), which is in favor of the DOAC-group. The corresponding RD (95%CI) is 0.17 (-0.10 to 0.45), which is considered clinically relevant.

Patients without cirrhosis

DOAC vs VKA

Naymagon (2020) and Naymagon (2021_B) reported on (partial) resolution of SVT for the comparison DOAC vs VKA. Results are reported in Table 3. Differences are in favor of the DOAC-group and are considered clinically relevant.

Table 3: Results on the effect of DOACs on the outcome measure (partial) resolution of SVT in patients with acute splanchnic vein thrombosis without cirrhosis, compared to VKA.

Study

DOAC-group (n/N (%))

VKA-group (n/N (%))

Effect estimate (95%CI)

Naymagon (2020)

61/93 (65.6)

33/108 (30.6)

RD: 0.35 (0.22 to 0.48)

RR: 2.15 (1.56 to 2.96)

Naymagon (2021_B)

22/23 (95.7)

12/22 (54.5)

RD: 0.41 (0.19 to 0.64)

RR: 1.75 (1.19 to 2.59)

RD: Risk difference, RR: risk ratio, DOAC: direct oral anticoagulants, VKA: vitamin K antagonist

DOAC vs LMWH

Naymagon (2020) and Naymagon (2021_B) reported on (partial) resolution of SVT for the comparison DOAC vs LMWH. Results are reported in Table 4. Differences are in favor of the DOAC-group and are considered clinically relevant.

Table 4: Results on the effect of DOACs on the outcome measure (partial) resolution of SVT in patients with acute splanchnic vein thrombosis without cirrhosis, compared to LMWH.

Study

DOAC-group (n/N (%))

LMWH-group (n/N (%))

Effect estimate (95%CI)

Naymagon (2020)

61/93 (65.6)

40/70 (57.1)

RD: 0.08 (-0.07 to 0.24)

RR: 1.15 (0.89 to 1.47)

Naymagon (2021_B)

22/23 (95.7)

10/13 (76.9)

RD: 0.19 (-0.06 to 0.43)

RR: 1.24 (0.91 to 1.70)

RD: Risk difference, RR: risk ratio, DOAC: direct oral anticoagulants, LMWH: low molecular weight heparin

Mortality

Naymagon (2020), Naymagon (2021) and Naymagon (2021_B) reported on mortality, which was not further defined.

Total group

DOAC vs VKA

Naymagon (2021) reported on mortality for the comparison DOAC versus VKA. In the DOAC group, 3/18 (16.7%) of the patients died, compared to 4/26 (15.4%) in the warfarin group. This corresponds to a RR (95%CI) of 1.08 (0.28 to 4.27), which is in favor of the VKA group. The corresponding RD (95%CI) is 0.01 (-0.21 to 0.23) which is not considered clinically relevant.

DOAC vs LMWH

Naymagon (2021) reported on mortality for the comparison DOAC versus LMWH. In the DOAC group, 3/18 (16.7%) of the patients died, compared to 8/42 (19.1%) in respectively the warfarin and enoxaparin group. This corresponds to a RR (95%CI) of 0.88 (0.26 to 2.92), which is in favor of the DOAC group. The corresponding RD (95%CI) is -0.02 (-0.23 to 0.19) which is not considered clinically relevant.

Naymagon (2020) and Naymagon (2021_B) reported also on mortality, but data was very limited. Naymagon (2020) reported that 12/330 (3.6%) patients died, of which three were related to PVT (enoxaparin group: N=1/70, warfarin group: N=1/108, DOAC group: N=0/93). Naymagon (2021_B) reported that 2/58 patients died during follow-up, of which one was related to PVT (warfarin group: N=1/22, enoxaparin group: N=0/13 and DOAC group: N=0/23). Since data is too limited, it cannot be used to draw conclusions on the effect of DOAC on the outcome measure mortality in patients with SVT, compared to conventional anticoagulation.

Patients with cirrhosis

DOAC vs VKA

Naymagon (2021) reported on mortality for the comparison DOAC versus VKA in patients with cirrhosis – see also results on the total group: in the DOAC group, 3/18 (16.7%) of the patients died, compared to 4/26 (15.4%) in the warfarin group. This corresponds to a RR (95%CI) of 1.08 (0.28 to 4.27), which is in favor of the VKA group. The corresponding RD (95%CI) is 0.01 (-0.21 to 0.23) which is not considered clinically relevant.

DOAC vs LMWH

Naymagon (2021) reported on mortality for the comparison DOAC vs LMWH – see also results on the total group: in the DOAC group, 3/18 (16.7%) of the patients died, compared to 8/42 (19.1%) in respectively the warfarin and enoxaparin group. This corresponds to a RR (95%CI) of 0.88 (0.26 to 2.92), which is in favor of the DOAC group. The corresponding RD (95%CI) is -0.02 (-0.23 to 0.19) which is not considered clinically relevant.

Patients without cirrhosis

Naymagon (2020) reported on mortality in patients without cirrhosis – see also results on the total group: they reported that 12/330 (3.6%) patients died, of which three were related to PVT (enoxaparin group: N=1/70, warfarin group: N=1/108, DOAC group: N=0/93). Results are too limited to draw conclusions.

Clinically relevant non-major bleeding (CRNMB)

Kawata (2021) reported on CRNMB, which was defined according to the criteria of ISTH.

Total group – DOAC versus LMWH/VKA

Kawata (2021) reported on CRNMB for the comparison DOAC versus LMWH/VKA. In the DOAC group, for 1/47 (2%) patients a CRNMB was reported, compared to 4/98 (4%) patients in the LMWH/VKA group. This corresponds to an RR (95%CI) of 0.52 (0.06 to 4.54), which is in favor of the DOAC group. Corresponding RD (95%CI) is -0.02 (-0.08 to 0.04). This difference is not considered clinically relevant.

Patients with cirrhosis

None of the included studies reported on CRNMB for patients with SVT and cirrhosis.

Patients without cirrhosis

None of the included studies reported on CRNMB for patients with SVT, without cirrhosis.

Recurrent VTE

Ilcewicz (2021) reported on recurrent thrombo-embolic events, which was defined as VTE of typical locations, including peripheral deep vein thrombosis and pulmonary embolism, new or worsened index PVT, and other atypical VTE. We considered data on worsening of PVT in the systematic analysis for the outcome measure progression of SVT.

Total group

DOAC vs VKA

Ilcewicz (2021) reported on recurrent thrombo-embolic events. In the DOAC group for none of the 13 patients a recurrent thrombo-embolic was reported, compared to 3/20 (15%) patients in the warfarin group. For all of them a new SVT was reported.

All comparisons

Naymagon (2020) reported that recurrence of SVT was not associated with type of anticoagulants and occurred in 9 of all included 330 patients (2.7%, patients without receiving anticoagulants were also included in this group, and effect measure was not reported). Data was too limited and was therefore not used to draw conclusions on the effect of DOAC on the outcome measure recurrent VTE in patients with SVT, compared to conventional anticoagulation.

Patients with cirrhosis

Ilcewicz (2021) reported that in none of the 10 patients with cirrhosis a recurrent VTE was found. Therefore, data is too limited to draw conclusions.

Patients without cirrhosis

Naymagon (2020) reported on recurrence of SVT in patients without cirrhosis – see also results for the total group. In short, they reported that recurrence of SVT was not associated with type of anticoagulants and occurred in 9 of all included 330 patients (2.7%, patients without receiving anticoagulants were also included in this group, and effect measure was not reported).

Liver failure and liver transplantation

None of the included studies reported on liver failure and liver transplantation.

Need for surgical or radiological intervention

Total group

None of the included studies reported on need for surgical or radiological intervention by the different anticoagulation groups. However, Naymagon (2021-B) reported that three of the patients who developed symptomatic portal hypertension (SPH) received a transjugular intrahepatic portosystemic shunt (enoxaparin-group: N=2/13, warfarin group: N=1/22, DOAC group: N=0/23). Besides, Naymagon (2020) reported that 24/104 (23%) of the patients developing chronic SPH received a TIPS. They concluded that this was not significantly different between the groups (including also the non-anticoagulants group). Data was too limited and was therefore not used to draw conclusions on the effect of DOAC on the outcome measure need for surgical or radiological intervention in patients with SVT, compared to conventional anticoagulation.

Patients with cirrhosis

None of the included studies reported on need for surgical or radiological intervention for patients with cirrhosis.

Patients without cirrhosis

Naymagon (2020) reported on patients without cirrhosis who developed chronic SPH and received a TIPS – see also results for the total group. In short, they reported that 24/104 (23%) of the patients developing chronic SPH received a TIPS. They concluded that this was not significantly different between the groups (including also the non-anticoagulants group).

Level of evidence of the literature

General remarks

In part of the studies, it was not specified whether patients with acute and/or chronic SVT were included (Nagaoki, 2018 and Zhang, 2023).

Major bleeding

All comparisons

The evidence regarding the outcome measure major bleeding (according to ISTH criteria) came from observational studies and therefore the level of evidence started as low. The level of evidence was downgraded to very low. There was high risk of bias in the studies (e.g. events might have been missed due to retrospective design of the study, risk on indication bias, time frame differed between the groups and risk on (residual) confounding, downgraded 2 levels). Besides, the effect estimate (95%CI) crossed the thresholds for clinical relevance (serious imprecision, downgraded 2 levels).

Patients without cirrhosis

None of the included studies reported on major bleeding (according to ISTH criteria) for patients without cirrhosis.

Progression of SVT

Total group (DOAC vs LMWH)

The evidence regarding the outcome measure progression of SVT came from observational studies and therefore the level of evidence started as low. The level of evidence was downgraded to very low. There was high risk of bias in the studies (e.g. progression might have been missed since there was no routine imaging/imaging was not standardized, risk on indication bias, time frame differed between the groups and risk on (residual) confounding, downgraded 2 levels). Besides, the effect estimate (95%CI) crossed one of the thresholds for clinical relevance (serious imprecision, downgraded 1 level).

Total group (DOAC vs VKA), patients with cirrhosis (DOAC vs VKA and DOAC vs LMWH)

The evidence regarding the outcome measure progression of SVT came from observational studies and therefore the level of evidence started as low. The level of evidence was downgraded to very low. There was high risk of bias in the studies (e.g. progression might have been missed since it was not sure whether there was routine imaging, risk on indication bias, time frame differed between the groups and risk on (residual) confounding, downgraded 2 levels). Besides, the effect estimate (95%CI) crossed the thresholds for clinical relevance (serious imprecision, downgraded 2 levels).

Patients without cirrhosis

None of the included studies reported on progression of SVT for patients without cirrhosis.

(partial) resolution of SVT

Total group (DOAC vs VKA) and patients without cirrhosis (DOAC vs VKA)

The evidence regarding the outcome measure progression of SVT came from observational studies and therefore the level of evidence started as low. The level of evidence was downgraded to very low. There was high risk of bias in the studies (e.g. (partial) resolution of SVT might have been missed since it was not sure whether there was routine imaging, risk on indication bias, time frame differed between the groups and risk on (residual) confounding, downgraded 2 levels). Besides, number of included patients was low (imprecision, downgraded 1 level).

Total group (DOAC vs LMWH)

The evidence regarding the outcome measure (partial) resolution of SVT came from observational studies and therefore the level of evidence started as low. The level of evidence was downgraded to very low. There was high risk of bias in the studies (e.g. (partial) resolution might have been missed since there was no routine imaging/imaging was not standardized, risk on indication bias, time frame differed between the groups and risk on (residual) confounding, downgraded 2 levels). Besides, the effect estimate (95%CI) crossed one of the thresholds for clinical relevance (imprecision, downgraded 1 level).

Patients with cirrhosis (DOAC vs VKA)

The evidence regarding the outcome measure (partial) resolution of SVT came from observational studies and therefore the level of evidence started as low. The level of evidence was downgraded to very low. There was high risk of bias in the studies (e.g. (partial) resolution might have been missed since there was no routine imaging/imaging was not standardized, risk on indication bias, time frame differed between the groups and risk on (residual) confounding, downgraded 2 levels). Besides, results were inconsistent (inconsistency, downgraded 1 level) and the effect estimate (95%CI) crossed the thresholds for clinical relevance (imprecision, downgraded 1 level).

Patients with cirrhosis (DOAC vs LMWH) and patients without cirrhosis (DOAC vs LMWH)

The evidence regarding the outcome measure (partial) resolution of SVT came from observational studies and therefore the level of evidence started as low. The level of evidence was downgraded to very low. There was high risk of bias in the study (e.g. (partial) resolution might have been missed since there was no routine imaging/imaging was not standardized, risk on indication bias, time frame differed between the groups and risk on (residual) confounding, downgraded 2 levels). Besides, the effect estimate (95%CI) crossed the thresholds for clinical relevance (imprecision, downgraded 2 levels).

Mortality

Total group (DOAC vs VKA and DOAC vs LMWH) and patients with cirrhosis (DOAC vs VKA and DOAC vs LMWH)

The evidence regarding the outcome measure mortality came from observational studies and therefore the level of evidence started as low. The level of evidence was downgraded to very low. There was high risk of bias in the studies (e.g. risk on indication bias, time frame differed between the groups, patients with short follow-up were excluded and risk on (residual) confounding, downgraded 2 levels). Besides, the effect estimate (95%CI) crossed the thresholds for clinical relevance (serious imprecision, downgraded 2 levels).

Patients without cirrhosis

Data was too limited and could therefore not be used to draw conclusions on the effect of DOAC on the outcome measure recurrent mortality in patients with SVT without cirrhosis, compared to conventional anticoagulation.

Clinically relevant non major bleeding

Total group (DOAC vs VKA or LMWH)

The evidence regarding the outcome measure clinically relevant non major bleeding came from an observational study and therefore the level of evidence started as low. The level of evidence was downgraded to very low. There was high risk of bias in the studies (e.g. events might have been missed due to retrospective design of the study, risk on indication bias, time frame differed between the groups and risk on (residual) confounding, downgraded 2 levels). Besides, the effect estimate (95%CI) crossed the thresholds for clinical relevance (serious imprecision, downgraded 2 levels).

Total group (DOAC vs VKA and DOAC vs LMWH), patients with cirrhosis and patients without cirrhosis

None of the included studies reported on CRNMB for patients with or without cirrhosis, nor for the comparisons between DOAC and VKA or DOAC and LMWH for the total group.

Recurrent VTE

Total group (DOAC vs VKA)

The evidence regarding the outcome measure recurrent VTE came from an observational study and therefore the level of evidence started as low. The level of evidence was downgraded to very low. There was high risk of bias in the study (e.g. recurrent VTE’s might have been missed since there was no routine imaging, risk on indication bias, time frame differed between the groups and risk on (residual) confounding, downgraded 2 levels). Besides, the number of events (and patients) was very low (serious imprecision, downgraded 2 levels).

Total group (DOAC vs LMWH) and patients with cirrhosis

None of the included studies reported on recurrent VTE for patients with cirrhosis nor for the comparison between DOAC and LMWH.

Patients without cirrhosis

Data was too limited and could therefore not be used to draw conclusions on the effect of DOAC on the outcome measure recurrent VTE in patients with SVT without cirrhosis, compared to conventional anticoagulation.

Liver failure, liver transplantation and clinically relevant non major bleeding

None of the included studies reported on liver failure and liver transplantation. Therefore, no conclusion can be drawn on the effect of DOACs on the outcome measures liver failure and liver transplantation in adults with SVT.

Need for surgical or radiological intervention

Data was too limited and could therefore not be used to draw conclusions on the effect of DOAC on need for surgical or radiological intervention in patients with SVT, compared to conventional anticoagulation.

Zoeken en selecteren

A systematic review of the literature was performed to answer the following question: what are the (un)desirable effects of treatment with Direct Oral Anticoagulants (DOAC) in adult patients with acute SVT, compared to treatment with low-molecular weight heparin (LMWH), vitamin K antagonist (VKA) or heparin?

P (Patients):	adult patients with acute SVT (acute portal vein thrombosis, acute Budd Chiari syndrome, acute hepatic vein thrombosis, acute splenic vein thrombosis, acute SVT, acute mesenteric vein thrombosis)
I (Intervention):	DOAC
C (Comparison):	LMWH, VKA, heparin
O (Outcomes):	major bleeding, clinically relevant non major bleeding (CRNMB), mortality, recurrent VTE, progression of SVT, (partial) resolution of SVT, liver failure, liver transplantation, need for surgical or radiological intervention

Relevant outcome measures

The guideline development group considered major bleeding, progression of SVT, (partial) resolution of SVT and mortality as critical outcome measures for decision making; CRNMB, recurrent venous thromboembolic event (VTE), liver failure, liver transplantation and need for surgical or radiological intervention as important outcome measures for decision making.

The working group defined the outcome measures as follows:

Major bleeding: fatal bleeding, and/or symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome, and/or bleeding causing a fall in hemoglobin levels of 1.24 mmol/L (20 g/L or greater) or more, or leading to a transfusion of 2 U or more of whole blood or red cells, as defined by International Society of Thrombosis and Haemostasis;
Recurrent VTE: objectively confirmed VTE, including recurrent SVT;
Need for surgical or radiological intervention: Transjugular Intrahepatic Portosystemic Shunt (TIPS), thrombosuction, bowel resection.

A priori, the working group did not define the other outcome measures listed above but used the definitions used in the studies.

The working group defined a risk difference of 3%* as a minimal clinically (patient) important difference for major bleeding, progression of SVT, (partial) resolution of SVT, mortality, clinically relevant non major bleeding and recurrent VTE. For all other outcome measures, the default thresholds proposed by the international GRADE working group were used as a threshold for clinically relevant differences: a 25% difference in relative risk (RR) for dichotomous outcomes (RR< 0.8 or RR> 1.25), and 0.5 standard deviations (SD) for continuous outcomes.

Since presence of liver cirrhosis is an important underlying cause for SVT and factor in deciding on type of anticoagulants for the treatment of patients with SVT, subgroup analysis will be performed for patients with liver cirrhosis and patients without liver cirrhosis.

*Based on the differences applied in the guidelines on thromboprophylaxis in patients with COVID-19. This working group derived the minimal clinically (patient) important differences from the ACCP (2012).

Search and select (Methods)

Two literature searches were performed. At first, we searched for systematic reviews and RCT and after this we performed an additional search to supplement the selected review(s) with observational studies that were published after the search date of the selected review(s).

Search 1: Systematic reviews (SR) and RCTs

The databases Medline (via OVID) and Embase (via Embase.com) were searched with relevant search terms until July 5th, 2023. The detailed search strategy is depicted under the tab Methods. The systematic literature search resulted in 669 hits. Studies were selected based on the following criteria: (systematic reviews of) RCTs and observational studies which evaluated the effectiveness of DOAC in adult patients with acute SVT, compared to treatment with heparin, LMWH or VKA. 37 studies were initially selected based on title and abstract screening. After reading the full text, 36 studies were excluded (see the table with reasons for exclusion under the tab Methods), and only one study was included (Valeriani, 2021).

Search 2: Observational studies

The search strategy of the systematic review (Valeriani, 2021) was completed on December 19^th, 2019. Therefore, we performed an additional search on observational studies in the databases Medline (via OVID) and Embase (via Embase.com) with relevant search terms between 1st of January 2019 until the 30^th of October 2023. The detailed search strategy is depicted under the tab Methods. The systematic literature search resulted in 553 hits. Studies were selected based on following criteria: observational studies which compared the effectiveness of DOAC in adult patients with acute SVT. The following studies were excluded:

Switch over studies in which patients that switched from (long-term) conventional anticoagulants to DOACs are considered as patients in the DOAC group.
Studies that primarily included patients with chronic SVT.
Studies that primarily included patients with hepatocellular carcinoma and SVT, because characteristics/treatment options/prognosis of those patients differ significantly from other patients with acute SVT.

In selection of the studies, it seemed difficult to select the studies that only included patients with an acute SVT. In the study of Khan (2022) 43% of the patients had a chronic SVT. This study was excluded. However, in other studies it was not specified whether patients with acute and/or chronic SVT were included (Nagaoki, 2018 and Zhang, 2023). The working group decided to include those studies in the literature analysis, as in clinical practice it is also often not known if an SVT is acute or of older age. It is however important to take this into account in interpreting the results.

18 studies were initially selected based on title and abstract screening. After reading the full text, 12 studies were excluded (see the table with reasons for exclusion under the tab Methods), and six studies were included.

In total, 1 SR (search 1) and six observational studies (search 2) were included.

Results

Seven studies were included in the analysis of the literature. Important study characteristics and results are summarized in the evidence tables. The assessment of the risk of bias is summarized in the risk of bias tables.

Referenties

Ageno W, Beyer Westendorf J, Contino L, Bucherini E, Sartori MT, Senzolo M, Grandone E, Santoro R, Carrier M, Delluc A, De Stefano V, Pomero F, Donadini MP, Tosetto A, Becattini C, Martinelli I, Nardo B, Bertoletti L, Di Nisio M, Lazo-Langner A, Schenone A, Riva N. Rivaroxaban for the treatment of noncirrhotic splanchnic vein thrombosis: an interventional prospective cohort study. Blood Adv. 2022 Jun 28;6(12):3569-3578. doi: 10.1182/bloodadvances.2022007397. PMID: 35439303; PMCID: PMC9631568.
Candeloro M, Valeriani E, Monreal M, Ageno W, Riva N, Lopez-Reyes R, Peris ML, Beyer Westendorf J, Schulman S, Rosa V, López-Núñez JJ, Garcia-Pagan JC, Magaz M, Senzolo M, De Gottardi A, Di Nisio M. Anticoagulant therapy for splanchnic vein thrombosis: an individual patient data meta-analysis. Blood Adv. 2022 Aug 9;6(15):4516-4523. doi: 10.1182/bloodadvances.2022007961. PMID: 35613465; PMCID: PMC9636325.
Carlin S, Cuker A, Gatt A, Gendron N, Hernández-Gea V, Meijer K, Siegal DM, Stanworth S, Lisman T, Roberts LN. Anticoagulation for stroke prevention in atrial fibrillation and treatment of venous thromboembolism and portal vein thrombosis in cirrhosis: guidance from the SSC of the ISTH. J Thromb Haemost. 2024 Sep;22(9):2653-2669. doi: 10.1016/j.jtha.2024.05.023. Epub 2024 May 31. PMID: 38823454.
Van Dijk CE, Heim N and Witteveen J. Evaluatie van de ervaringen en kosten van antistollingszorg. Zorginstituut Nederland. 2020. https://www.zorginstituutnederland.nl/publicaties/rapport/2020/10/20/evaluatie-antistollingszorg
de Franchis R, Bosch J, Garcia-Tsao G, Reiberger T, Ripoll C; Baveno VII Faculty. Baveno VII - Renewing consensus in portal hypertension. J Hepatol. 2022 Apr;76(4):959-974. doi: 10.1016/j.jhep.2021.12.022. Epub 2021 Dec 30. Erratum in: J Hepatol. 2022 Apr 14;: PMID: 35120736; PMCID: PMC11090185.
Hutchinson A, Rees S, Young A, Maraveyas A, Date K, Johnson MJ. Oral anticoagulation is preferable to injected, but only if it is safe and effective: An interview study of patient and carer experience of oral and injected anticoagulant therapy for cancer-associated thrombosis in the select-d trial. Palliat Med. 2019 May;33(5):510-517. doi: 10.1177/0269216318815377. Epub 2018 Nov 29. PMID: 30488789; PMCID: PMC6506899.
Ilcewicz HN, Martello JL, Piechowski K. Evaluation of the efficacy and safety of direct oral anticoagulants in the treatment of portal vein thrombosis. Eur J Gastroenterol Hepatol. 2021 Jun 1;33(6):911-916. doi: 10.1097/MEG.0000000000001958. PMID: 33079786; PMCID: PMC8371984.
Kawata E, Siew DA, Payne JG, Louzada M, Kovacs MJ, Lazo-Langner A. Splanchnic vein thrombosis: Clinical manifestations, risk factors, management, and outcomes. Thromb Res. 2021 Jun;202:90-95. doi: 10.1016/j.thromres.2021.03.018. Epub 2021 Mar 21. PMID: 33798804.
Nagaoki Y, Aikata H, Daijyo K, Teraoka Y, Shinohara F, Nakamura Y, Hatooka M, Morio K, Nakahara T, Kawaoka T, Tsuge M, Hiramatsu A, Imamura M, Kawakami Y, Ochi H, Chayama K. Efficacy and safety of edoxaban for treatment of portal vein thrombosis following danaparoid sodium in patients with liver cirrhosis. Hepatol Res. 2018 Jan;48(1):51-58. doi: 10.1111/hepr.12895. Epub 2017 Apr 27. PMID: 28342265.
Naymagon L, Tremblay D, Zubizarreta N, Moshier E, Troy K, Schiano T, Mascarenhas J. The efficacy and safety of direct oral anticoagulants in noncirrhotic portal vein thrombosis. Blood Adv. 2020 Feb 25;4(4):655-666. doi: 10.1182/bloodadvances.2019001310. PMID: 32078681; PMCID: PMC7042983.
Naymagon L, Tremblay D, Zubizarreta N, Moshier E, Mascarenhas J, Schiano T. Safety, Efficacy, and Long-Term Outcomes of Anticoagulation in Cirrhotic Portal Vein Thrombosis. Dig Dis Sci. 2021 Oct;66(10):3619-3629. doi: 10.1007/s10620-020-06695-4. Epub 2020 Nov 5. PMID: 33151401.
Naymagon L_B, Tremblay D, Zubizarreta N, Moshier E, Naymagon S, Mascarenhas J, Schiano T. The Natural History, Treatments, and Outcomes of Portal Vein Thrombosis in Patients With Inflammatory Bowel Disease. Inflamm Bowel Dis. 2021 Jan 19;27(2):215-223. doi: 10.1093/ibd/izaa053. PMID: 32185400; PMCID: PMC8427727.
Valeriani E, Di Nisio M, Riva N, Cohen O, Garcia-Pagan JC, Magaz M, Porreca E, Ageno W. Anticoagulant therapy for splanchnic vein thrombosis: a systematic review and meta-analysis. Blood. 2021 Mar 4;137(9):1233-1240. doi: 10.1182/blood.2020006827. PMID: 32911539.
Valeriani E, Di Nisio M, Riva N, Cohen O, Porreca E, Senzolo M, De Gottardi A, Magaz M, Garcia-Pagan JC, Ageno W. Anticoagulant Treatment for Splanchnic Vein Thrombosis in Liver Cirrhosis: A Systematic Review and Meta-Analysis. Thromb Haemost. 2021 Jul;121(7):867-876. doi: 10.1055/s-0040-1722192. Epub 2021 Feb 1. PMID: 33525037.
Zhang Z, Zhao Y, Li D, Guo M, Li H, Liu R, Cui X. Safety, efficacy and prognosis of anticoagulant therapy for portal vein thrombosis in cirrhosis: a retrospective cohort study. Thromb J. 2023 Jan 30;21(1):13. doi: 10.1186/s12959-023-00454-x. PMID: 36717831; PMCID: PMC9885579.

Evidence tabellen

Evidence table for systematic review of RCTs and observational studies (intervention studies)

Research question: What are the (un)desirable effects of treatment with Direct Oral Anticoagulants (DOAC) in adult patients with acute abdominal vein thrombosis, compared to treatment with low-molecular weight heparine (LMWH), vitamin K antagonist (VKA) or heparin?

Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Valeriani, 2021

Study characteristics and results are extracted from the SR (unless stated otherwise)

SR and meta-analysis of RCTs/ cohort studies.

Literature search up to December, 2019

A: Hanafy (2018)*

B: Nagaoki (2018)

C: Sharma (2020)**

D: Wille (2019)***

*Retracted article and therefore not considered in this literature review.

**Part of the patients switched from VKA to DOACs and were considered in the DOAC-group. Study is excluded.

***Data on DOACs is to limited and therefore this study is not considered in this literature review.

Study design: Retrospective studies

Setting and Country:

B: University hospital, Japan

C: Tertiary centre, India

Source of funding and conflicts of interest:

B: No funding declared, no COI

C: None

Systematic review was not funded. However, publication costs of article were defrayed in part by page charge

payment.

Inclusion criteria SR:

diagnosis of SVT;

observational study or RCT including ≥10 patients; availability of radiological or clinical outcomes; and anticoagulant treatment with LMWH, unfractionated heparin, fondaparinux,

VKAs, DOACs

or no anticoagulant therapy.

Exclusion criteria SR: study design different from those specified in the inclusion criteria; inclusion of < 10 patients; and anticoagulant

therapy different from those specified in the inclusion criteria.

97 studies included of which 4 studies on DOACs.

Important patient characteristics at baseline:*

B: I: 20, C: 30)

C: I: 36, C:62

Age

B: I: 69 (53-74)

C: 67 (24-83)

C: I:29.5 (22–35)

C: 28 (23–37)

Sex (male):

B: I: 65%, C: 57%

C: I: 53%, C: 61%

Child-Pugh score (mean or %)

B: A/B/C

I: 15/5/0, C: 15/10/5

C: I: 7 (6-8), C: 6 (5.7-7)

MELD score

B: NR

C: I: 10.8 (8.6-13), C: 11.7 (9.2-13.8)

INR

B: NR

C: I: 1.3 (1.2-1.4), C: 1.4 (1.2-1.6)

Etiology (%)

HBV/HCV/NBNC:

I: 4/6/10, C: 7/16/7

*Extracted from individual studies.

Groups comparable at baseline?

Describe intervention:

B: Edoxaban (60 mg once daily for 6 months, dosage was halved in patients with eGFR 30-50 ml/min, patients <60 kg and patients with concurrent treatment with a strong P-glycoprotein inhibitor)

C: Dabigatran (duration of therapy: 14.1 ± 6.9 months)

Describe control:

B: Warfarin (dosage adjusted to achieve INR 1.5-2.0)

C: vitamin K antagonists (duration of therapy: 10.5 ± 6.7 months)

End-point of follow-up:

B: 6 months (regular clinical FU at 2 wks, 1 month, 3 months and 6 months)

C: NR (once a month for the

initial 3 months followed by once in 3 months)

For how many participants were no complete outcome data available?

B: NR

C: NR

Outcome major bleeding

Defined as major bleeding by study authors or interpreted as major by the review authors.

DOAC (n/N)

B: 3/20

C: 1/36

VKA (n/N)

B: 2/30

C: 3/62

Outcome mortality

Defined as overall mortality

DOAC (n/N)

B: NR

C: 1/36

VKA (n/N)

B: NR

C: 3/62

LMWH (n/N)

B: NA

C: NA

Outcome progressive SVT

Defined as progression of SVT at follow-up imaging.

DOAC (n/N)

B: 1/20

C: NR

VKA (n/N)

B: 14/30

C: NR

LMWH (n/N)

B: NR

C: NA

(recurrent) VTE

Defined as deep vein

thrombosis of the lower or upper extremities, pulmonary

embolism, or recurrent SVT

DOAC (n/N)

B: NR

C: 4/36

VKA (n/N)

B: NR

C: 4/62

LMWH (n/N)

B: NA

C: NA

Recanalization of SVT

Defined as any grade of recanalization (partial or complete) at follow-up imaging

DOAC

B: 18/20

VKA

B: 9/30

Risk of bias (high, some concerns or low):

Tool used by authors: ROBINS-I

B: high

C: high

Author’s conclusion

In summary, anticoagulant therapy for SVT is associated with vein recanalization and low probability of thrombosis progression.

The risks of recurrent VTE and major bleeding in patients receiving anticoagulation therapy and the proportion of events

in those left untreated strongly suggest the need for additional studies to optimize SVT management.

Remarks

Sharma (2020): Any patient who was switched over to dabigatran from VKAs

was considered in dabigatran arm.

Evidence table for intervention studies (randomized controlled trials and non-randomized observational studies [cohort studies, case-control studies, case series])

Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Naymagon, 2020

Type of study:

Retrospective study

Setting and country:

Urban tertiary care center, USA

Funding and conflicts of interest:

Non commercial funding and no COI.

Inclusion criteria:

Patients with ICD code for non-cirrhotic (acute) PVT seen between January 2000 and February 2019.

Exclusion criteria:

Splanchnic vein thrombosis

without portal vein involvement, had cirrhosis or tumor thrombus,

received interventional thrombolysis/thrombectomy, lacked baseline

imaging of PVT at diagnosis, lacked subsequent follow-up imaging at least 3 months after diagnosis, or seemed to have chronic rather than acute PVT (eg, had known prior history of PVT or

had evidence of cavernous transformation or other radiographic features to suggest chronic PVT at the time of initial diagnosis).

N total at baseline: 330 of which 57 did not receive anticoagulation

Intervention: 93

Control1: 108

Control 2: 70

Important prognostic factors²:

age (median (IQR)):

I: 47.1 (15.2)

C1: 50.4 (14.8)

C2: 51.4 (16.9)

Sex (M/F (%)):

I: 50.5/49.5

C1: 52.8/47.2

C2: 38.6/61.4

Etiology

IBD (%)

I: 6.5

C1: 5.6

C2: 4.3

IBD + surgery

I: 14

C1: 12

C2: 7.1

Intraabdominal infection (%)

I: 5.4

C1: 8.3

C2: 7.1

JAK2V617 mutation (%)

I: 7.5

C1: 13.9

C2: 7.1

Non-HCC malignancy (%)

I: 5.4

C1: 1.9

C2: 14.3

Pancreatitis (%)

I: 5.4

C1: 3.7

C2: 2.9

Pregnancy (%)

I: 2.2

C1: 0

C2: 2.9

Multiple (%)

I: 9.7

C1: 5.6

C2: 27.1

OCP use (%)

I: 6.5

C1: 1.9

C2: 5.7

Other (%)

I:1.1

C1: 2.8

C2: 2.9

PV occlusion (%)

Occlusive

I: 57

Cl1: 63

Cl2: 51.4

Nonocclusive

I: 43

Cl1: 37

Cl2: 48.6

Meld-score, Child-pugh score, INR:

Groups comparable at baseline?

DOAC

At least for 3 months

Control 1: Warfarin

Control 2: Enoxaparin

At least for 3 months

Length of follow-up (mean number of months):

Intervention: 28.1±11.3

Control1: 55.8±27.4

Control2: 33.0±18.9

Loss-to-follow-up:

Incomplete outcome data:

Major bleeding

Defined as grade 3 or 4 bleeding, WHO.

Intervention: 2/93

Control1: 26/108

Control2: 10/70

Effect measure (95%CI) I vs C1: 0.20 (0.05-0.86)

P=.0307;

Mortality*

Twelve patients (3.6%) died during follow-up. Three of these deaths were related to PVT (one on enoxaparin, one no AC and one warfarin).

*Study excluded

patients < 3 months follow-up, and thus patients who

may have died of acute complications of their initial PVT would not have been included.

Recurrence of SVT

Recurrence of SVT was rare in this cohort, occurring in only 9/330 (2.7%) of patients. (not associated with type of AC).

Need for intervention

23% who developed chronic portal hypertensive symptoms received a TIPS. Frequency did not differ significantly among groups.

Complete radiographic resolution (CRR)

Defined as complete radiographic

resolution of PVT established on follow-up imaging

I:61/93

C1: 33/108

C2: 40/70

P=NR

Authors conclusion

This study should help establish the role of DOACs in the treatment of ncPVT. Given that more than half of the patients in this cohort had concurrent thrombosis of at least 1 other splanchnic vessel, our conclusions can likely be generalized to all ncSVT. These findings

further the ongoing trend toward expanding the indications for DOACs across subtypes of venous thromboembolism, most

recently exemplified by evidence favoring their use in cancer associated thrombosis, cerebral venous thrombosis, and among

morbidly obese patients.Long-term outcomes among patients with ncPVT remain somewhat disappointing, and future studies should investigate the role of early thrombolysis and/or thrombectomy

(in addition to AC), particularly among those patient groups most recalcitrant to AC alone (those with JAK2V617F, those with no evident predisposing factor for PVT, and those with occlusive thrombus at diagnosis).

Remarks

Duration of follow-up differed significantly between the groups.
Mean year of diagnosis of patients in the DOAC group was 2017 compared to 2013 and 2015 in the control groups.
In many cases intravenous heparin was used as initial short-term (or bridging) AC, and in these instances, the first long-term AC transitioned to thereafter was considered.
4% had a change in anticoagulation during follow-up, though only 2 of these changes occurred in the first 3 months of therapy and only 8 in the first year (but ITT analysis).
All patients completed at least 3 months of AC. 44% discontinued AC during follow-up, with the most common reasons for discontinuation being resolution of PVT and bleeding.
Patients with follow-up <3 months were excluded.
Study primarily focused on the comparison between anticoagulation and non-anticoagulation.
No information on assessment of exposure, confounding factors (but radiology reports).
Imaging during follow-up (yearly) was not significantly different between the groups.

Ilcewicz (2021)

Type of study:

Retrospective cohort study

Setting and country:

Single academic center, USA

Funding and conflicts of interest:

Inclusion criteria:

Adults, admitted to academic medical center, from 2014 to 2018, initiated DOAC or warfarin for the treatment of a new PVT based on radiographic imaging.

Exclusion criteria:

Receiving full-dose anticoagulation for any indication other than PVT, active hepatocarcinoma, and pregnancy.

N total at baseline: 33

Intervention: 13

Control: 20

Important prognostic factors²:

Age (mean ± SD):

I: 60 ± 18

C: 51 ± 12

Sex (M/F (%))

I: 69/31

C: 75/25

Admitting diagnosis

Pancreatitis (%)

I: 15

C: 20

GI-bleed (%)

I: 8

C: 0

Abdominal pain (%)

I: 46

C: 70

Cholecystitis (%)

I: 23

C: 5

Cirrhosis (%)

I: 38

C: 25

INR:

I: 1.15 ± 0.6

C: 1.1 ± 0.2

Meld-score, PV occlusion and Child-pugh score:

Groups comparable at baseline?

DOAC for three months

Dosing

Rivaroxaban 20 mg daily, N=5 (38%)

Rivaroxaban 15 mg daily, N=1 (8%)

Apixaban 2.5 mg BID, N=3 (23%)

Apixaban 5 mg BID, N=4 (31%)

Warfarin for three months

Length of follow-up:

90 days

Loss-to-follow-up:

Incomplete outcome data:

Recurrent thrombo-embolic events

Defined as VTE of typical locations, including peripheral deep vein thrombosis (DVT) and pulmonary embolism, new or worsened index PVT, and other atypical VTE

I: 0

C: 4 (of which one worsening of index PVT, and 3 experienced new SVT)

Bleeding events

Severity was determined according to ISTH

I: 0

C: 1 (which fulfilled criteria of major bleeding)

Effect measure (95%CI): NR

P= NR

Of the 10 patients with previous diagnoses of cirrhosis, five patients received a DOAC, and the other five received warfarin. No patients with previous diagnoses of cirrhosis experienced a recurrent thrombo-embolic event or bleeding.

Authors conclusion

DOACs appear to be effective and safe in the treatment of PVT and prevention of worsening and recurrent VTE. Future studies with larger sample sizes are warranted to confirm DOACs’ efficacy and safety in the treatment of PVT, particularly in regard to optimal DOAC dosing regimens as well as in patients with Child-Pugh B and C cirrhosis.

Remarks

Groups differed significantly with regard to concomitant medications (e.g. antiplatelet, beta-blocker, PPI and NSAID), which were, but NSAIDS, more frequently used in DOAC group.
4 patients using DOACs were sub optimally dosed.
Routine re-imaging was no inclusion criterium.

Kawata (2021)

Type of study:

Retrospective study

Setting and country:

Single center, tertiary care, Canada

Funding and

conflicts of interest:

funding not reported, no COI

Inclusion criteria:

Adults with newly diagnosed episode of SVT evaluated at the Thrombosis Clinic between 2007 and 2018. SVT was defined as any objectively documented thrombosis by imaging such as ultrasound (US), computed tomography (CT) or magnetic resonance

imaging (MRI), including portal, superior/inferior mesenteric, hepatic,

and/or splenic veins, or Budd Chiari syndrome

Exclusion criteria:

N total at baseline: 155

Intervention: NR

Control: NR

Important prognostic factors²:

Sex (M/F):

I 64/36:

C: 59/41

Age (years±SD):

I: 59±15

C: 55±15

Any local risk factors (%)

I 74:

C: 83

Local risk factors (%)

NR for separate groups, only for total group.

Malignancy: 31

Cirrhosis: 19.4

Abdominal infection: 12.9

IBD: 3.9

Abdominal surgery: 20.6

Liver transplantation: 5.2

Splenectomy: 4.5

Abdominal trauma: 1.3

Pancreatitis: 11

Cholecystitis: 5.2

Appendicitis: 2

Groups comparable at baseline?

DOAC

LMWH or VKA

Length of follow-up (median (IQR)):

9 (4-16) months

Loss-to-follow-up:

Incomplete outcome data:

Total: N=22 for SVT status/progression

SVT progression (n/N (%))

Defined as extension into previously uninvolved vessels or increase in the length/volume of the clot in the same vessel.

I: 3/43 (7)

C: 5/83 (6)

Effect measure (95%CI):

P= NR

Major bleeding (n/N (%))

Defined according to criteria of ISTH.

I: 3/47 (6)

C: 6/98 (6)

Effect measure (95%CI):

P>0.9999

Clinically relevant non-major bleeding (n/N (%))

Defined according to criteria of ISTH.

I: 1/47 (2)

C: 4/98 (4)

Effect measure (95%CI):NR

P>0.9999

SVT status

Complete/partial resolution

Defined as no evidence of thrombus in subsequent imaging) or objective reduction in the number of vessels involved or the length of the clot.

I: 25/43 (58)

C: 54/83 (65)

P = 0.446

Authors conclusion

In conclusion, our study results suggest that in SVT patient anticoagulation

results in partial or complete thrombosis resolution in a

significant proportion of patients with an acceptable bleeding risk and

that outcomes are similar between patients with or without local risk

factors.

Remarks

Two patients received more than one DOAC.

Naymagon (2021)

Type of study:

Retrospective study

Setting and country:

Single center, tertiary care, USA

Funding and conflicts of interest:

Non-commercial funding, no COI

Inclusion criteria:

Patients with ICD code for PVT and cirrhosis, seen between 2000 and 2019.

Exclusion criteria:

Splanchnic vein thrombosis

without portal vein involvement, did not have cirrhosis, tumor thrombus, received interventional thrombolysis/

thrombectomy, lack of baseline imaging of PVT at diagnosis, lack of subsequent follow-up imaging at least 3 months following diagnosis, or seem to be chronic rather than acute PVT (e.g., had known prior history of PVT or had evidence of cavernous transformation or other radiographic features to suggest chronic PVT at the time of initial diagnosis), proceeded to orthotropic

liver transplantation within 3 months of PVT diagnosis, or without interval re-imaging prior to surgery.

N total at baseline: 86

Intervention: 18

Control 1: 26

Control 2: 42

Important prognostic factors²:

NR for separate groups, only for total group of 86 patients.

Sex (M/F (%)): 60.5/39.5

Age (median, IQR): 60 (54–67)

Concurrent HCC (%): 15.1%

MELD (median, IQR): 10 (7-13)

Child-Pugh (%): A: 24.4, B: 48.8, C: 26.7

INR (median, IQR): 1.3 (1.2-1.4)

Degree of PV occlusion (%):

Occlusive 29.9:

Non-occlusive: 70.1

Groups comparable at baseline?

DOAC

Dosing

Rivaroxaban 20 mg daily (following a

21 day loading period of 15 mg twice daily), Apixaban 5 mg

twice daily (following a 7 day loading period of 10 mg twice

daily), and Dabigatran 150 mg twice daily.

Control 1: Warfarin

Control 2: enoxaparin

Dosing

Warfarin titrated to INR of 2–3

Enoxaparin

1 mg/kg twice daily

Length of follow-up (median, IQR)

21 (11–44) – total group AC

Loss-to-follow-up:

Patients were followed from time of diagnosis until

the end of the study period, or until they were lost to follow up within the health system

Incomplete outcome data:

Major bleeding (n/N (%))

Defined according to criteria of ISTH.

I: 3/18 (16.7)

C: 5/26 (19.2)

C2: 9/42 (21.4)

Effect measure (95%CI):NR

P=NR

PVT extension (n/N (%))

Not defined

I: 1/18 (5.6)

C1: 4/26 (15.4)

C2: 8/42 (19.1)

Effect measure (95%CI):NR

P=NR

Mortality (n/N (%))

I: 3/18 (16.7)

C1: 4/26 (15.4)

C2: 8/42 (19.1)

Effect measure (95%CI): NR

P=NR

Complete radiographic resolution (CRR)

Defined as CRR established at follow-up imaging

I: 10/18 (56)

C1: 15/26 (58)

C2: 16/42 (38)

P=NR

Authors conclusion

AC appeared safe in this large cohort of patients with cirrhotic PVT and was associated with higher

rates of CRR and RCO, albeit without a significant improvement in OS. More data are needed to clarify whether AC may be associated with improvement in clinical outcomes such as decompensation of cirrhosis, eventual liver transplantation,

and mortality. Prospective clinical trials will be needed to effectively evaluate such outcomes.

Remarks

Study primarily focused on the comparison between anticoagulation and non-anticoagulation.
Patients were included in the treatment group if they started AC within 4 weeks of diagnosis. Discontinuation of AC was addressed via an intent-to-treat-style analysis, wherein patients were maintained in the AC group

Naymagon (2021_IBD)

Type of study:

Retrospective study

Setting and country:

Single center, tertiary care, USA

Funding and conflicts of interest:

No funding, no COI

Inclusion criteria:

Patients with an

ICD code for PVT seen between 2000 – 2019, concurrent history of IBD, medical records confirmed

a history of acute PVT, with or without concurrent thrombosis in additional splanchnic vessels.

Exclusion criteria:

Tumor thrombus, receipt of thrombolysis/

thrombectomy, absence of baseline imaging at PVT diagnosis, absence of subsequent follow-up imaging 3 or more months

after diagnosis, and evidence of chronic as opposed to acute PVT at diagnosis (eg, known clinical history of long-standing PVT, or

presence of portal cavernoma, portal collaterals, or other radiographic findings suggestive of chronic PVT at diagnosis).

N total at baseline: 58

Intervention: 23

Control1:22

Control2:13

Important prognostic factors²:

Age (median (IQR)):

I: 42 (29-53)

C1: 43 (33-54)

C2: 44 (32-53)

Sex (M/F (%)):

I: 73.9/26.1

C1: 46.2/53.8

C2: 63.6/36.4

Type of IBD (%)

I: 65.2

C1: 54.5

C2: 69.2

I: 34.8

C1: 45.5

C2: 30.8

Degree of PVT occlusion

Occlusive

I: 30.4

C1: 36.4

C2: 38.5

Nonocclusive

I: 69.6

C1: 63.6

C2: 61.5

Meld-score, Child-pugh score, INR:

Groups comparable at baseline?

DOAC

Control1: Warfarin

Control2: Enoxaparin

Length of follow-up:

I: 12 (6-35)

C1: 43 (9-80)

C2: 23 (10-58)

Loss-to-follow-up:

Incomplete outcome data:

Major bleeding

Defined as WHO grade 3 or 4

I: 0/18

C1: 3/22

C2: 1/13

Mortality

Two patients died during follow-up, with 1 death a direct complication of PVT (this person was treated with warfarin).

Need for intervention

One of the 3 patients (N=2 on enoxaparin and N=1 on warfarin), who developed SPH went on to receive a transjugular intrahepatic portosystemic shunt with subsequent improvement in portal hypertensive symptoms

Complete radiographic resolution (CRR)

Definition not reported

I: 22/23 (96)

C1: 12/22 (55)

C2: 10/13 (77)

P=NR

Authors conclusion

This study demonstrates that the use of AC may potentially

lead to excellent outcomes in IBD-associated PVT.

Administered DOACs were associated with particularly favorable outcomes among such patients in this retrospective study

and were in particular associated with favorable efficacy and safety profiles relative to warfarin. Rates of recurrent VTE were low, and such patients may likely discontinue AC following at

least 3 months of treatment, assuming that follow-up imaging shows resolution of PVT. The incidence of clinically meaningful

results in thrombophilia testing was low, and such testing need not be routinely sent among this patient population. Further studies, both prospective and retrospective, would be helpful to confirm these findings.

Remarks

Study primarily focused on the comparison between anticoagulation and non-anticoagulation.
The initial long-term AC used in each instance was recorded and formed the basis for comparison across patients.
In many patients intravenous heparin was used as initial shortterm (or bridging) AC, and in these instances the first long-term. AC transitioned to thereafter was considered.

Zhang (2023)

Type of study:

Retrospective study

Setting and country:

Single center, liver disease center, China

Funding and conflicts of interest:

No funding, no COI

Inclusion criteria:

age ≥ 18 years; (2)

liver cirrhosis was diagnosed according to the criteria

of the JSGE and (3) PVT was diagnosed by abdominal Doppler ultrasound, MRI and CT.

Exclusion criteria:

1)malignant related PVT; (2) isolate splenic or mesenteric

venous thrombosis; (3) those receiving non-anticoagulant

treatment such TIPS, antithrombotic, thrombolysis, or

thrombectomy during liver transplantation; (4) platelet

count < 10 × 109/L; (5) creatinine clearance ≤30 mL/min; (6) primary thrombophilia; (7) Budd-Chiari syndrome; (8) pregnancy or breast-feeding women; (9) severe cardiopulmonary

diseases; (10) cases without imaging followup information

N total at baseline: 77 of which 27 were using anticoagulants. Only 24 patients were included in the analysis (DOAC vs warfarin).

Intervention: 18

Control: 6

Important prognostic factors²:

NR for separate groups, only for total group of 27 patients

Age (mean±SD): 60.4 ± 12.3

Sex (M/F (%)): 67

Meld-score (mean±SD): 5.2 ± 4.0

Etiology (%)

HBV: 37

PBC: 11

Alcohol 26:

NASH: 7

Drug: 4

Other: 15

Malignancies (HCC): 7

PV-occlusion (%)

Occlusive: 4

Non-occlusive: 96

INR (mean±SD): 1.2 ± 0.1

Child-pugh score: NR

Groups comparable at baseline?

DOAC

Dosing

rivaroxaban

20 mg qd (n = 3), rivaroxaban 10 mg qd (n = 14), edoxaban

30 mg qd (n = 1).

Warfarin

Dosing

INR target level of 1.5–2.5

Length of follow-up (median):

28.5 months – total group anticoagulants

Loss-to-follow-up:

In case of

loss to follow-up, patients were followed until the last

record within our health system.

Incomplete outcome data:

Major bleeding

According to the criteria of the ISTH

I: 1/18

C: 0/6

Effect measure (95%CI): NR

P= 1.000

PVT recanalization

Defined as both complete and partial recanalization.

Complete recanalization referred to the complete

disappearance of the thrombus and partial recanalization to more than 50% reduction of the thrombus

I: NR

C: NR

HR (95%CI): 4.045 (0.52-37.67)

Authors conclusion

In conclusion, anticoagulant therapy could increase the rate of PVT recanalization without increasing the rate of bleeding in patients with liver cirrhosis and could reduce the rate of variceal bleeding. Compared with the non-anticoagulant group, anticoagulant therapy may be beneficial to the liver function of patients with cirrhotic PVT. There was no significant difference in the safety and efficacy of different anticoagulants

in the treatment of cirrhotic PVT. Further studies are

needed to optimize the use of anticoagulants in patients

with cirrhotic PVT.

Remarks

Median duration of anticoagulant therapy was 6 (IQR 2–11) months.
Study primarily focused on the comparison between anticoagulation and non-anticoagulation.
Patients were followed until death, liver transplantation, or the end of the study.
MRI or CT was performed every 6 months

Risk of bias table for interventions studies (cohort studies based on risk of bias tool by the CLARITY Group at McMaster University)

Author, year

Selection of participants

Was selection of exposed and non-exposed cohorts drawn from the same population?

Exposure

Can we be confident in the assessment of exposure?

Outcome of interest

Can we be confident that the outcome of interest was not present at start of study?

Confounding-assessment

Can we be confident in the assessment of confounding factors?

Confounding-analysis

Did the study match exposed and unexposed for all variables that are associated with the outcome of interest or did the statistical analysis adjust for these confounding variables?

Assessment of outcome

Can we be confident in the assessment of outcome?

Follow up

Was the follow up of cohorts adequate? In particular, was outcome data complete or imputed?

Co-interventions

Were co-interventions similar between groups?

Overall Risk of bias

Naymagon (2020)

Probably no

Reason:

Time frame was different between the groups and there might have been indication bias. Patients with short follow-up were excluded, thus patients who

may have died of acute complication of PVT were not included.

Probably yes

Reason:

No information (initial long-term AC used in each instance was recorded), but it is most likely that exposure is determined correctly.

Definitely yes

Reason: mortality was logically not present at the start of the study, for the outcome measure major bleeding it is also not likely.

Probably yes

Reason: radiological reports were used; for other confounders it is not sure how they were assessed.

Definitely no

Reason:

analysis was adjusted for confounding, but high risk on residual confounding

Probably no

Reason:

due to the retrospective nature of the study, it is possible that bleeding events were missed.

Probably no

Reason:

Follow-up period differed significantly between the groups. Loss to follow-up is not reported.

No information

High (all outcomes)

Ilcewicz (2021)

Probably no

Reason:

Time frame might be different between the groups, there might have been indication bias.

Probably yes

Reason:

No information, but it is most likely that exposure is determined correctly.

Definitely yes

Reason: recurrent thrombo-embolic event was logically not present at the start of the study, for the outcome measure major bleeding it is also not likely.

No information

Definitely no

Reason:

no adjustment for confounding

Probably no

Reason:

due to retrospective nature of the study, it is possible that bleeding events were missed. Besides, there was no routine imaging and therefore worsening or recurrence of PVT might have been underestimated.

Probably no

Reason: follow-up time might be short, especially for the outcome measure PVT recurrence. Loss to follow-up is not reported.

Probably no

Reason:

Groups differed significantly with regard to concomitant medications (e.g. antiplatelet, beta-blocker, PPI and NSAID), which were, but NSAIDS, more frequently used in DOAC group.

High (all outcomes)

Kawata (2021)

Probably no

Reason:

Time frame might be different between the groups, there might have been indication bias.

Probably yes

Reason:

No information, but it is most likely that exposure is determined correctly (i.e. initial anticoagulant therapy).

Definitely yes

Reason: progression of SVT was logically not present at the start of the study, for the outcome measure bleeding it is also not likely.

Probably yes

Reason: imaging reports were used; for other confounders it is not sure how they were assessed.

Definitely no

Reason:

no adjustment for confounding

Probably no

Reason:

Due to retrospective nature of the study, it is possible that bleeding events were missed.

No information

Reason: Follow-up period was not reported by anticoagulant group. Loss to follow-up is not reported. Imaging was performed at 3, 6, and between 6 and 24 months, with a minimum observation period of 6 months. Result at the last assessment was reported.

No information

High (all outcomes

Naymagon (2021)

Probably no

Reason:

Time frame might be different between the groups, there might have been indication bias. Patients with short follow-up (imaging < 3 months) were excluded, thus patients who

may have died of acute complication of PVT were not included.

Probably yes

Reason:

No information (initial long-term AC used in each instance was

recorded), but it is most likely that exposure is determined correctly.

Definitely yes

Reason:

PVT extension and mortality was logically not present at the start of the study, for the outcome measure major bleeding it is also not likely.

Probably yes

Reason: radiological reports were used; for other confounders it is not sure how they were assessed.

Definitely no

Reason:

no adjustment for confounding

Probably no

Reason:

due to retrospective nature of the study, it is possible that bleeding events were missed.

No information

Reason: Follow-up period was not reported by anticoagulatn group. Loss to follow-up is not reported. Follow-up intervals (imaging) were not standardized.

No information

High (all outcomes)

Naymagon (2021 -–B)

Probably no

Reason:

Time frame might be different between the groups, there might have been indication bias. Patients with short follow-up (imaging < 3 months) were excluded, thus patients who

may have died of acute complication of PVT were not included.

Probably yes

Reason:

No information (initial long-term AC used in each instance was

recorded), but it is most likely that exposure is determined correctly.

Definitely yes

Reason:

It is not likely that

the outcome measure major bleeding was present at the start of the study.

Probably yes

Reason: radiological reports were used; for other confounders it is not sure how they were assessed.

Definitely no

Reason:

no adjustment for confounding

Probably no

Reason:

due to retrospective nature of the study, it is possible that bleeding events were missed.

Probably no

Reason: length of follow-up differed between the groups. Loss to follow-up is not reported. Follow-up intervals (imaging) were not standardized.

No information

High (all outcomes)

Zhang (2023)

Probably no

Reason:

Time frame might be different between the groups, there might have been indication bias.

Probably yes

Reason: Information was collected from medical records, and it is most likely that exposure is determined correctly.

Definitely yes

Reason:

It is not likely that

the outcome measure major bleeding was present at the start of the study.

Probably yes

Reason: Information was collected from medical records, and confounders might be determined correctly

Definitely no

Reason:

No adjustment for confounding

Probably no

Reason:

Due to retrospective nature of the study, it is possible that bleeding events are missed.

No information

Reason: Follow-up period was not reported by anticoagulatn group. Loss to follow-up is not reported.

No information

High (all outcomes)

Table of excluded studies

Search I – Systematic reviews and RCTs

Reference	Reason for exclusion
Ding H, Zhang Y, Zhao L, Wu S, Liu J, Wang C, Pei T, Su Y. What intervention regimen is most effective prevention for Portal venous system thrombosis after splenectomy in cirrhotics patients with Portal hypertension? Systematic review and network meta-analysis. Pharmacol Res. 2020 Jul;157:104825. doi: 10.1016/j.phrs.2020.104825. Epub 2020 Apr 21. PMID: 32330553.	Wrong comparison
Yao W, Feng Y, Liu T, Li W, Zhang M, Yao Y, Wu S. Rivaroxaban versus low-molecular weight heparin plus warfarin prevents portal vein system thrombosis after splenectomy and pericardial devascularization: A randomized clinical trial. EXCLI J. 2021 Mar 4;20:537-549. doi: 10.17179/excli2020-3120. PMID: 33883982; PMCID: PMC8056059.	Wrong population, wrong outcome
Yao C, Zhao M, Ibrahim B, Saab S. Anticoagulation for the Treatment of Portal Vein Thrombosis in Cirrhosis: A Systematic Review and Meta-Analysis of Comparative Studies. J Clin Exp Hepatol. 2023 May-Jun;13(3):404-413. doi: 10.1016/j.jceh.2022.12.016. Epub 2023 Jan 3. PMID: 37250883; PMCID: PMC10213860.	Wrong comparison (anticoagulation vs no treatment)
Li Z, Xu W, Wang L, Chai L, Ageno W, Romeiro FG, Li H, Qi X. Risk of Bleeding in Liver Cirrhosis Receiving Direct Oral Anticoagulants: A Systematic Review and Meta-analysis. Thromb Haemost. 2023 Jun 19. doi: 10.1055/s-0043-1770100. Epub ahead of print. PMID: 37336474.	Wrong population
Guerrero A, Campo LD, Piscaglia F, Scheiner B, Han G, Violi F, Ferreira CN, Téllez L, Reiberger T, Basili S, Zamora J, Albillos A; Baveno Cooperation: an EASL consortium. Anticoagulation improves survival in patients with cirrhosis and portal vein thrombosis: The IMPORTAL competing-risk meta-analysis. J Hepatol. 2023 Jul;79(1):69-78. doi: 10.1016/j.jhep.2023.02.023. Epub 2023 Feb 28. PMID: 36858157.	Wrong comparison (anticoagulation vs no treatment)
Candeloro M, Valeriani E, Monreal M, Ageno W, Riva N, Schulman S, Bang SM, Mellado M, Díaz-Peromingo JA, Moisés J, Díaz-Brasero AM, Garcia-Pagan JC, Perez-Campuzano V, Senzolo M, De Gottardi A, Di Nisio M. Clinical course and treatment of incidentally detected splanchnic vein thrombosis: an individual patient data meta-analysis. J Thromb Haemost. 2023 Jun;21(6):1592-1600. doi: 10.1016/j.jtha.2023.03.002. Epub 2023 Mar 11. PMID: 36907381.	Wrong comparison
Zhang Z, Zhao Y, Han B, Zhu Z, Sun L, Cui X. The Efficacy and Safety of Anticoagulants in the Treatment of Cirrhotic Portal Vein Thrombosis: A Systematic Review and Meta-Analysis. Clin Appl Thromb Hemost. 2022 Jan-Dec;28:10760296221104797. doi: 10.1177/10760296221104797. PMID: 35656719; PMCID: PMC9168872.	Incomplete search strategy/search strategy is very specific
Koh JH, Liew ZH, Ng GK, Liu HT, Tam YC, De Gottardi A, Wong YJ. Efficacy and safety of direct oral anticoagulants versus vitamin K antagonist for portal vein thrombosis in cirrhosis: A systematic review and meta-analysis. Dig Liver Dis. 2022 Jan;54(1):56-62. doi: 10.1016/j.dld.2021.07.039. Epub 2021 Aug 13. PMID: 34393072.	Wrong population
Candeloro M, Valeriani E, Monreal M, Ageno W, Riva N, Lopez-Reyes R, Peris ML, Beyer Westendorf J, Schulman S, Rosa V, López-Núñez JJ, Garcia-Pagan JC, Magaz M, Senzolo M, De Gottardi A, Di Nisio M. Anticoagulant therapy for splanchnic vein thrombosis: an individual patient data meta-analysis. Blood Adv. 2022 Aug 9;6(15):4516-4523. doi: 10.1182/bloodadvances.2022007961. PMID: 35613465; PMCID: PMC9636325.	Missing information on included studies (subgroup analysis on DOAC)
Valeriani E, Di Nisio M, Riva N, Cohen O, Porreca E, Senzolo M, De Gottardi A, Magaz M, Garcia-Pagan JC, Ageno W. Anticoagulant Treatment for Splanchnic Vein Thrombosis in Liver Cirrhosis: A Systematic Review and Meta-Analysis. Thromb Haemost. 2021 Jul;121(7):867-876. doi: 10.1055/s-0040-1722192. Epub 2021 Feb 1. PMID: 33525037.	Included case series
Ng CH, Tan DJH, Nistala KRY, Syn N, Xiao J, Tan EXX, Woo FZ, Chew NWS, Huang DQ, Dan YY, Sanyal AJ, Muthiah MD. A network meta-analysis of direct oral anticoagulants for portal vein thrombosis in cirrhosis. Hepatol Int. 2021 Oct;15(5):1196-1206. doi: 10.1007/s12072-021-10247-x. Epub 2021 Aug 21. PMID: 34417718.	Included retracted RCT of Hanafy, no update possible
Ghazaleh S, Beran A, Aburayyan K, Nehme C, Patel D, Khader Y, Sharma S, Aziz M, Abdel-Aziz Y, Hammad T, Nawras A. Efficacy and safety of anticoagulation in non-malignant portal vein thrombosis in patients with liver cirrhosis: a systematic review and meta-analysis. Ann Gastroenterol. 2021;34(1):104-110. doi: 10.20524/aog.2020.0544. Epub 2020 Oct 2. PMID: 33414629; PMCID: PMC7774659.	Wrong comparison
Qi X, De Stefano V, Li H, Dai J, Guo X, Fan D. Anticoagulation for the treatment of portal vein thrombosis in liver cirrhosis: a systematic review and meta-analysis of observational studies. Eur J Intern Med. 2015 Jan;26(1):23-9. doi: 10.1016/j.ejim.2014.12.002. Epub 2015 Jan 5. PMID: 25566699.	Wrong comparison
Semmler G, Lindorfer A, Schäfer B, Bartl S, Hametner-Schreil S, Gensluckner S, Balcar L, Pomej K, Lampichler K, Trauner M, Aigner E, Datz C, Zoller H, Hofer H, Schöfl R, Mandorfer M, Reiberger T, Scheiner B. Outcome of Budd-Chiari Syndrome Patients Treated With Direct Oral Anticoagulants: An Austrian Multicenter Study. Clin Gastroenterol Hepatol. 2023 Apr;21(4):978-987.e2. doi: 10.1016/j.cgh.2022.04.024. Epub 2022 May 6. PMID: 35533994.	Retrospective study, insufficient information on the control group
Sharma S, Kumar R, Rout G, Gamanagatti SR, Shalimar. Dabigatran as an oral anticoagulant in patients with Budd-Chiari syndrome post-percutaneous endovascular intervention. J Gastroenterol Hepatol. 2020 Apr;35(4):654-662. doi: 10.1111/jgh.14843. Epub 2019 Nov 25. PMID: 31476024.	Included in Valeriani, 2021
Salim S, Ekberg O, Elf J, Zarrouk M, Gottsäter A, Acosta S. Evaluation of direct oral anticoagulants and vitamin K antagonists in mesenteric venous thrombosis. Phlebology. 2019 Apr;34(3):171-178. doi: 10.1177/0268355518779517. Epub 2018 May 31. PMID: 29848218.	Switch over study
Hanafy AS, Abd-Elsalam S, Dawoud MM. Randomized controlled trial of rivaroxaban versus warfarin in the management of acute non-neoplastic portal vein thrombosis. Vascul Pharmacol. 2019 Feb;113:86-91. doi: 10.1016/j.vph.2018.05.002. Epub 2018 Jun 7. Retraction in: Vascul Pharmacol. 2023 Jan 12;:107142. PMID: 29886103.	Retracted article
Janczak DT, Mimier MK, McBane RD, Kamath PS, Simmons BS, Bott-Kitslaar DM, Lenz CJ, Vargas ER, Hodge DO, Wysokinski WE. Rivaroxaban and Apixaban for Initial Treatment of Acute Venous Thromboembolism of Atypical Location. Mayo Clin Proc. 2018 Jan;93(1):40-47. doi: 10.1016/j.mayocp.2017.10.007. Epub 2017 Dec 6. PMID: 29217335.	Wrong population
Yin Y, Wang L, Gao F, Liu L, Qi X. Anticoagulation Therapy for Splanchnic Vein Thrombosis Associated With Acute Pancreatitis: A Systematic Review and Meta-Analysis. Clin Appl Thromb Hemost. 2023 Jan-Dec;29:10760296231188718. doi: 10.1177/10760296231188718. PMID: 37461391; PMCID: PMC10357047.	Wrong comparison
Sissingh NJ, Groen JV, Koole D, Klok FA, Boekestijn B, Bollen TL, van Santvoort HC, Verdonk RC, Bonsing BA, van Eijck CHJ, van Hooft JE, Mieog JSD; Dutch Pancreatitis Study Group. Therapeutic anticoagulation for splanchnic vein thrombosis in acute pancreatitis: A systematic review and meta-analysis. Pancreatology. 2022 Mar;22(2):235-243. doi: 10.1016/j.pan.2021.12.008. Epub 2021 Dec 22. PMID: 35012902.	Wrong comparison
Ghazaleh S, Chuang J, Sayeh W, Iqbal A, Beran A, Khader Y, Burmeister C, Aziz M, Assaly R, Nawras A. Comparative Efficacy of Anticoagulant Medications in Nonmalignant Portal Vein Thrombosis in Liver Cirrhosis-A Systematic Review and Network Meta-analysis. Am J Ther. 2022 Jul 8. doi: 10.1097/MJT.0000000000001538. Epub ahead of print. PMID: 36927678.	Wrong publication type
Anis FS, Adiamah A, Lobo DN, Sanyal S. Incidence and treatment of splanchnic vein thrombosis in patients with acute pancreatitis: A systematic review and meta-analysis. J Gastroenterol Hepatol. 2022 Mar;37(3):446-454. doi: 10.1111/jgh.15711. Epub 2021 Nov 3. PMID: 34657310.	Wrong comparison
Wang L, Guo X, Xu X, De Stefano V, Plessier A, Noronha Ferreira C, Qi X. Anticoagulation Favors Thrombus Recanalization and Survival in Patients With Liver Cirrhosis and Portal Vein Thrombosis: Results of a Meta-Analysis. Adv Ther. 2021 Jan;38(1):495-520. doi: 10.1007/s12325-020-01550-4. Epub 2020 Nov 5. PMID: 33155180; PMCID: PMC7854392.	Missing studies compared to other systematic reviews
Gupta S, Hidalgo J, Singh B, Iyer A, Yang Y, Short A, Singh S, Bhatt H, Gupta S. Usage of Direct Acting Oral Anticoagulants in Cirrhotic and Non-Cirrhotic Portal Vein Thrombosis: A Systematic Review. Cureus. 2021 Aug 5;13(8):e16922. doi: 10.7759/cureus.16922. PMID: 34367844; PMCID: PMC8342267.	No meta-analysis
Coons EM, Staubes BA, Casey AL, Elagizi-Youssef SA, Mohammed AE, Sharma N, Kline ER. Direct Oral Anticoagulants Versus Warfarin for Treatment of Thrombosis or Atrial Fibrillation in Patients With Cirrhosis: A Retrospective Cohort Study. Ann Pharmacother. 2022 May;56(5):533-540. doi: 10.1177/10600280211025050. Epub 2021 Sep 1. PMID: 34470525.	No meta-analysis
Gao Y, Liu H, Tang F, Zhang X, Li F, Ye Q, Yuan H, Lv H, Han T. Efficacy and safety of anticoagulants in liver cirrhosis patients with portal vein thrombosis: A meta-analysis. Clin Res Hepatol Gastroenterol. 2021 Mar;45(2):101649. doi: 10.1016/j.clinre.2021.101649. Epub 2021 Feb 16. PMID: 33601064.	Wrong comparison
Dong S, Qi H, Li Y, Men P, Alifu M, Zhang Y, Li Y, Zhao R. A systematic review and meta-analysis of anticoagulation therapy for portal vein thrombosis in patients with cirrhosis: to treat or not to treat? Hepatol Int. 2021 Dec;15(6):1356-1375. doi: 10.1007/s12072-021-10233-3. Epub 2021 Sep 6. PMID: 34487316.	Wrong comparison
Chen H, Lei J, Liang S, Luo G, Deng M, Lü M. Safety and Efficacy of Anticoagulation in Patients with Cirrhosis: A Meta-Analysis. Can J Gastroenterol Hepatol. 2021 Apr 21;2021:8859602. doi: 10.1155/2021/8859602. PMID: 34007837; PMCID: PMC8102101.	No complete information on search strategy
Mohan BP, Aravamudan VM, Khan SR, Ponnada S, Asokkumar R, Adler DG. Treatment response and bleeding events associated with anticoagulant therapy of portal vein thrombosis in cirrhotic patients: Systematic review and meta-analysis. Ann Gastroenterol. 2020 Sep-Oct;33(5):521-527. doi: 10.20524/aog.2020.0503. Epub 2020 May 30. PMID: 32879600; PMCID: PMC7406805.	Included studies which were also included in Zhang (2022), additional study was of Scheiner (no-comparative study) and did not include Ilzewics.
Di Nisio M, Valeriani E, Riva N, Schulman S, Beyer-Westendorf J, Ageno W. Anticoagulant therapy for splanchnic vein thrombosis: ISTH SSC Subcommittee Control of Anticoagulation. J Thromb Haemost. 2020 Jul;18(7):1562-1568. doi: 10.1111/jth.14836. PMID: 32619346.	Guidance document
Priyanka P, Kupec JT, Krafft M, Shah NA, Reynolds GJ. Newer Oral Anticoagulants in the Treatment of Acute Portal Vein Thrombosis in Patients with and without Cirrhosis. Int J Hepatol. 2018 Jun 5;2018:8432781. doi: 10.1155/2018/8432781. PMID: 29973997; PMCID: PMC6008786.	Narrative review
Hoolwerf EW, Kraaijpoel N, Büller HR, van Es N. Direct oral anticoagulants in patients with liver cirrhosis: A systematic review. Thromb Res. 2018 Oct;170:102-108. doi: 10.1016/j.thromres.2018.08.011. Epub 2018 Aug 17. PMID: 30153564.	Wrong population
Zhang W, Zhou DM, Li Y. [Clinical effect of low-molecular-weight heparin in prevention and treatment of liver cirrhosis and portal vein thrombosis after splenectomy: a systematic review and meta-analysis]. Zhonghua Gan Zang Bing Za Zhi. 2016 Oct 20;24(10):732-737. Chinese. doi: 10.3760/cma.j.issn.1007-3418.2016.10.004. PMID: 27938557.	Wrong language
Lv Y, Bai W, Li K, Wang Z, Guo W, Luo B, Wang J, Wang Q, Wang E, Xia D, Li X, Yuan J, Han N, Niu J, Yin Z, Fan D, Han G. Anticoagulation and Transjugular Intrahepatic Portosystemic Shunt for the Management of Portal Vein Thrombosis in Cirrhosis: A Prospective Observational Study. Am J Gastroenterol. 2021 Jul 1;116(7):1447-1464. doi: 10.14309/ajg.0000000000001194. Erratum in: Am J Gastroenterol. 2022 Jan 1;117(1):200. PMID: 33630766.	Wrong intervention/comparison
Li A, Zhang MC, Li P, Eshaghpour A, Li K, Carrier M, Wells P, Crowther MA. Direct oral anticoagulants for the treatment of splanchnic vein thrombosis - A systematic review and meta-analysis. Thromb Res. 2023 Sep;229:209-218. doi: 10.1016/j.thromres.2023.06.003. Epub 2023 Jun 20. PMID: 37544136.	Incomplete search strategy
Tang K, Weinberg EM. Direct oral anticoagulants in the treatment of portal vein thrombosis in patients with portal hypertension. Clin Liver Dis (Hoboken). 2023 Jul 10;22(2):37-41. doi: 10.1097/CLD.0000000000000063. PMID: 37663556; PMCID: PMC10473309.	No systematic review with meta-analysis, wrong publication type

Search II – Observational studies

Reference	Reason for exclusion
Bergère M, Erard-Poinsot D, Boillot O, Valette PJ, Guillaud O, Chambon-Augoyard C, Dumortier J. Portal vein thrombosis and liver cirrhosis: Long-term anticoagulation is effective and safe. Clin Res Hepatol Gastroenterol. 2019 Aug;43(4):395-402. doi: 10.1016/j.clinre.2018.11.011. Epub 2018 Dec 18. PMID: 30578107.	wrong comparison
Serrao A, Merli M, Lucani B, Aprile F, Fiori L, Gioia S, Breccia M, Riggio O, Chistolini A. Outcomes of long-term anticoagulant treatment for the secondary prophylaxis of splanchnic venous thrombosis. Eur J Clin Invest. 2021 Jan;51(1):e13356. doi: 10.1111/eci.13356. Epub 2020 Aug 11. PMID: 33180323.	wrong study population, wrong comparison
Pettinari I, Vukotic R, Stefanescu H, Pecorelli A, Morelli M, Grigoras C, Sparchez Z, Andreone P, Piscaglia F; BO-LIVES (BOlogna LIVEr vascular Studies). Clinical Impact and Safety of Anticoagulants for Portal Vein Thrombosis in Cirrhosis. Am J Gastroenterol. 2019 Feb;114(2):258-266. doi: 10.1038/s41395-018-0421-0. PMID: 30538290.	wrong comparison
K T, Chan SJ, Varghese C, Lim WB, Cheemungtoo GM, Akter N, Nayar M, Pandanaboyana S. A selective anticoagulation policy for splanchnic vein thrombosis in acute pancreatitis is associated with favourable outcomes: experience from a UK tertiary referral centre. HPB (Oxford). 2022 Nov;24(11):1937-1943. doi: 10.1016/j.hpb.2022.06.003. Epub 2022 Jun 16. PMID: 35786365.	wrong comparison
Saleh S, Dalal S, Desai A, Thomas C, Chitsaz E. Outcomes of Anticoagulation in Patients With Splanchnic Vein Thrombosis From Acute Pancreatitis: A Population-Based Nationwide Retrospective Cohort Study. Pancreas. 2022 Sep 1;51(8):e105-e106. doi: 10.1097/MPA.0000000000002122. PMID: 36607956.	wrong publication type
Acuna-Villaorduna A, Tran V, Gonzalez-Lugo JD, Azimi-Nekoo E, Billett HH. Natural history and clinical outcomes in patients with portal vein thrombosis by etiology: A retrospective cohort study. Thromb Res. 2019 Feb;174:137-140. doi: 10.1016/j.thromres.2018.12.019. Epub 2018 Dec 27. PMID: 30597344.	wrong comparison
Barbui T, De Stefano V, Carobbio A, Iurlo A, Alvarez-Larran A, Cuevas B, Ferrer Marín F, Vannucchi AM, Palandri F, Harrison C, Sibai H, Griesshammer M, Bonifacio M, Elli EM, Trotti C, Koschmieder S, Carli G, Benevolo G, Ianotto JC, Goel S, Falanga A, Betti S, Cattaneo D, Arellano-Rodrigo E, Mannelli L, Vianelli N, Doyle A, Gupta V, Wille K, Tremblay D, Mascarenhas J. Direct oral anticoagulants for myeloproliferative neoplasms: results from an international study on 442 patients. Leukemia. 2021 Oct;35(10):2989-2993. doi: 10.1038/s41375-021-01279-1. Epub 2021 May 19. PMID: 34012132; PMCID: PMC8132485.	wrong publication type
Naymagon L, Tremblay D, Mascarenhas J, Schiano T. Characteristics, anticoagulation, and outcomes of portal vein thrombosis after intra-abdominal surgery. Surgery. 2021 May;169(5):1175-1181. doi: 10.1016/j.surg.2020.11.016. Epub 2020 Dec 24. PMID: 33358635.	wrong outcomes
Hajibandeh S, Hajibandeh S, Agrawal S, Irwin C, Obeidallah R, Subar D. Anticoagulation Versus No Anticoagulation for Splanchnic Venous Thrombosis Secondary to Acute Pancreatitis: Do We Really Need to Treat the Incidental Findings? Pancreas. 2020 Oct;49(9):e84-e85. doi: 10.1097/MPA.0000000000001644. PMID: 33003093.	wrong publication type
Noronha Ferreira C, Cortez-Pinto H, Serejo F, Velosa J, Marinho RT. Anticoagulation in patients with cirrhosis and portal vein thrombosis: Safety and beneficial effect on OLT-free survival. Liver Int. 2019 Oct;39(10):2002. doi: 10.1111/liv.14231. Epub 2019 Sep 18. PMID: 31461802.	wrong publication type
Andraska E, Haga L, Reitz K, Li X, Ramos R, Avgerinos E, Singh M, Eslami M, Makaroun M, Chaer R. Acute superior mesenteric venous thrombosis results in high rates of readmission and morbidity. J Vasc Surg Venous Lymphat Disord. 2020 Sep;8(5):748-755. doi: 10.1016/j.jvsv.2020.01.007. Epub 2020 Mar 3. PMID: 32139329; PMCID: PMC7434641.	wrong comparison

Verantwoording

Beoordelingsdatum en geldigheid

Laatst beoordeeld : 23-09-2025

Initiatief en autorisatie

Initiatief:

Nederlandse Internisten Vereniging

Geautoriseerd door:

Nederlands Huisartsen Genootschap
Nederlandse Internisten Vereniging
Nederlandse Orthopaedische Vereniging
Nederlandse Vereniging van Artsen voor Longziekten en Tuberculose
Nederlandse Vereniging van Maag-Darm-Leverartsen
Nederlandse Vereniging voor Anesthesiologie
Nederlandse Vereniging voor Cardiologie
Nederlandse Vereniging voor Dermatologie en Venereologie
Nederlandse Vereniging voor Heelkunde
Nederlandse Vereniging voor Kindergeneeskunde
Nederlandse Vereniging voor Klinische Geriatrie
Nederlandse Vereniging voor Neurologie
Nederlandse Vereniging voor Thoraxchirurgie
Nederlandse Vereniging van Ziekenhuisapothekers
Koninklijke Nederlandse Maatschappij ter bevordering der Pharmacie
Nederlandse Vereniging voor Klinische Chemie en Laboratoriumgeneeskunde
Nederlandse Vereniging voor Intensive Care
Nederlandse Vereniging voor Mond- Kaak- en Aangezichtschirurgie
Harteraad

Algemene gegevens

Voor meer details over de gebruikte richtlijnmethodologie verwijzen wij u naar de Werkwijze. Relevante informatie voor de ontwikkeling/herziening van deze richtlijnmodule is hieronder weergegeven.

De ontwikkeling/herziening van deze richtlijnmodule werd ondersteund door het Kennisinstituut van de Federatie Medisch Specialisten (www.demedischspecialist.nl/kennisinstituut) en werd gefinancierd uit de Stichting Kwaliteitsgelden Medisch Specialisten (SKMS). Patiëntenparticipatie bij deze richtlijn werd medegefinancierd uit de Kwaliteitsgelden Patiënten Consumenten (SKPC) binnen het programma KIDZ. De financier heeft geen enkele invloed gehad op de inhoud van de richtlijnmodule.

Samenstelling werkgroep

Voor het ontwikkelen van de richtlijnmodule is in 2021 een multidisciplinaire werkgroep ingesteld, bestaande uit vertegenwoordigers van alle relevante specialismen (zie hiervoor de Samenstelling van de werkgroep) die betrokken zijn bij de zorg voor patiënten die antitrombotische therapie dan wel tromboseprofylaxe gebruiken.

Kerngroep

Prof. dr. M.V. (Menno) Huisman, internist-vasculaire geneeskunde, LUMC, NIV (voorzitter)
Dr. M.J.H.A. (Marieke) Kruip, internist-hematoloog, Erasmus MC, NIV, NVVH (Nederlandse Vereniging voor Hematologie)
Prof. Dr. F.A. (Erik) Klok, internist-vasculaire geneeskunde, LUMC, NIV
Dr. J. (Jenneke) Leentjens, internist-vasculaire geneeskunde, RadboudUMC, NIV (vanaf 2023)
Dr. N. (Nick) van Es, internist-vasculaire geneeskunde, Amsterdam UMC, NIV (vanaf 2023)
Dr. M.A. (Marc) Brouwer, cardioloog, RadboudUMC, NVVC
Dr. H.B. (Harmen) Ettema, orthopedisch chirurg, Isala, NOV
Dr. B. (Banne) Nemeth, aios orthopedie, LUMC, NOV
Dr. A.M. (Arno) Wiersema, vaatchirurg, Dijklander Ziekenhuis, NVVH (tot 2023)
Dr. M.C. (Michiel) Warlé, vaatchirurg, RadboudUMC, NVVH (vanaf 2024)
Dr. M.E. (Maarten) Tushuizen, maag-darm-leverarts, LUMC, NVMDL
Dr. J.M. (Jonathan) Coutinho, neuroloog, Amsterdam UMC, NVN
Drs. M.H. (Monique) Suijker, kinderarts-hematoloog, UMC Utrecht, NVK
Drs. P (Paul) Smits, huisarts/ Kaderhuisarts HVZ, NHG

Klankbordgroep

Dr. J.J.C.M. (Sjef) van de Leur, arts klinische chemie, Isala, NVKC
Dr. M.G. (Mariëlle) van Pampus, gynaecoloog, OLVG, NVOG
Drs. R.J. (Rutger) Lely, radioloog, Amsterdam UMC, NVVR
Dr. C. (Bibi) van Montfrans, dermatoloog, Erasmus MC, NVDV
Dr. R.A. (Richard) Faaij, klinisch geriater, Diakonessenhuis, NVKG
Dr. B. (Baucke) van Minnen, kaakchirurg, UMCG, NVMKA
Drs. N. (Noa) Rosenberg, beleidsadviseur, Harteraad (vanaf mei 2024)
I.G.J. (Ilse) Verstraaten MSc, beleidsadviseur, Harteraad (tot 2024)
Dr. N. (Nakisa) Khorsand, ziekenhuisapotheker, OLVG, NVZA
Dr. M.F. (Margreet) van Herwaarden, openbaar apotheker, KNMP
Dr. E.T.T.L. (Eric) Tjwa, MDL-arts, RadboudUMC, NVMDL
Dr. L.M. (Linda) de Heer, cardio-thoracaal chirurg, UMC Utrecht, NVT
Prof. dr. S. (Saskia) Middeldorp, internist-vasculaire geneeskunde, Radboudumc, NIV
Dr. J.M.M.B. (Hans-Martin) Otten, internist-oncoloog, Meander MC, NIV
Dr. E.J. (Esther) Nossent, longarts, Amsterdam UMC, NVALT
Dr. C.H. (Heleen) van Ommen, kinderarts-hematoloog, Erasmus MC, NVK
Dr. K.M.J. (Katja) Heitink, kinderarts-oncoloog, Prinses Maxima Centrum, NVK
Prof. dr. N.P. (Nicole) Juffermans, intensivist, Amsterdam UMC, NVIC
Dr. M.C.A. (Marcella) Muller, intensivist, Amsterdam UMC, NVIC

Met ondersteuning van

H. (Hanneke) Olthuis, adviseur, Kennisinstituut van de Federatie Medisch Specialisten
H.J. (Harm-Jan) van der Hart, adviseur, Kennisinstituut van de Federatie Medisch Specialisten

Belangenverklaringen

Een overzicht van de belangen van werkgroepleden en het oordeel over het omgaan met eventuele belangen vindt u in onderstaande tabel. De ondertekende belangenverklaringen zijn op te vragen bij het secretariaat van het Kennisinstituut van de Federatie Medisch Specialisten via secretariaat@kennisinstituut.nl.

Werkgroeplid	Functie	Nevenfuncties	Gemelde belangen	Ondernomen actie
Huisman (voorzitter)	Internist vasculaire geneeskunde	voorzitter Dutch Thrombosis Network – onbetaald voorzitter Nationaal Kennisplatform Antistollingszorg – onbetaald medisch leider Trombosedienst Leiden - detachering LUMC	ZonMW Dutch Healthcare Fund – herseninfarct na covid-19 en register van patienten met atrium fibrilleren NHS – herseninfarct na covid-19 Boehringer Ingelheim – register atriumfibrilleren – afgesloten Bristol-Myers Squibb/Pfizer – VTE behandeling bij patienten met maligniteit – afgesloten Bayer Health Care - VTE behandeling bij patienten met maligniteit – afgesloten Aspen – webinar anti-Xa bepaling bij LMWH – afgesloten Daiichi-Sankyo – deelname studie cancer associated thrombosis – afgesloten à op geen van deze projecten projectleider, betreft unrestricted grants en veelal financiering promotietrajecten.	Geen restricties
Banne Nemeth	Orthopedisch chirurg in opleiding	Postdoc klinische epidemiologie en orthopedie, LUMC	Trombosestichting - “VTE following total hip and knee arthroplasty: prediction is the future“	Geen restricties
Harmen Ettema	Orthopedisch chirurg Isala zwolle	Geen	Gemeld bij herbevestiging in 2025: ZonMW, Distinct trial, tromboseprofylaxe bij orthopedische ingrepen, geen projectleider	Geen restricties
Jonathan Coutinho	neuroloog Amsterdam UMC	Geen	Bayer - Pacific stroke en Oceanic stroke study, onderzoek naar inzet van nieuw middel bij patienten met een beroerte, national leader en SC member) Boehringer Ingelheim - RESPECT CVT, vergelijking dabigatran Etexilate met Warfarin, SC member, AstraZeneca, Portola - ANNEXA-I studie, onderzoek naar inzet van Andexanet alfa bij patienten met intracraniele bloeding, national leader Gemeld bij herbevestiging in 2025: ZonMw, Hartstichting, Eurostars, Trombosestichting, Europese Unie, Health-Holland, NWO, onderzoek naar diagnostiek en behandeling van een beroerte Co-founder TrianecT BV fellow European Stroke Organization lid richtlijn commissie ESO over cerebrale sinustrombose editorial board member Stroke en Journal of Neurology leadership International cerebral venous thrombosis consortium	Restricties t.a.v. besluitvorming modules over andexanet alfa bij bloedingen geen restricties ten gevolge van rol pacific stroke study en dabigatran etixilate/warfarin bij CVT, aangezien deze patientengroepen geen onderwerp zijn van deze richtlijnherziening.
Klok	Internist vasculaire geneeskunde LUMC Leiden	Bestuur NVIVG Bestuur ESC werkgroep pulmonale circulatie Bestuur ISTH SSC werkgroep diagnostische en predictieve variabelen (tot 2024) Bestuur Dutch Thrombosis Network Gastwetenschapper Universiteit Mainz (Duitsland) Gemeld bij herbevestiging in 2024: Medisch leider Trombosedienst Leiden (tot 1-1-25)	Bayer, Leo Pharma en BSCI – voorzitter van een internationale werkgroep om een standaard set van uitkomsten (ICHOM) te maken voor VTE – inmiddels afgesloten Actelion en The Netherlands Organisation for Health Research and Development - mede-aanvrager van 3 ZonMw beurzen voor onderzoek naar voorkomen van VTE en herseninfarcten bij COVID-19 patiënten (DC&TC en CORONIS consortium - DC&TC wordt ook ondersteund door TSN en een unrestricted grant van Actelion voor diagnostiek deel - afgesloten The Dutch Thrombosis Association -onderzoek naar nieuwe beeldvormende technieken van trombose The Dutch Heart Foundation - lange termijn prognose van longembolie - afgesloten the Horizon Europe Program - voorzitter van een Europees consortium dat tot doel heeft het gebruik van antitrombotische medicatie in de laatste levensfase te optimaliseren	Geen restricties
Kruip	Hematoloog Gemeld bij herbevestiging in 2024: Directeur Kwaliteit & Patientenzorg, Erasmus MC, betaald	Medisch leider trombosedienst Star-shl (0.2FTE), gedetacheerd vanuit Erasmus MC, betaald voorzitter Federatie Nederlandse Trombosediensten (FNT), onbetaald Gemeld bij herbevestiging in 2024: RvC Lenticure, onbetaald RvT Trombosestichting, onbetaald	Horizon Europe programme Trombosestichting/ZonMw Sprekers vergoedingen gehad van Sobi, Roche en Bristol Myers Squibb; betaling aan het Erasmus MC	Geen restricties
Maarten Tushuizen	MDL-arts LUMC	Geen	Maag-Lever-Darmstichting (MLDS)	Geen restricties
Marc Brouwer	Cardioloog Radboudumc	Geen	Nee	Geen restricties
Paul Smits	huisarts, zelfstandig	Coördinator onderwijscommissie harvaatHAG	geen	Geen restricties
Monique Suijker	Kinderarts-hematoloog werkzaam bij Van Creveldkliniek, UMCU	Geen	Geen lopende studies Bayer en Janssen - Einstein Jr studie - gebruik Rivaroxaban bij kinderen – afgesloten	Geen restricties
Arno Wiersema (teruggetrokken, tot 2024)	Vaatchirurg, Dijklander ziekenhuis	Geen	ZonMw, Amsterdam UMC, Dijklander zh en Medtronic - www.action-1.nl - betreft onderzoek naar rol van heparine bij een open buikslagader operatie, rol als projectleider	Restricties ten aanzien van besluitvorming over heparine.
Michiel Warlé (vanaf 2024)	Vaatchirurg Radboudumc	Werkgroep Landelijk Kennisplatform Antistolling	ZEGG/ZonMw- GENPAD studie (Cyp2c19 genotypering bij Clopidogrel en perifeer arterieel vaatlijden – hoofdonderzoeker Gemeld bij herbevestiging in 2025: NWO-OTP, Wireless clot retriever, projectleider	Geen restricties
Nick van Es (vanaf 2023)	Internist-vasculaire geneeskunde, Amsterdam UMC, locatie AMC	Geen	Trombosestichting – PREVENT (PREdicting VENous Thromboembolism in pancreatic cancer patients) NWO - Blood vessels-on-chip to understand and target COVID-19 intravascular coagulation Gemeld bij herbevestiging in 2024: Deelname Podcast LEO Pharma (2024) Sprekersvergoeding Werfen en Amgen (2024) Eenmalige adviesraad Pfizer (2019) Anthos Therapeutics, ASTER-study en MAGNOLIA-study, effectiviteit en veiligheid van abelacimab (niet geregistreerd middel) in patienten met kankergerelateerde trombose, rol als national lead investigator. NWO, Atherosclerotic cardiovascular disease induced by immune checkpoint inhibitors, rol als projecteleider	Geen restricties
Leentjens (vanaf 2023)	Internist-vasculair geneeskundige, Radboudumc	Geen	Astra Zeneca - scientific steering comité van database studie over bloedingen bij ptn die Xa remmers gebruiken (apixaban, edoxaban Adviesraad Viatris (tot begin 2024) Synapse B.V. – studie naar interactie tussen hemostase en inflammatie bij patiënten met een herseninfarct op jonge leeftijd	Geen restricties
Actieve klankbordgroepleden
Esther Nossent	Longarts Amsterdam UMC	Geen	Janssen, Bayer, MSD, United Therapeutics, Ferrer - OPTICS Boehringer Ingelheim B.V., AbbVie, PEXAS – P402 ILD-extension Gemeld bij herbevestiging in 2025: Deelnemer ICHOM-project, internationale werkgroep om een standaardset van uitkomsten te maken voor VTE Sprekersvergoedingen voor onderwijsevents in afgelopen 5 jaar: Astra Zeneca, Janssen, Bayer/ MSD, Boehringer Ingelheim B.V., Chiesi, GlaxoSmithKline B.V., Novartis, Roche, United Therapeutics/Ferrer Deelname adviesraden: Bayer/MSD (lopend) en Boehringer Ingelheim (afgesloten)	Geen restricties
Heleen van Ommen	Hoofd afd. Kinderhematologie & kinderoncologie Erasmus MC Sophia Kinderziekenhuis	Geen	Daiicho Sankyo - Fase 3 trial effectiviteit van edoxaban voor behandeling van trombose bij kinderen, local PI en steeringCie - afgesloten Octopharma - Microscopic evaluation of clots in ECMO systems, rol als PI BI/BMS en INVENT – chair IPTN ThromPED registry (international observational registry/study of children with thrombosis, Adviseur voor verschillende farmaceuten voor ontwikkeling van onderzoek van antistollingsmiddelen of antidota bij kinderen zoals Asundexian (Bayer BV), andexanet (Astra Zeneca) – tot deelname clusterstuurgroep	Geen restricties
Eric Tjwa	MDL arts, Radboudumc	Geen	Geen Gemeld bij herbevestiging in 2025: Geen betrokkenheid bij onderzoeken die direct/indirect verband houden met de inhoud van de richtlijn	Geen restricties
Hans-Martin Otten (vanaf 2024)	Internist Meander MC	Lid METC UMCU, betaald	Eenmalig advies aan Leo Pharma: standpunten over de zorg bij patiënten met VTE en kanker in NL (19-11-2019) ANT-007 & ANT-008 multi-center studies, abelcimab vs apixaban bij kankergerelateerde VTE, participatie in Meander MC Hukusai-study, participatie - afgesloten Einstein-study, adjudicatie-cie - afgesloten	Geen restricties
Noa Rosenberg (vanaf 2024)	Beleidsadviseur		Geen	Geen restricties
Katja Heitink – Pollé	Kinderoncoloog Prinses Máxima Centrum	Landelijke werkgroep trombose bij kinderen	geen	Geen restricties

Inbreng patiëntenperspectief

De werkgroep besteedde aandacht aan het patiëntenperspectief door uitnodigen van Stichting Harteraad voor de schriftelijke knelpuntenanalyse en door een patiëntvertegenwoordiger van Stichting Harteraad toe te voegen aan de klankbordgroep. De verkregen input is meegenomen bij het opstellen van de uitgangsvragen, de keuze voor de uitkomstmaten en bij het opstellen van de overwegingen (zie alinea waarden en voorkeuren van patiënten). De conceptrichtlijn is tevens voor commentaar voorgelegd aan Stichting Harteraad en Stichting Kind en Ziekenhuis en de eventueel aangeleverde commentaren zijn bekeken en verwerkt.

Kwalitatieve raming van mogelijke financiële gevolgen in het kader van de Wkkgz

Bij de richtlijnmodule voerde de werkgroep conform de Wet kwaliteit, klachten en geschillen zorg (Wkkgz) een kwalitatieve raming uitom te beoordelen of de aanbevelingen mogelijk leiden tot substantiële financiële gevolgen. Bij het uitvoeren van deze beoordeling is de richtlijnmodule op verschillende domeinen getoetst (zie het stroomschema bij Werkwijze).

Module	Uitkomst raming	Toelichting
Behandeling buikvene trombose	geen financiële gevolgen	Uit de toetsing volgt dat de aanbevelingen niet breed toepasbaar zijn (<5.000 patiënten) en daarom naar verwachting geen substantiële financiële gevolgen zullen hebben voor de collectieve uitgaven.

Zoekverantwoording

Zoekstrategie

Embase

No.	Query	Results
#19	#17 AND #18 sleutelartikelen gevonden	3
#18	#9 OR #10	624
#17	#15 AND #16	3
#16	#9 OR #10 OR #11	1707
#15	#12 OR #13 OR #14 sleutelartikelen	3
#14	'anticoagulant therapy for splanchnic vein thrombosis: a systematic review and meta-analysis' AND 2021 NOT [2020]/py	1
#13	'rivaroxaban for the treatment of noncirrhotic splanchnic vein thrombosis: an interventional prospective cohort study'	1
#12	'randomized controlled trial of rivaroxaban versus warfarin in the management of acute non-neoplastic portal vein thrombosis'	1
#11	#4 AND (#7 OR #8) NOT #9 NOT #10 Observationele studies	1083
#10	#4 AND #6 NOT #9 Clinical trials, RCTs	377
#9	#4 AND #5 SR	247
#8	'case control study'/de OR 'comparative study'/exp OR 'control group'/de OR 'controlled study'/de OR 'controlled clinical trial'/de OR 'crossover procedure'/de OR 'double blind procedure'/de OR 'phase 2 clinical trial'/de OR 'phase 3 clinical trial'/de OR 'phase 4 clinical trial'/de OR 'pretest posttest design'/de OR 'pretest posttest control group design'/de OR 'quasi experimental study'/de OR 'single blind procedure'/de OR 'triple blind procedure'/de OR (((control OR controlled) NEAR/6 trial):ti,ab,kw) OR (((control OR controlled) NEAR/6 (study OR studies)):ti,ab,kw) OR (((control OR controlled) NEAR/1 active):ti,ab,kw) OR 'open label':ti,ab,kw OR (((double OR two OR three OR multi OR trial) NEAR/1 (arm OR arms)):ti,ab,kw) OR ((allocat NEAR/10 (arm OR arms)):ti,ab,kw) OR placebo:ti,ab,kw OR 'sham-control':ti,ab,kw OR (((single OR double OR triple OR assessor) NEAR/1 (blind* OR masked)):ti,ab,kw) OR nonrandom:ti,ab,kw OR 'non-random':ti,ab,kw OR 'quasi-experiment':ti,ab,kw OR crossover:ti,ab,kw OR 'cross over':ti,ab,kw OR 'parallel group':ti,ab,kw OR 'factorial trial':ti,ab,kw OR ((phase NEAR/5 (study OR trial)):ti,ab,kw) OR ((case* NEAR/6 (matched OR control)):ti,ab,kw) OR ((match NEAR/6 (pair OR pairs OR cohort* OR control* OR group* OR healthy OR age OR sex OR gender OR patient* OR subject* OR participant)):ti,ab,kw) OR ((propensity NEAR/6 (scor OR match)):ti,ab,kw) OR versus:ti OR vs:ti OR compar:ti OR ((compar* NEAR/1 study):ti,ab,kw) OR (('major clinical study'/de OR 'clinical study'/de OR 'cohort analysis'/de OR 'observational study'/de OR 'cross-sectional study'/de OR 'multicenter study'/de OR 'correlational study'/de OR 'follow up'/de OR cohort:ti,ab,kw OR 'follow up':ti,ab,kw OR followup:ti,ab,kw OR longitudinal:ti,ab,kw OR prospective:ti,ab,kw OR retrospective:ti,ab,kw OR observational:ti,ab,kw OR 'cross sectional':ti,ab,kw OR cross?ectional:ti,ab,kw OR multicent:ti,ab,kw OR 'multi-cent':ti,ab,kw OR consecutive:ti,ab,kw) AND (group:ti,ab,kw OR groups:ti,ab,kw OR subgroup:ti,ab,kw OR versus:ti,ab,kw OR vs:ti,ab,kw OR compar:ti,ab,kw OR 'odds ratio':ab OR 'relative odds':ab OR 'risk ratio':ab OR 'relative risk*':ab OR 'rate ratio':ab OR aor:ab OR arr:ab OR rrr:ab OR ((('or' OR 'rr') NEAR/6 ci):ab)))	14286706
#7	'major clinical study'/de OR 'clinical study'/de OR 'case control study'/de OR 'family study'/de OR 'longitudinal study'/de OR 'retrospective study'/de OR 'prospective study'/de OR 'comparative study'/de OR 'cohort analysis'/de OR ((cohort NEAR/1 (study OR studies)):ab,ti) OR (('case control' NEAR/1 (study OR studies)):ab,ti) OR (('follow up' NEAR/1 (study OR studies)):ab,ti) OR (observational NEAR/1 (study OR studies)) OR ((epidemiologic NEAR/1 (study OR studies)):ab,ti) OR (('cross sectional' NEAR/1 (study OR studies)):ab,ti)	6767914
#6	'clinical trial'/exp OR 'randomization'/exp OR 'single blind procedure'/exp OR 'double blind procedure'/exp OR 'crossover procedure'/exp OR 'placebo'/exp OR 'prospective study'/exp OR rct:ab,ti OR random:ab,ti OR 'single blind':ab,ti OR 'randomised controlled trial':ab,ti OR 'randomized controlled trial'/exp OR placebo:ab,ti	3302394
#5	'meta analysis'/exp OR 'meta analysis (topic)'/exp OR metaanaly:ti,ab OR 'meta analy':ti,ab OR metanaly:ti,ab OR 'systematic review'/de OR 'cochrane database of systematic reviews'/jt OR prisma:ti,ab OR prospero:ti,ab OR (((systemati OR scoping OR umbrella OR 'structured literature') NEAR/3 (review* OR overview)):ti,ab) OR ((systemic NEAR/1 review):ti,ab) OR (((systemati OR literature OR database* OR 'data base') NEAR/10 search):ti,ab) OR (((structured OR comprehensive* OR systemic) NEAR/3 search):ti,ab) OR (((literature NEAR/3 review):ti,ab) AND (search:ti,ab OR database:ti,ab OR 'data base':ti,ab)) OR (('data extraction':ti,ab OR 'data source':ti,ab) AND 'study selection':ti,ab) OR ('search strategy':ti,ab AND 'selection criteria':ti,ab) OR ('data source':ti,ab AND 'data synthesis':ti,ab) OR medline:ab OR pubmed:ab OR embase:ab OR cochrane:ab OR (((critical OR rapid) NEAR/2 (review* OR overview* OR synthes)):ti) OR ((((critical OR rapid) NEAR/3 (review OR overview* OR synthes)):ab) AND (search:ab OR database:ab OR 'data base':ab)) OR metasynthes:ti,ab OR 'meta synthes':ti,ab	733409
#4	#3 AND [2008-2023]/py NOT ('conference abstract'/it OR 'editorial'/it OR 'letter'/it OR 'note'/it) NOT (('animal'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 'nonhuman'/exp) NOT 'human'/exp)	3567
#3	#1 AND #2	4816
#2	'direct oral anticoagulant'/exp OR 'direct oral anticoagulant agent'/exp OR 'anticoagulant agent'/exp OR 'apixaban'/exp OR 'non vitamin k antagonist oral anticoagulant'/exp OR 'thrombin inhibitor'/exp OR 'edoxaban'/exp OR 'rivaroxaban'/exp OR 'dabigatran'/exp OR 'thrombin inhibitor':ti,ab,kw OR 'aboxoma':ti,ab,kw OR 'apixaban':ti,ab,kw OR 'apixaben':ti,ab,kw OR doac*:ti,ab,kw OR 'bms 562247':ti,ab,kw OR 'bms562247':ti,ab,kw OR 'eliques':ti,ab,kw OR 'eliquis':ti,ab,kw OR 'lunast':ti,ab,kw OR 'pf 0465257':ti,ab,kw OR 'pf0465257':ti,ab,kw OR 'tah 3311':ti,ab,kw OR 'tah3311':ti,ab,kw OR 'bibr 953':ti,ab,kw OR 'bibr953':ti,ab,kw OR 'dabigatran':ti,ab,kw OR 'du 176':ti,ab,kw OR 'du 176b':ti,ab,kw OR 'du176':ti,ab,kw OR 'du176b':ti,ab,kw OR 'edoxaban':ti,ab,kw OR 'endoxaban':ti,ab,kw OR 'lixiana':ti,ab,kw OR 'roteas':ti,ab,kw OR 'savaysa':ti,ab,kw OR 'assubex':ti,ab,kw OR 'ast 8294':ti,ab,kw OR 'ast8294':ti,ab,kw OR 'bay 59 7939':ti,ab,kw OR 'bay 597939':ti,ab,kw OR 'bay59 7939':ti,ab,kw OR 'bay597939':ti,ab,kw OR 'bs 112':ti,ab,kw OR 'bs112':ti,ab,kw OR 'dst 8294':ti,ab,kw OR 'dst8294':ti,ab,kw OR 'jnj 39039039':ti,ab,kw OR 'jnj39039039':ti,ab,kw OR 'kriva':ti,ab,kw OR 'naxat':ti,ab,kw OR 'rivaro':ti,ab,kw OR 'rivarolto':ti,ab,kw OR 'rivaroxaban':ti,ab,kw OR 'rivaxa':ti,ab,kw OR 'throsaben':ti,ab,kw OR 'xanirva':ti,ab,kw OR 'xarelto':ti,ab,kw OR 'xerdoxo':ti,ab,kw OR 'xindus':ti,ab,kw	812381
#1	'budd chiari syndrome'/exp OR 'mesenteric thrombosis'/exp OR 'portal vein thrombosis'/exp OR 'splanchnic vein thrombosis'/exp OR (('hepatic portal vein'/exp OR 'mesenteric vein'/exp OR 'splenic vein'/exp) AND 'thrombosis'/exp) OR (((splanchnic OR splenic OR 'vena lienalis' OR mesenter* OR abdom* OR portal OR porto OR hepatic) NEAR/3 (thromb* OR occlusi)):ti,ab,kw) OR 'pylethromb':ti,ab,kw OR 'budd-chiari':ti,ab,kw OR ((chiari NEAR/2 (deform* OR disease* OR syndrom*)):ti,ab,kw) OR 'endophlebitis obliterans hepatica':ti,ab,kw OR 'splenic vein thrombosis'/exp	44815

Ovid/Medline

#	Searches	Results
9	(5 and 7) not 8 Clinical trials, RCTs	103
8	5 and 6 SR	84
7	exp clinical trial/ or randomized controlled trial/ or exp clinical trials as topic/ or randomized controlled trials as topic/ or Random Allocation/ or Double-Blind Method/ or Single-Blind Method/ or (clinical trial, phase i or clinical trial, phase ii or clinical trial, phase iii or clinical trial, phase iv or controlled clinical trial or randomized controlled trial or multicenter study or clinical trial).pt. or random.ti,ab. or (clinic adj trial).tw. or ((singl or doubl* or treb* or tripl) adj (blind$3 or mask$3)).tw. or Placebos/ or placebo.tw.	2616982
6	meta-analysis/ or meta-analysis as topic/ or (metaanaly* or meta-analy* or metanaly).ti,ab,kf. or systematic review/ or cochrane.jw. or (prisma or prospero).ti,ab,kf. or ((systemati or scoping or umbrella or "structured literature") adj3 (review* or overview)).ti,ab,kf. or (systemic adj1 review).ti,ab,kf. or ((systemati or literature or database* or data-base) adj10 search).ti,ab,kf. or ((structured or comprehensive* or systemic) adj3 search).ti,ab,kf. or ((literature adj3 review) and (search or database* or data-base)).ti,ab,kf. or (("data extraction" or "data source") and "study selection").ti,ab,kf. or ("search strategy" and "selection criteria").ti,ab,kf. or ("data source" and "data synthesis").ti,ab,kf. or (medline or pubmed or embase or cochrane).ab. or ((critical or rapid) adj2 (review or overview* or synthes)).ti. or (((critical or rapid) adj3 (review or overview* or synthes)) and (search or database* or data-base)).ab. or (metasynthes or meta-synthes*).ti,ab,kf.	684473
5	4 not ((exp animals/ or exp models, animal/) not humans/) not (letter/ or comment/ or editorial/)	1007
4	limit 3 to yr="2008 - 2023"	1132
3	1 and 2	1885
2	exp Anticoagulants/ or Rivaroxaban/ or exp Dabigatran/ or thrombin inhibitor.ti,ab,kf. or aboxoma.ti,ab,kf. or apixaban.ti,ab,kf. or apixaben.ti,ab,kf. or doac*.ti,ab,kf. or bms 562247.ti,ab,kf. or bms562247.ti,ab,kf. or eliques.ti,ab,kf. or eliquis.ti,ab,kf. or lunast.ti,ab,kf. or "pf 0465257".ti,ab,kf. or pf0465257.ti,ab,kf. or tah 3311.ti,ab,kf. or tah3311.ti,ab,kf. or bibr 953.ti,ab,kf. or bibr953.ti,ab,kf. or dabigatran.ti,ab,kf. or du 176.ti,ab,kf. or du 176b.ti,ab,kf. or du176.ti,ab,kf. or du176b.ti,ab,kf. or edoxaban.ti,ab,kf. or endoxaban.ti,ab,kf. or lixiana.ti,ab,kf. or roteas.ti,ab,kf. or savaysa.ti,ab,kf. or assubex.ti,ab,kf. or ast 8294.ti,ab,kf. or ast8294.ti,ab,kf. or bay 59 7939.ti,ab,kf. or bay 597939.ti,ab,kf. or bay59 7939.ti,ab,kf. or bay597939.ti,ab,kf. or bs 112.ti,ab,kf. or bs112.ti,ab,kf. or dst 8294.ti,ab,kf. or dst8294.ti,ab,kf. or jnj 39039039.ti,ab,kf. or jnj39039039.ti,ab,kf. or kriva.ti,ab,kf. or naxat.ti,ab,kf. or rivaro.ti,ab,kf. or rivarolto.ti,ab,kf. or rivaroxaban.ti,ab,kf. or rivaxa.ti,ab,kf. or throsaben.ti,ab,kf. or xanirva.ti,ab,kf. or xarelto.ti,ab,kf. or xerdoxo.ti,ab,kf. or xindus.ti,ab,kf.	247867
1	Budd-Chiari Syndrome/ or exp Mesenteric Vascular Occlusion/ or ((Portal System/ or Mesenteric Veins/ or Portal Vein/ or Splenic Vein/) and exp Thrombosis/) or ((splanchnic or splenic or vena lienalis or mesenter* or abdom* or portal or porto or hepatic) adj3 (thromb* or occlusi)).ti,ab,kf. or pylethromb.ti,ab,kf. or budd-chiari.ti,ab,kf. or (chiari adj2 (deform* or disease* or syndrom*)).ti,ab,kf. or endophlebitis obliterans hepatica.ti,ab,kf.	27836

Richtlijnendatabase

Antitrombotisch beleid

Antitrombotisch beleid

Behandeling buikvenetrombose

Uitgangsvraag

Aanbeveling

Overwegingen

Onderbouwing

Achtergrond

Conclusies / Summary of Findings

Samenvatting literatuur

Zoeken en selecteren

Referenties

Evidence tabellen

Verantwoording

Beoordelingsdatum en geldigheid

Initiatief en autorisatie

Algemene gegevens

Samenstelling werkgroep

Belangenverklaringen

Inbreng patiëntenperspectief

Module

Zoekverantwoording

Bijlagen