Tromboseprofylaxe volwassenen met maligniteit

Beoordeeld: 23-09-2025

Uitgangsvraag

In hoeverre zouden poliklinische patiënten met een maligniteit tromboseprofylaxe moeten krijgen?

Aanbeveling

Overweeg tromboseprofylaxe voor te schrijven in de vorm van een DOAC (apixaban 2,5 mg 2dd of rivaroxaban 10 mg 1dd) aan poliklinische patiënten met een solide maligniteit of maligne lymfoom en een hoog risico op veneuze trombo-embolie (Khorana score ≥2 punten) die starten met systemische kankerbehandeling (exclusief monotherapie met hormonale therapie) en geen risicofactoren hebben voor een bloeding (zie Tabel 3. Overzicht risicofactoren voor bloedingen en contra-indicaties voor het starten van tromboseprofylaxe bij patiënten met een maligniteit die starten met systemische therapie).

Overweeg tromboseprofylaxe te continueren na de eerste 6 maanden, en pas te stoppen bij het beëindigen van de systemische kankerbehandeling.

Stop tromboseprofylaxe bij het optreden van klinisch relevante bloedingen, als er een hoog risico op bloedingen ontstaat of als de terminale fase aanbreekt.

Overwegingen

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

DOACs

Ten opzichte van placebo zou tromboseprofylaxe met directe orale anticoagulantia (DOACs) kunnen leiden tot een net clinical benefit die klinisch relevant is bij volwassen patiënten met een maligniteit die starten met chemotherapie en die een gemiddeld tot hoog risico op een VTE hebben en geen risicofactoren voor een bloeding. De bewijskracht voor deze cruciale uitkomst is laag. Verder zijn we onzeker over het effect van tromboseprofylaxe met DOACs op de andere cruciale uitkomst mortaliteit (zeer laag GRADE). Voor beide uitkomsten wordt de bewijskrachtbeperkt vanwege het risico op bias en imprecisie.

Ook zijn we onzeker over de effecten van tromboseprofylaxe met DOACs op de belangrijke uitkomst arteriële trombo-embolie (ATE, zeer laag GRADE). De bewijskracht voor de belangrijke uitkomstmaten VTE, majeure bloeding en klinische niet relevante majeure bloeding is laag. Ten opzichte van placebo leidt tromboseprofylaxe mogelijk tot minder veneuze trombo-embolieën (VTE). Voor de uitkomstmaten majeure bloedingen en klinisch relevante niet majeure bloedingen is er mogelijk geen verschil tussen patiënten die tromboseprofylaxe met DOAC ontvingen, vergeleken met patiënten die een placebo kregen. Daarbij moet worden opgemerkt dat patiënten met risicofactoren op een bloeding of een eerdere bloeding werden uitgesloten. Geen van de studies rapporteerde over de uitkomstmaten kwaliteit van leven, aanvulling of stoppen van oncologische behandeling en kwaliteit van sterven en dood. Er kan derhalve geen conclusie worden getrokken over de effecten van tromboseprofylaxe met DOACs op de genoemde uitkomstmaten.

LMWH

Op basis van de geïncludeerde studies zijn we onzeker over het effect van tromboseprofylaxe met laagmoleculairgewicht heparine (LMWH) op de cruciale uitkomstmaten net clinical benefit en mortaliteit, vergeleken met placebo of geen tromboseprofylaxe bij volwassen patiënten met een maligniteit die starten met chemotherapie (zeer laag GRADE). De bewijskracht van de gevonden resultaten is erg beperkt vanwege het risico op bias, inconsistentie en imprecisie. De gegevens met betrekking tot de uitkomstmaat net clinical benefit waren beperkt; er waren slechts twee studies die voldoende gegevens rapporteerden om de net clinical benefit te kunnen berekenen. Dit bemoeilijkt de interpretatie van deze gegevens.

De bewijskracht voor de belangrijke uitkomstmaat VTE is laag. Ten opzichte van placebo of standaardzorg leidt tromboseprofylaxe met LMWH mogelijk tot minder VTE. Verder zijn we onzeker over het effect van tromboseprofylaxe met LMWH op de belangrijke uitkomstmaten ATE, majeure bloeding, klinische relevante niet majeure bloeding en kwaliteit van leven. Ook hiervoor geldt dat de bewijskracht beperkt werd door het risico op bias, inconsistentie en imprecisie.

Geen van de studies rapporteerde over de uitkomstmaten aanvulling of stoppen van oncologische behandeling en kwaliteit van sterven en dood. Er kan derhalve geen conclusie worden getrokken over de effecten van tromboseprofylaxe met LMWH op de genoemde uitkomstmaten.

Fondaparinux

Er zijn geen studies gevonden die de effectiviteit van tromboseprofylaxe met fondaparinux onderzochten bij patiënten met een maligniteit die startten met systeemtherapie.

Selectie van patiënten en generaliseerbaarheid

Het risico op VTE verschilt zeer sterk tussen patiëntengroepen. Het nut (meestal uitgedrukt als Number Needed tot Treat (NNT)) van tromboseprofylaxe hangt in belangrijke mate af van dit uitgangsrisico op VTE. Het risico is met name hoger bij patiënten met lokaal gevorderde of gemetastaseerde maligniteit en bij patiënten met een hoog-risico tumor, zoals een maag- of pancreascarcinoom. De meest gebruikte risicoscore om hoog-risico patiënten te identificeren is de Khorana score. Het voordeel van de Khorana score is dat deze goed gevalideerd is en makkelijk te berekenen is o.b.v. tumortype, bloedbeeld en BMI. Het nadeel is dat de discriminerende waarde beperkt is en dat de sensitiviteit en specificiteit variëren tussen tumortypen. In het onderzoek van Alexander (2023, TARGET-TP) werden hoog-risico patiënten geïdentificeerd op basis van D-dimeer en fibrinogeenconcentraties, maar deze manier van risicostratificatie is niet gevalideerd.

In de twee DOAC-trials werden enkel patiënten geïncludeerd met een Khorana score van twee of hoger (Carrier, 2019 en Khorana, 2019). Als deze trials als uitgangspunt worden genomen, dan heeft iedere aanbeveling over DOACs dus automatisch ook betrekking op het gebruik van de Khorana score om hoog-risico patiënten te identificeren. Door gebruik van de Khorana score werd een groep patiënten geselecteerd met een uitgangsrisico van 9.3% in zes maanden (cumulatieve incidentie VTE in placebogroepen: 65/696 = 9.3%). Dit komt goed overeen met de zes-maanden incidentie van 8.9% die werd geschat in een meta-analyse (Mulder, 2019). Bij gebruik van een afkapwaarde van drie punten stijgt de zes-maanden incidentie naar 11%. In deze groep is het nut van tromboseprofylaxe groter (Bosch, 2020).

In één van de DOAC-trials (Khorana, 2019) werden patiënten geëxcludeerd bij wie een DVT van het been werd geconstateerd bij een screeningsecho vóór randomisatie; dit betrof 4.5% van de patiënten. Ook werd een screenende echo verricht na acht, 16 en 26 weken. Een asymptomatisch proximale DVT werd hierbij geconstateerd bij 4.3% in de placebogroep en 2.1% in de rivaroxaban groep. Dit beperkt de generaliseerbaarheid van de uitkomsten van deze studie, aangezien in de Nederlandse praktijk geen screenende echografie wordt toegepast. Het is onbekend of het effect van rivaroxaban groter of kleiner was geweest als screening voorafgaand aan randomisatie en tijdens het onderzoek níet was toegepast.

In de DOAC-trials werden patiënten geïncludeerd met een solide maligniteit of maligne lymfoom die gingen starten met nieuwe chemotherapie of andere systemische kankertherapie (behoudens hormoontherapie als monotherapie). Het is niet gerapporteerd welk deel van de patiënten neoadjuvante, adjuvante of palliatieve behandeling kregen. Hoewel het overgrote deel van de patiënten behandeld werd met chemotherapie, is de werkgroep van mening dat de resultaten ook toepasbaar zijn op patiënten die andere vormen van systemische kankerbehandeling krijgen, zoals immuuntherapie of tyrosine kinase remmers, aangezien deze behandelingen geassocieerd zijn met een gelijk dan wel hoger tromboserisico. Aangezien er niet tot nauwelijks patiënten met acute leukemie of multipel myeloom werden geïncludeerd, kunnen de resultaten niet naar deze groepen vertaald worden. Overigens krijgen patiënten met multipel myeloom meestal reeds tromboseprofylaxe aangeboden op basis van patiënt- en behandeling specifieke criteria conform hematologische richtlijnen.

Patiënten met een verhoogd risico op bloedingen werden uitgesloten van deelname. Er zijn geen gevalideerde scores beschikbaar die specifiek bij patiënten met kanker het bloedingsrisico schatten. Bepaalde patiëntgroepen dienen doorgaans geen tromboseprofylaxe te krijgen vanwege het verhoogde risico op bloedingen of andere contra-indicaties (zie Tabel 3, welke grotendeels gebaseerd is op de exclusiecriteria van de trials die tromboseprofylaxe hebben onderzocht in patiënten met kanker i.c.m. internationale richtlijnen (Lyman, 2021)). Er dient opgemerkt te worden dat het baseline risico op bloedingen (met name gastro-intestinale bloedingen) waarschijnlijk het hoogst is bij patiënten met een tumor van de slokdarm of maag in situ. Deze patiënten werden niet uitgesloten van de trials die tromboseprofylaxe onderzochten. Derhalve is de werkgroep van mening dat deze groep patiënten ook in aanmerking dient te komen voor tromboseprofylaxe. Een subgroepanalyse van de CASSINI-trial toonde dat ernstige bloedingen optraden bij 4 van 88 patiënten met een maagcarcinoom of gastro-oesofageaal carcinoom in de rivaroxaban groep (4.6%; waarvan 3 gastro-intestinale bloedingen) vergeleken met 1 van 85 patiënten in de placebogroep (1.2%) (HR 3.77; 95% BI 0.42-33.73; Mones, 2021). In de AVERT-trial ontwikkelde geen van de patiënten met een tumor van de bovenste tractus digestivus (n=44) of colorectaal carcinoom (n=11) een ernstige bloeding (Ladha, 2021).

Tabel 3. Overzicht risicofactoren voor bloedingen en contra-indicaties voor het starten van tromboseprofylaxe bij patiënten met een maligniteit die starten met systemische therapie

Verhoogd bloedingsrisico

Bekende bloedingsziekte

Leverdysfunctie met coagulopathie (bv. verlengde PT en/of aPTT)

(Verwachte) trombopenie <50 x 10⁹/L

eGFR <30 mL/min/1.73 m²

Geplande stamceltransplantatie

Dubbele trombocytenaggregatieremming

Chronisch gebruik NSAID

Zeer laag lichaamsgewicht (<40 kg)

Gelijktijdig gebruik van sterke remmers van CYP3A4 of P-glycoproteine^≠

Absolute contra-indicatie voor gebruik directe orale anticoagulantia

Zwangerschap

Borstvoeding

Relatieve contra-indicatie

Levensverwachting <6 maanden

^{* Hiervoor kan gebruikt gemaakt worden van de tabellen uit de EHRA-Practical Guide to NOAC use in AF uit 2021 (Steffel, 2021). ≠ Bijvoorbeeld ketoconazol, itraconazol, voriconazol, posaconazol of HIV-proteaseremmers}

De meeste onderzoeken naar tromboseprofylaxe hadden een follow-up duur van zes maanden. De meeste VTE ontstaan in de eerste drie maanden na het starten van de kankerbehandeling. Het is derhalve onduidelijk of de voordelen van tromboseprofylaxe ook na zes maanden blijven bestaan. De werkgroep is echter van mening dat systemische kankerbehandeling een persisterende risicofactor is voor VTE, en dat tromboseprofylaxe dan ook gecontinueerd dient te worden tijdens de gehele behandeling, ook als deze langer dan zes maanden duurt, om het risico op een VTE na staken van tromboseprofylaxe te verlagen. De werkgroep is van mening dat bij patiënten bij wie de terminale palliatieve fase aanbreekt tromboseprofylaxe ook gestaakt dient te worden omdat het risico op bloedingen in deze fase groter lijkt dan het risico op trombose.

Net clinical benefit

Er is in deze module gekozen voor net clinical benefit als één van de cruciale uitkomstmaten. Hierdoor wordt naast een eventuele reductie in VTE ook de belangrijkste bijwerking van tromboseprofylaxe (majeure bloeding) meegewogen. Daarnaast kan tromboseprofylaxe in theorie een direct effect hebben op mortaliteit door het voorkómen van een fatale longembolie of het induceren van een fatale bloeding, en een indirect effect door het voorkómen van gevolgen van een VTE (bv. gecompliceerde ziekenhuisopname of bloeding door therapeutische antistolling). Daarbij moet aangetekend worden dat er geen bewijs is dat tromboseprofylaxe tot significante verbetering van overleving leidt (Schünemann, 2020). De beperking van de net clinical benefit is dat VTE en majeure bloeding binnen deze uitkomst een gelijke waarde hebben, terwijl dit voor de patiënt of arts niet zo hoeft te zijn. Daarnaast zijn andere relevante uitkomstmaten die beïnvloed kunnen worden door tromboseprofylaxe, zoals klinisch relevante niet-majeure bloedingen en ATE, geen onderdeel van de gebruikte definitie van net clinical benefit. Ook kan niet voor alle onderzoeken een net clinical benefit berekend worden doordat fatale bloedingen en VTE niet apart gerapporteerd worden, waardoor een risico staat op dubbele telling met mortaliteit.

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

Er is weinig onderzoek gedaan naar de waarden en voorkeuren van patiënten met betrekking tot tromboseprofylaxe. De uitkomst van de kankerbehandeling (bijvoorbeeld progressievrije overleving en mortaliteit) en kwaliteit van leven zijn voor de meeste patiënten met kanker doorgaans het belangrijkst. Aangezien VTE kan interfereren met de kankerbehandeling (bv. door een ziekenhuisopname of uitgestelde ingreep) en kan leiden tot morbiditeit (bv. pijn of dyspneu) is de werkgroep van mening dat het relevant is om het risico op VTE te bespreken en eventueel counseling over tromboseprofylaxe aan te bieden. Recent internationaal onderzoek laat echter zien dat 62% van de patiënten met kanker geen informatie had gekregen over het verhoogde risico op VTE en dat 69% geen informatie over symptomen passend bij VTE had gekregen (Potere, 2022).

Besluitvorming over tromboseprofylaxe dient expliciet gedeeld te worden met de patiënt. Er dient aangemerkt te worden dat er geen bewijs is dat tromboseprofylaxe tot verbetering van overleving leidt. Bij de counseling dient besproken te worden: het effect van tromboseprofylaxe op net clinical benefit, VTE en (majeure) bloedingen. Daarnaast dient de toedieningsvorm besproken te worden. Tromboseprofylaxe kan aangeboden worden middels LMWH (dagelijkse subcutane injecties) of DOACs (tabletten rivaroxaban 10 mg eenmaal daags of apixaban 2,5 mg tweemaal daags). Hoewel weinig onderzoek is gedaan naar het effect van subcutane injecties vs orale medicatie op de kwaliteit van leven, neemt de werkgroep aan dat patiënten (bij gelijke effectiviteit en veiligheid) een voorkeur zullen hebben voor orale medicatie, mits orale medicatie mogelijk is.

Kosten (middelenbeslag)
Er is geen kosteneffectiviteitsanalyse gedaan naar tromboseprofylaxe voor poliklinische patiënten met kanker in de Nederlandse setting. In een onderzoek uit Spanje werd geschat dat tromboseprofylaxe met apixaban leidde tot een daling van de kosten met €64,- en een klinisch niet significante toename van 0.008 quality adjusted life years (QALY’s) op de korte termijn (zes maanden, Muñoz, 2023). Tromboseprofylaxe middels rivaroxaban was geassocieerd met een stijging van de kosten met €121,- en een klinisch niet significante toename van 0.008 QALY’s. Een Canadees onderzoek schatte dat tromboseprofylaxe middels apixaban geassocieerd is met een daling van de kosten met 257 CAD en een toename van 0.001 QALY’s op de korte termijn (zes maanden) en een daling van 6.973 CAD en toename van 0.083 QALY’s op de lange termijn (Kimpton, 2021). Tot slot toonde onderzoek uit de Verenigde Staten aan dat tromboseprofylaxe met rivaroxaban of apixaban leidde tot een toename in kosten van $1.445 en toename van 0.12 QALY’s op de korte termijn (zes maanden) (Li, 2020)). Op basis van deze onderzoeken lijkt, voor de Nederlandse praktijk, tromboseprofylaxe middels apixaban en rivaroxaban niet tot onaanvaardbare zorgkosten te leiden, en waarschijnlijk een geringe toename in QALY’s. Wat niet is meegewogen in de kosteneffectiviteitsanalyses, zijn de kosten die gepaard gaan met de eventuele counseling van hoog-risico patiënten m.b.t. tromboseprofylaxe. De kosten van LMWH en DOACs in profylactische dosering zijn ten tijde van het opstellen van de richtlijn ongeveer gelijk, afhankelijk van het gekozen preparaat, waardoor er vanuit kostenperspectief geen duidelijke voorkeur is.

Aanvaardbaarheid, haalbaarheid en implementatie

Het bespreken van het risico op VTE en klachten passend bij VTE zou bij voorkeur onderdeel van het informatiegesprek met patiënten die starten met systemische kankerbehandeling moeten zijn. De praktijk leert echter dat het merendeel van de Nederlandse kankerbehandelaren het risico op VTE nooit of soms bespreken, en dat slechts een klein aantal de Khorana score kent en ook daadwerkelijk gebruikt (Kapteijn, 2022). Hieruit kan afgeleid worden dat counseling over tromboseprofylaxe momenteel zelden wordt aangeboden aan patiënten met kanker in Nederland. Mogelijke verklaringen hiervoor zijn dat (i) patiënten al veel informatie krijgen over de prognose, behandeling en andere complicaties, (ii) er niet voldoende tijd is voor het bespreken van het risico op VTE en counseling over tromboseprofylaxe, (iii) VTE niet beschouwd wordt als een relevante complicatie of (iv) dat kankerbehandelaren niet op de hoogte zijn van de literatuur over tromboseprofylaxe.

De resultaten uit de beschikbare gerandomiseerde onderzoeken suggereren dat er een mogelijk voordeel is van tromboseprofylaxe met beperkte belasting voor de patiënt (orale behandeling). Daarom is de werkgroep van mening dat tromboseprofylaxe overwogen dient te worden bij hoog-VTE-risico patiënten zonder risicofactoren voor bloedingen die starten met systemische behandeling, bijvoorbeeld patiënten met een hoog-risico tumor, zoals maag- of pancreascarcinoom, of (andere) patiënten met een Khorana score van twee punten of hoger. Daarnaast dienen patiënten geïnformeerd te worden over de klachten en symptomen die kunnen duiden op een DVT of longembolie en, indien gekozen wordt voor tromboseprofylaxe, de klachten en symptomen die kunnen duiden op een bloeding. Deze informatievoorziening kan onderdeel zijn van het algemene informatiegesprek dat reeds voorafgaand aan het starten van een nieuwe behandeling wordt gevoerd. Tromboseprofylaxe dient doorgaans gestaakt te worden bij het optreden van ernstige bloedingen en bij het staken van de kankerbehandeling. Ook in andere situaties kan besloten worden dat het voordeel van tromboseprofylaxe niet meer opweegt tegen het risico op bloedingen, bijvoorbeeld bij het ontstaan van ernstige nierinsufficiëntie of trombopenie.

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

De werkgroep is van mening dat er op basis van lage bewijskracht een voordeel zou kunnen zijn van tromboseprofylaxe met een DOAC bij poliklinische patiënten met een solide maligniteit of maligne lymfoom die starten met systemische behandeling (o.a. chemotherapie, immuuntherapie of orale kankerbehandeling zoals tyrosine kinase remmers) en een hoog risico hebben op VTE en geen risicofactoren voor een bloeding. Dit voordeel bestaat uit een klinisch relevant lager risico op het gecombineerd eindpunt van VTE, ernstige bloedingen en mortaliteit. Dit eindpunt wordt gedreven door een klinisch relevant lager risico op VTE ten koste van een gering verhoogd risico op ernstige bloedingen, zonder een effect op mortaliteit. Het risico op VTE kan ingeschat worden met de Khorana score, waarbij patiënten met twee of meer punten geclassificeerd worden als ‘hoog risico’. Patiënten met een verhoogd risico op bloedingen dienen geen tromboseprofylaxe te krijgen, zoals patiënten met (verwachte) diepe trombopenie, een eerdere klinisch relevante bloeding, moeilijk te behandelen ernstige hypertensie, hersenmetastasen of primaire hersentumor of een eGFR <30 mL/min/1.73 m². De werkgroep geeft de voorkeur aan een DOAC (tabletten rivaroxaban 10 mg eenmaal daags of apixaban 2,5 mg tweemaal daags) boven LMWH op basis van de aanvaardbaarheid voor patiënten (orale vs. subcutane toediening) bij gelijke kosten. Indien orale toediening niet mogelijk is of er contra-indicaties zijn voor een DOAC of belangrijke interacties met andere medicatie, kan LMWH als alternatief gegeven worden, hoewel het effect van LMWH op het net clinical benefit zeer onzeker is. De werkgroep schat in dat de kosteneffectiviteit van tromboseprofylaxe met een DOAC voor de Nederlandse maatschappij acceptabel is o.b.v. extrapolatie van buitenlandse kosteneffectiviteitsanalyses. Ondanks dat de onderzoeken een follow-up duur hadden van maximaal zes maanden, is de werkgroep van mening dat overwogen moet worden de tromboseprofylaxe te continueren gedurende de duur van de systemische kankerbehandeling, aangezien het risico op VTE verhoogd is en blijft tijdens kankerbehandeling. Daarnaast is de werkgroep van mening dat tromboseprofylaxe gestaakt dient te worden als er contra-indicaties optreden (bijvoorbeeld ernstige trombopenie, ernstige nierinsufficiëntie, ernstige hypertensie of ernstige bloedingen). Het besluit omtrent tromboseprofylaxe (zowel start als stop) dient zeer nadrukkelijk genomen te worden samen met de patiënt (‘gedeelde besluitvorming’). Daarnaast dienen patiënten voorlichting te krijgen over het verhoogde risico op VTE en klachten passend bij een DVT of longembolie, zodat adequate diagnostiek tijdig ingezet kan worden, en over het risico op bloedingen als gekozen wordt voor tromboseprofylaxe.

Onderbouwing

Achtergrond

Patients with cancer have an 8.5-fold increased risk of venous thromboembolism compared to the general population (Mulder, 2021). The 1-year cumulative incidence varies widely across different tumor types, ranging from 1% in patients with breast or prostate cancer to 10-20% in patients with gastric or pancreatic cancer. Cancer-associated thrombosis can lead to morbidity, decreased quality of life, interruption or delays in cancer treatment, and mortality, and is associated with increased healthcare costs. Ambulatory patients with cancer currently do not receive routine pharmacological thromboprophylaxis, but prevention of venous thromboembolism may prevent morbidity and mortality, particularly in high-risk patients. The term ambulatory is used for patients for whom care is usually organized and provided at the outpatient clinic, excluding those admitted to the hospital because of surgery or a medical illness, for whom the risk-benefit ratio of thromboprophylaxis is different. The current guideline does also not discuss prevention of catheter-associated thrombosis in patients with a central venous catheter, but focuses on thromboprophylaxis for prevention of any form of venous thromboembolism in a broad oncology population. Finally, recommendations do not pertain to patients with multiple myeloma, since these patients are already routinely treated with either aspirin or anticoagulation during cancer treatment based on hematological guidelines.

Conclusies / Summary of Findings

All outcome measures – fondaparinux

GRADE

None of the included studies used fondaparinux as thromboprophylaxis in patients with malignancy receiving chemotherapy. Therefore, no conclusion can be drawn on the effect of thromboprophylaxis with fondaparinux on all outcome measures in adult ambulatory patients with malignancy initiating chemotherapy.

Sources: none

Net clinical benefit

DOAC

Low

GRADE

In adult ambulatory patients with malignancy initiating chemotherapy and an intermediate to high risk Khorana-score and no risk factors for bleeding, thromboprophylaxis with DOACs may result in a net clinical benefit which is clinically relevant, compared to placebo.

Sources: Carrier, 2019 and Khorana, 2019

LMWH

Very low

GRADE

The evidence is very uncertain about the effect of thromboprophylaxis with LMWH on the outcome net clinical benefit when compared with placebo or standard of care in adult ambulatory patients with malignancy initiating chemotherapy.

Sources: Agnelli, 2009 and Sideras, 2006

Mortality

DOAC

Very low

GRADE

The evidence is very uncertain about the effect of thromboprophylaxis with DOACs on the outcome mortality when compared with placebo in adult ambulatory patients with malignancy initiating chemotherapy and an intermediate to high risk Khorana-score.

Sources: Carrier, 2019 and Khorana, 2019

LMWH

Very low GRADE

The evidence is very uncertain about the effect of thromboprophylaxis with LMWHs on the outcome mortality when compared with placebo or standard of care in adult ambulatory patients with malignancy initiating chemotherapy.

Sources: Agnelli, 2009; Alexander, 2023; Altinbas, 2004; Kakkar, 2004; Macbeth, 2016; Perry, 2010 and Sideras, 2006

Venous thromboembolism

DOAC

Low

GRADE

In adult ambulatory patients with malignancy initiating chemotherapy and an intermediate to high risk Khorana-score and no risk factors for bleeding, thromboprophylaxis with DOACs may result in a reduction in number of patients with a VTE, compared to placebo.

Sources: Carrier, 2019 and Khorana, 2019

LMWH

Low

GRADE

In adult ambulatory patients with malignancy initiating chemotherapy, thromboprophylaxis with LMWHs may result in a reduction in number of patients with a VTE, compared to placebo or standard of care.

Sources: Agnelli, 2009; Alexander, 2023; Altinbas, 2004; Kakkar, 2004; Macbeth, 2016; Perry, 2010 and Sideras, 2006

Major bleeding

DOAC

Low

GRADE

In adult ambulatory patients with malignancy initiating chemotherapy and an intermediate to high risk Khorana-score and no risk factors for bleeding, thromboprophylaxis with DOACs may result in little to no difference in number of patients with a major bleeding, compared to placebo.

Sources: Carrier, 2019 and Khorana, 2019

LMWH

Very low GRADE

The evidence is very uncertain about the effect of thromboprophylaxis with LMWHs on the outcome major bleeding when compared with placebo or standard of care in adult ambulatory patients with malignancy initiating chemotherapy.

Sources: Alexander, 2023; Agnelli, 2009; Kakkar, 2004; Macbeth, 2016; Perry, 2010 and Sideras, 2006

Clinically relevant non-major bleeding (CRNMB)

DOAC

Low

GRADE

In adult ambulatory patients with malignancy initiating chemotherapy and an intermediate to high risk Khorana-score and no risk factors for bleeding, thromboprophylaxis with DOACs may result in little to no difference in number of patients with a CRNMB, compared to placebo.

Source: Carrier, 2019 and Khorana, 2019

LMWH

Very low GRADE

The evidence is very uncertain about the effect of thromboprophylaxis with LMWHs on the outcome CRNMB when compared with standard of care in adult ambulatory patients with malignancy initiating chemotherapy and a high risk on thrombosis.

Source: Alexander, 2023

Arterial thromboembolism

DOAC

Very low

GRADE

The evidence is very uncertain about the effect of thromboprophylaxis with DOACs on the outcome ATE when compared with placebo in adult ambulatory patients with malignancy initiating chemotherapy and an intermediate to high risk Khorana-score and no risk factors for bleeding.

Source: Carrier, 2019 and Khorana, 2019

LMWH

Very low

GRADE

The evidence is very uncertain about the effect of thromboprophylaxis with LMWHs on the outcome ATE when compared with standard of care in adult ambulatory patients with malignancy initiating chemotherapy.

Source: Agnelli, 2009; Alexander, 2023 and Macbeth, 2016

Quality of life

DOAC

GRADE

None of the included studies on the effect of thromboprophylaxis with DOACs in patients with malignancy initiating chemotherapy reported on the outcome measure quality of life. Therefore, no conclusion can be drawn on the effect of thromboprophylaxis with DOACs on the outcome measure quality of life in adult ambulatory patients with malignancy initiating chemotherapy.

Sources: none

LMWH

Very low GRADE

The evidence is very uncertain about the effect of thromboprophylaxis with LMWHs on the outcome measure quality of life when compared with placebo or standard of care in adult ambulatory patients with malignancy initiating chemotherapy.

Sources: Macbeth, 2016 and Sideras, 2006

Discontinuation of oncological treatment/complementary treatments and quality of dying and death

GRADE

None of the included studies reported on the outcome measures discontinuation of oncological treatment/complementary treatments and quality of dying and death. Therefore, no conclusion can be drawn on the effect of thromboprophylaxis with DOAC or LMWH on the outcome measures discontinuation of oncological treatment/complementary treatments and quality of dying and death in adult ambulatory patients with malignancy initiating chemotherapy.

Sources: none

Samenvatting literatuur

Description of studies

Rutjes (2020) performed a systematic review to evaluate the effect of primary thromboprophylaxis in adult ambulatory patients with malignancy initiating chemotherapy. Several databases were searched up to August 2020, including The Cochrane Vascular Specialized Register, Cochrane Central Register of Controlled Trials, Medline, Embase, CINAHL EBSCO, and AMED Ovid. They included studies including ambulatory patients (outpatient) (children and adults) with either solid or hematological cancer at any stage. In total, 32 studies (N=15,678) were included. Of those studies, eight (≥ Phase III) studies* reported data on the effect of thromboprophylaxis with DOAC, LMWH, or fondaparinux in adult patients, compared to placebo or standard of care (no thromboprophylaxis). Quality of the studies was assessed using the Cochrane’s risk of bias tool. Table 1 lists more details on the eight studies that were included in our literature analysis. Most studies were (partly) funded by pharmaceutical companies. For the studies of Agnelli (2009) and Khorana (2019), it was reported that the sponsoring party had an active role in writing and/or editing the manuscript and/or in interpreting the data.

In general, the studies included patients who are at (higher) risk of developing thrombosis. Therefore, the included study population will not reflect the full spectrum of the target population, namely patients with a malignancy initiating systemic treatment.

*Reasons for exclusion of studies are described in the table under the tab Methods.

Alexander (2023) performed an open-label RCT (TARGET-TP) to evaluate the effect of thromboprophylaxis with enoxaparin in adult patients with lung or gastrointestinal cancer, receiving anti-cancer therapy with or without radiotherapy/immunotherapy. Based on fibrinogen and D-dimer levels, 200 patients (61%) were classified as being at high risk of venous thromboembolism. These 200 high-risk patients were randomized to receive either enoxaparin (40 mg, subcutaneously, once daily for ≤ 90 days, N=100) or no thromboprophylaxis (control group, N=100). Median age (range) was 67 (30-87) years in the enoxaparin group and 66 (31-85) in the control group. Of the patients in the enoxaparin group, 62 (62%) were male, compared to 55 (55%) in the control group. In the enoxaparin group were 52 (52%) and 5 (5%) patients with respectively metastatic disease and prior thromboembolism, compared to 44 (44%) and 7 (7%) patients in the control group. Primary follow-up was 180±30 days.

Table 1. Details of studies that are included in the literature analysis on the effect of thromboprophylaxis in ambulatory patients with cancer initiating chemotherapy, adapted from Rutjes (2020)

Author, year	Participants (N)	Disease characteristics	Intervention	Comparison	Follow-up (median (IQR))
Agnelli, 2009 (PROTECHT-trial)	I: 779, C: 387	Metastatic or locally advanced lung, gastrointestinal, pancreatic, breast, ovarian, or head and neck cancer	Nadroparin 3800 IU SC, once daily for max. 120±10 days /duration of chemotherapy, median duration: NR	Placebo	I: 111 days (NR), C: 113 (NR) days
Altinbas, 2004	I: 42, C: 42	Small-cell lung carcinoma, ECOG performance <3 and normal haematological, renal, and hepatic function tests	Dalteparin 5000 IU SC, once daily, median (IQR) duration: 18 weeks (NR)	No dalteparin	10 (2-33 (range)) months
Sideras, 2006*	first part: n=50, I: 24, C:26 second part: n=88, I: 44, C: 44	Advanced breast cancer, failed first-line chemotherapy; advanced prostate cancer, failed primary hormonal therapy; advanced lung cancer; or advanced colorectal cancer	Dalteparin 5000 IU SC, for 18 weeks or until disease progression, median duration: NR	First part from dec 1998 to feb 2020 placebo, second part from feb 2020 to June 2021 standard care alone	NR, 18 months was planned
Kakkar, 2004 (FAMOUS-trial)	I: 196, C: 189	Advanced stage III/IV cancer of the breast, lung, gastrointestinal tract, pancreas, liver, genitourinary tract, ovary, or uterus.	Dalteparin 5000 IU SC, once daily for 1 year or until death, median duration: NR	Placebo	I: 10 (NR) months, C: 9 (NR) months
Perry, 2010 (PRODIGE trial)	I: 98, C: 88	Grade 3 or grade 4 Glioma	Dalteparin 5000 IU SC, once daily, median (IQR) duration: 183 (NR) days.	Placebo Median (IQR) duration: 157 (NR) days	NR, 12 months was planned
Macbeth, 2016 (FRAGMATIC-trial)	I: 102, C: 1101	Primary bronchial carcinoma of any stage and histology	Dalteparin 5000 IU SC, once daily for 24 weeks (median duration: NR, reported was that 180 (18.4%) patients received full number of syringes)	Standard care	23.1 (3.6-31.2) months
Khorana, 2019 (CASSINI-trial)	I: 436, C: 421	High-risk ambulatory patients with solid cancer or lymphoma who had a Khorana score of ≥ 2, had a plan to start a new systemic regimen within 1 week before or after initiating the trial regimen and had no DVT on baseline screening ultrasonography.	Rivaroxaban 10 mg, once daily up to 180 days, mean (range) duration: 4.3 (NR) months	Placebo	NR
Carrier, 2019 (AVERT- trial)	I: 291, C: 283	Patients with a newly diagnosed cancer site or progression of the malignant disease after complete or partial remission who were initiating a new course of chemotherapy with a minimum intent of 3 months' therapy and who had a Khorana score of ≥ 2.	Apixaban 2.5 mg, twice daily for 6 months, median (IQR) duration:157 (78-168) days	Placebo Median (IQR) duration:155 (83-168) days	183 (NR) days

^{C: control, I: intervention, NR: not reported, ECOG: Eastern Cooperative Oncology Group}

^{*The study was modified because of concerns that the low accrual rate was related to the requirements for placebo injections (first phase). The saline placebo injections were eliminated, then, unblinded LMWH was compared with standard clinical care (second phase)}

Results

Net clinical benefit

Net clinical benefit was defined as a composite outcome of non-fatal VTE, non-fatal major bleeding and mortality. We used non-fatal VTE and non-fatal major bleeding in calculating net clinical benefit to prevent double counting of fatal events. In randomized controlled trials evaluating thromboprophylaxis, major bleeding events are usually assessed during the study treatment period, while VTE is assessed during the whole follow-up period. This should have prevented double counting of patients who potentially developed a non-fatal VTE and subsequently developed a non-fatal major bleeding after initiating anticoagulation. Only studies that reported on non-fatal VTE, non-fatal major bleeding, and mortality are included in the analysis on the outcome measure net clinical benefit.

We first describe the results on the outcomes VTE, major bleeding, and mortality separately and thereafter report the results on the outcome measure net clinical benefit.

Venous thromboembolism

Rutjes (2020) defined the outcome VTE as symptomatic and incidental VTE (DVT and PE).

DOACs

Two studies reported on the outcome VTE (Carrier, 2019 and Khorana, 2019). In the trial evaluating apixaban (Carrier, 2019), the outcome was symptomatic or incidentally detected VTE (DVT and PE). In the trial evaluating rivaroxaban (Khorana, 2019), the outcome was symptomatic or incidentally detected VTE (DVT and PE), also including DVT detected by serial screening ultrasonography, which was performed at weeks 8, 16, and 26.

In the apixaban group, 12/288 (4.2%) patients developed VTE compared to 28/275 (10.2%) patients in the placebo group (Carrier, 2019). This corresponds to a risk ratio (RR, 95%CI) of 0.41 (0.21 to 0.79). Risk difference (RD, 95%CI) was -0.06 (-0.10 to -0.02), which was in favour of the apixaban group and was considered clinically relevant. Corresponding NNT is -17 (-10 to -50).

In the rivaroxaban group, 25/420 (6.0%) patients developed VTE compared to 37/421 (8.8%) patients in the placebo group (Khorana, 2019). This corresponds to a RR (95%CI) of 0.68 (0.42 to 1.10). RD (95%CI) was -0.03 (-0.06 to 0.01), which was in favour of the rivaroxaban group and considered to be (borderline) clinically relevant. Corresponding NNT (95%CI) is -33 (-17 to 100).

LMWH

Three studies reported on the outcome VTE (Agnelli, 2009; Alexander, 2023 and Macbeth, 2016). Other studies reported on symptomatic VTE (Altinbas, 2004; Kakkar, 2004; Sideras, 2006 and Perry, 2010). Despite this, results of those seven studies were pooled.

In the LMWH-group 105/2369 (4.4%) patients developed VTE, compared to 169/1965 (8.6%) patients in the control group (Figure 1). This corresponds to a RR (95%CI) of 0.57 (0.45 to 0.72). RD (95%CI) was -0.03 (-0.05 to -0.01), which was in favour of the LMWH-group and considered to be clinically relevant (borderline). Corresponding NNT (95%CI) is -33 (-20 to -100).

Figure 1. The effect of LMWH on the outcome VTE in adult patients with malignancy initiating chemotherapy

^{Based on Rutjes (2020) and Alexander (2023)}

Fondaparinux

None of the included studies used fondaparinux as thromboprophylaxis in patients with malignancy initiating chemotherapy.

Major bleeding

Rutjes (2020) defined the outcome major bleeding as an overt bleeding associated with a decrease in hemoglobin of 2 g/dL or more or leading to a transfusion of two or more units of packed red blood cells or whole blood; bleeding that occurred at a critical site (intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal); or bleeding contributing to death. This definition is identical to the definition of major bleeding as per the International Society on Thrombosis and Haemostasis.

DOACs

Two studies reported on the outcome major bleeding (Carrier, 2019 and Khorana, 2019). In the apixaban group 10/288 (3.5%) patients had a major bleeding while receiving study drug, compared to 5/275 (1.8%) patients in the placebo group (Carrier, 2019). This corresponds to a RR (95%CI) of 1.91 (0.66 to 5.52). RD (95%CI) was 0.02 (-0.01 to 0.04), which was in favour of the placebo group and not considered to be clinically relevant. Corresponding NNH (95%CI) is 50 (-100 to 25).

In the rivaroxaban-group 8/405 (2%) patients had a major bleeding while receiving study drug, compared to 4/404 (1%) patients in the placebo group (Khorana, 2019). This corresponds to a RR (95%CI) of 2.00 (0.61 to 6.57). RD (95%CI) was 0.01 (-0.01 to 0.03), which was in favour of the placebo group and not considered to be clinically relevant. Corresponding NNH (95%CI) is 100 (-100 to 33).

LMWH

Six studies reported on the outcome major bleeding (Alexander, 2023; Agnelli, 2009; Kakkar, 2004; Macbeth, 2016; Perry, 2010 and Sideras, 2006).

In the LMWH-group 26/2327 (1.1%) patients had a major bleeding while receiving study drug, compared to 16/1923 (0.8%) patients in the control group (Figure 2). This corresponds to a RR (95%CI) of 1.35 (0.67 to 2.70). RD (95%CI) was 0.01 (0.00 to 0.01), which was in favour of the control group and not considered to be clinically relevant. Corresponding NNH (95%CI) is 100 (0 to 100).

Figure 2. The effect of LMWH on the outcome major bleeding in adult patients with malignancy initiating chemotherapy

^{Based on Rutjes (2020) and Alexander (2023)}

Fondaparinux

None of the included studies used fondaparinux as thromboprophylaxis treatment in patients with malignancy initiating chemotherapy.

Mortality

Rutjes (2020) defined the outcome mortality as one year overall mortality and therefore we derived the data on all-cause mortality from the individual studies. Macbeth (2016), Carrier (2019) and Khorana (2019) defined mortality as all-cause mortality within the study period.

DOACs

Two studies reported on the outcome mortality (Carrier, 2019 and Khorana, 2019). In the apixaban group 35/288 (12.2%) patients died, compared to 27/275 (9.8%) patients in the placebo group (Carrier, 2019). This corresponds to a RR (95%CI) of 1.24 (0.77 to 1.99). RD (95%CI) was 0.02 (-0.03 to 0.07), which was in favour of the placebo group and not considered to be clinically relevant. Corresponding NNT (95%CI) is 50 (-33.3 to 14.3).

In the rivaroxaban group 84/420 (20%) patients died, compared to 100/421 (23.8%) patients in the placebo group (Khorana, 2019). This corresponds to a RR (95%CI) of 0.84 (0.65 to 1.09). RD (95%CI) was -0.04 (-0.09 to 0.02), which was in favour of the rivaroxaban group and not considered to be clinically relevant. Corresponding NNT (95%CI) is -25 (-11 to 50).

LMWH

Seven studies reported on the outcome mortality (Agnelli, 2009; Alexander, 2023; Altinbas, 2004; Kakkar, 2004; Macbeth, 2016; Perry, 2010 and Sideras, 2006). In the LMWH-group 1552/2369 (65.5.%) patients died compared to 1414/1965 (72.0%) patients in the control group (Figure 3). This corresponds to a RR (95%CI) of 0.97 (0.87 to 1.08). RD (95%CI) was -0.03 (-0.08 to 0.03), which was in favour of the LMWH-group and considered to be (borderline) clinically relevant. Corresponding NNT (95%CI) was -33 (-12.5 to 33).

Figure 3. The effect of LMWH on the outcome all-cause mortality in adult patients with malignancy initiating chemotherapy

^{Based on Rutjes (2020) and Alexander (2023)}

Fondaparinux

None of the included studies used fondaparinux as thromboprophylaxis in patients with malignancy initiating chemotherapy.

Net clinical benefit

DOACs

Carrier (2019) and Khorana (2019) reported on the outcomes non-fatal VTE, non-fatal major bleeding and all-cause mortality, from which the net clinical benefit could be calculated. Results are described in Table 2. Net clinical benefit calculated using results of Khorana (2019) was considered clinically relevant, which was not the case for net clinical benefit calculated based on Carrier (2019).

LMWH

Agnelli (2009) and Sideras (2006) reported on the outcomes non-fatal VTE, non-fatal major bleeding and one-year mortality, from which the net clinical benefit could be calculated. Results are described in Table 2. The calculated net clinical benefit was not considered to be clinically relevant.

Table 2. Net clinical benefit of thromboprophylaxis in adult patients with malignancy initiating chemotherapy (Agnelli, 2009; Sideras, 2006; Carrier, 2019 and Khorana, 2019)

	Non-fatal VTE (n/N)	Non-fatal major bleeding (n/N)	Mortality (n/N)	Net clinical benefit (n/N)
LMWH
Agnelli (2009)	I: 18/769 C: 16/381	I: 4/769 C: 0/381	I: 333/769 C: 155/381	RD (95%CI): 0.01 (-0.05 to 0.07)
Sideras (2006)	I: 4/68 C: 5/70	I: 1/68 C: 4/70	I: 45/68 C: 41/70	RD (95%CI): 0.02 (-0.13 to 0.17)
DOAC
Carrier (2019)	I: 12/288 C: 28/275	I: 10/288 C: 5/275	I: 35/288 C: 27/275	RD (95%CI): -0.02 (-0.09 to 0.05)
Khorana (2019)	I: 24/420 C: 34/421	I: 7/405 C: 4/404	I: 84/420 C: 100/421	RD (95%CI): -0.05 (-0.12 to 0.01)

^{DOAC: direct oral anticoagulants; LMWH: low molecular weight heparin, RD: Risk Difference, VTE: venous thromboembolism, I:intervention , C:comparison, CI: confidence interval}

Clinically relevant non-major bleeding

Rutjes (2020) reported on the outcome clinically relevant bleeding, which was defined as major and clinically relevant non-major bleeding. Therefore, data on CRNMB is derived from the individual studies.

DOACs

Two studies reported on the outcome CRNMB, which was defined according to ISTH criteria as bleeding not meeting the definition of major bleeding, but leading to an intervention, hospitalization, increased level of care, or face to face evaluation (Carrier, 2019 and Khorana, 2019). In the apixaban group 21/288 (7.3%) patients developed CRNMB while receiving study drug, compared to 15/275 (5.5%) patients in the placebo group (Carrier, 2019). This corresponds to a hazard ratio (HR, 95%CI) 1.28 (0.89 to 1.84). RD (95%CI) was 0.02 (-0.02 to 0.06), which was in favour of the placebo group and not considered to be clinically relevant. Corresponding NNH (95%CI) is 50 (-50 to 17).

In the rivaroxaban-group 11/405 (2.7%) patients developed CRNMB while receiving study drug, compared to 8/404 (2%) patients in the placebo group (Khorana, 2019). This corresponds to a hazard ratio (HR, 95%CI) 1.34 (0.54 to 3.32). RD (95%CI) was 0.01 (-0.01 to 0.03), which was in favour of the placebo group and not considered to be clinically relevant. Corresponding NNH (95%CI) is 100 (-100 to 33).

LMWH

One study reported on the outcome CRNMB, which was defined as bleeding not meeting criteria for major bleeding but that would be considered relevant and not trivial by a patient (Alexander, 2023). In the LMWH-group, 16/100 (16%) patients developed CRNMB while receiving study drug, compared to 9/100 (9%) patients in the control group. Adjusted HR (95%CI) was 2.63 (0.23 to 29.71). RD (95%CI) was 0.07 (-0.02 to 0.16), which was in favour of the control group and considered to be clinically relevant. Corresponding NNH (95%CI) was 14 (-50 to 6).

Fondaparinux

None of the included studies used fondaparinux as thromboprophylaxis in patients with malignancy initiating chemotherapy.

Arterial thromboembolism

Rutjes (2020) reported on the outcome ATE, which was defined as symptomatic ATE. However, for the study of Carrier (2019) data on ATE were not available in Rutjes (2020). The working group knew the systematic review and meta-analysis of Xu (2023) in which this data was reported. Therefore, for the study of Carrier (2019) data on the outcome ATE are deduced from Xu (2023). Xu (2023) did not have complementary data on the outcome ATE for the comparisons on LMWH.

DOACs

Two studies reported on the outcome ATE (Carrier, 2019 and Khorana, 2019).

In the apixaban group 1/288 (0.3%) patients developed ATE, compared to 0/275 (0%) patients in the placebo group. This corresponds to a RR (95%CI) of 2.87 (0.12 to 70.03). RD (95%CI) was 0.00 (-0.01 to 0.01), which was in favour of the placebo group and not considered to be clinically relevant. Corresponding NNT (95%CI) was 0 (-100 to 100).

In the rivaroxaban-group 4/420 (1%) patients developed ATE, compared to 7/421 (1.7%) patients in the placebo group. This corresponds to a RR (95%CI) of 0.57 (0.17 to 1.94). RD (95%CI) was -0.01 (-0.02 to 0.01), which was in favour of the rivaroxaban group and not considered to be clinically relevant. Corresponding NNT (95%CI) was -100 (-50 to 100).

LMWH

Three studies reported on the outcome ATE, which was not further specified in Rutjes (2020) (Agnelli, 2009; Alexander, 2023 and Macbeth, 2016). In the LMWH-group, 28/1970 (1.4%) patients developed ATE, compared to 31/1582 (2.0%) patients in the control group (Figure 4). This corresponds to a RR (95%CI) of 0.84 (0.51 to 1.40). RD (95%CI) was -0.00 (-0.01 to 0.00), which was in favour of the LMWH-group and not considered to be clinically relevant. Corresponding NNT (95%CI) was 0 (-100 to 0).

Figure 4. The effect of LMWH on the outcome arterial thromboembolic events in adult patients with malignancy initiating chemotherapy

^{Based on Rutjes (2020) and Alexander (2023)}

Fondaparinux

None of the included studies used fondaparinux as thromboprophylaxis in patients with malignancy initiating chemotherapy.

Quality of life

DOACs

None of the included studies on the effect of thromboprophylaxis with DOACs in patients with malignancy initiating chemotherapy reported on the outcome QoL.

LMWH

Two studies reported on the outcome QoL (Macbeth, 2016 and Sideras, 2006). Sideras (2006) measured QoL using the single-item tool Uniscale and a 5-item series of self-assessment measures supplemented by a 13-item symptom distress scale. In the LMWH-group, 37/68 (54.4%) patients had a decrease of ≥ 10 points on the 100-point scale Uniscale, compared to 36/70 (51.4%) patients in the control group. This corresponds to a RR (95%CI) of 1.06 (0.77 to 1.45), which was in favour of the control group. This difference was not considered clinically relevant.

Macbeth (2016) used the Hospital Anxiety and Depression Score and the EuroQol 5 Dimensions (EQ-5D) to assess QoL. At six months follow-up, the mean EQ-5D score (±SD) was 69.95±26.65 in the LMWH-group (N=486), compared to 69.84±24.89 in the control group (N=454). This corresponds to a mean difference (95%CI) of 0.11 (–3.18 to 3.40), which was in favour of the LMWH-group. This difference was not considered clinically relevant.

At 12 months follow-up, the mean EQ-5D score (±SD) was 68.08±25.92 in the LMWH-group (N=221), compared to 68.42±26.95 in the control group (N=224). This corresponds to a mean difference (95%CI) of –0.34 (–5.25 to 4.57), which is in favour of the control group. This difference was not considered clinically relevant.

Fondaparinux

None of the included studies used fondaparinux as thromboprophylaxis in patients with malignancy initiating chemotherapy.

Discontinuation of oncological treatment/complementary treatments and quality of dying and death

None of the included studies reported on the outcome measures discontinuation of oncological treatment/complementary treatments and quality of dying and death.

Level of evidence of the literature

Fondaparinux

None of the included studies used fondaparinux as thromboprophylaxis in patients with malignancy initiating chemotherapy. Therefore, no conclusion can be drawn on the effect of thromboprophylaxis with fondaparinux on all outcome measures in adult ambulatory patients with malignancy, initiating chemotherapy compared with placebo or no thromboprophylaxis.

General remarks on industry sponsorship
Most studies were (partly) funded by pharmaceutical companies. For the studies of Agnelli (2009) and Khorana (2019) it was reported that the sponsoring party had an active role (e.g. interpretation of the data, writing and/or editing the manuscript). However, the level of evidence was not further downgraded because it is unlikely to have had an influence on the results because of the a priori defined outcomes, double blind design, and adjudication of outcome events.

Net clinical benefit

DOACs

Evidence regarding the outcome measure net clinical benefit comes from RCTs and therefore the level of evidence started as high. The level of evidence was downgraded to low. There was risk of bias (attrition bias, sampling bias, serial screening for DVT; downgraded one level). Furthermore, the 95%CI of the effect estimate crossed one of the thresholds for clinical relevance (imprecision, downgraded one level).

LMWH
Evidence regarding the outcome measure net clinical benefit comes from RCTs and therefore the level of evidence started as high. The level of evidence was downgraded to very low. There was risk of bias (open label trial, attrition bias, selection bias; downgraded one level). Furthermore, the 95%CI of the effect estimate crossed the thresholds for clinical relevance (imprecision, downgraded two levels).

Venous thromboembolism

DOACs

Evidence regarding the outcome VTE comes from RCTs and therefore the level of evidence started as high. The level of evidence was downgraded to low. There was risk of bias (attrition bias, sampling bias, serial screening on DVT; downgraded one level). Furthermore, the 95%CI of the effect estimate crossed one of the thresholds for clinical relevance (imprecision, downgraded one level).

LMWH

Evidence regarding the outcome VTE comes from RCTs and therefore the level of evidence started as high. The level of evidence was downgraded to low. There was risk of bias (e.g. attrition bias and open-label trials, downgraded one level). Furthermore, the 95%CI of the effect estimate crossed one of the thresholds for clinical relevance (imprecision, downgraded one level).

Major bleeding

DOACs

Evidence regarding the outcome major bleeding comes from RCTs and therefore the level of evidence started as high. The level of evidence was downgraded to low. There was risk of bias (attrition bias, sampling bias; downgraded one level). Furthermore, the 95%CI of the effect estimate crossed one of the thresholds for clinical relevance (imprecision, downgraded one level).

LMWH

Evidence regarding the outcome major bleeding comes from RCTs and therefore the level of evidence started as high. The level of evidence was downgraded to very low. There was high risk of bias (attrition bias, open label trials, downgraded one level). The results were inconsistent (inconsistency, downgraded one level) and the number of events was low (imprecision, downgraded one level).

Mortality

DOACs

Evidence regarding the outcome mortality comes from RCTs and therefore the level of evidence started as high. The level of evidence was downgraded to very low. There was risk of bias (attrition bias, sampling bias; downgraded one level). Furthermore, the 95%CI of the effect estimate crossed the thresholds for clinical relevance (imprecision, downgraded two levels).

LMWH

Evidence regarding the outcome mortality comes from RCTs and therefore the level of evidence started as high. The level of evidence was downgraded to very low. There was risk of bias (e.g. attrition bias, downgraded one level). Results were inconsistent (inconsistency, downgraded one level) and 95%CI of the effect estimate crossed the thresholds for clinical relevance (imprecision, downgraded one level). It was decided to downgrade one level for imprecision, due to the fact that part of the imprecision might be attributable to the inconsistent results.

Clinically relevant non-major bleeding

DOACs

Evidence regarding the outcome mortality comes from RCTs and therefore the level of evidence started as high. The level of evidence was downgraded to low. There was risk of bias (attrition bias, sampling bias; downgraded one level). Furthermore, the number of events was low (imprecision, downgraded one level).

LMWH

Evidence regarding the outcome CRNMB comes from a RCT and therefore the level of evidence started as high. The level of evidence was downgraded to very low. There was risk of bias (unclear follow-up and open label trial, downgraded one level). Furthermore, the 95%CI of the effect estimate crossed one of the thresholds for clinical relevance and the number of events was low (imprecision, downgraded two levels).

Arterial thromboembolism

DOACs

Evidence regarding the outcome ATE comes from RCTs and therefore the level of evidence started as high. The level of evidence was downgraded to very low. There was risk of bias (attrition bias, sampling bias; downgraded one level). Furthermore, the number of events was very low (serious imprecision, downgraded two levels).

LMWH

Evidence regarding the outcome ATE comes from RCTs and therefore the level of evidence started as high. The level of evidence was downgraded to very low. There was risk of bias (e.g. attrition bias, open label trials, downgraded one level). Furthermore, the number of events was very low (imprecision, downgraded two levels).

Quality of life

DOACs

None of the included studies on the effect of thromboprophylaxis with DOACs in patients with malignancy receiving chemotherapy reported on the outcome measure quality of life. Therefore, no conclusion can be drawn on the effect of thromboprophylaxis with DOACs on the outcome measure quality of life in adult ambulatory patients with malignancy, receiving chemotherapy.

LMWH

Evidence regarding the outcome measure QoL comes from RCTs and therefore the level of evidence started as high. The level of evidence was downgraded to very low. There was risk of bias (e.g. open label trials, downgraded two levels). Furthermore the 95%CI of the effect estimate crossed the thresholds for clinical relevance (imprecision, downgraded two levels).

Discontinuation of oncological treatment/complementary treatments and quality of dying and death in the palliative care setting

None of the included studies reported on the outcome measures discontinuation of oncological treatment/complementary treatments and quality of dying and death. Therefore, no conclusion can be drawn on the effect of thromboprophylaxis with DOAC, LMWH, or fondaparinux on the outcome measures discontinuation of oncological treatment/complementary treatments and quality of dying and death in adult ambulatory patients with malignancy, initiating chemotherapy compared to placebo or no thromboprophylaxis.

Zoeken en selecteren

A systematic review of the literature was performed to answer the following question: what are the (un)desirable effects of thromboprophylaxis with Direct Oral Anticoagulants (DOAC), Low-Molecular-Weight Heparin (LMWH) or fondaparinux in adult ambulatory patients with malignancy* in whom systemic anticancer treatment was initiated, compared to placebo or standard of care?

P (Patients):	Adult ambulatory patients with malignancy* initiating systemic anticancer treatment
I (Intervention):	Thromboprophylaxis (DOAC, LMWH, or fondaparinux)
C (Comparison):	Placebo, standard of care
O (Outcomes):	Net clinical benefit, venous thromboembolism, major bleeding, mortality, clinically relevant non-major bleeding (CRNMB), arterial thromboembolism (ATE), quality of life, discontinuation of oncological treatment/complementary treatments, quality of dying and death

*Excluding patients with multiple myeloma, since these patients are already routinely treated with either aspirin or anticoagulation during cancer treatment based on hematological guidelines.

Relevant outcome measures

The guideline development group considered net clinical benefit and mortality as critical outcome measures for decision making; any thromboembolism and CRNMB, quality of life, discontinuation of oncological treatment/complementary treatments, and quality of dying and death as an important outcome measure for decision making.

The working group defined the outcomes as follows:

VTE: incidental or symptomatic deep vein thrombosis (DVT) or pulmonary embolism (PE)
Net clinical benefit: composite of non-fatal VTE, non-fatal major bleeding and mortality
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 on Thrombosis and Haemostasis;

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 the following as a minimal clinically (patient) important difference:

Net clinical benefit, VTE, major bleeding, mortality, CRNMB, ATE: risk difference of 3%*
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.

*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)

First search

The databases Medline (via OVID) and Embase (via Embase.com) were searched with relevant search terms until July 4^th, 2023. The systematic literature search resulted in 104 hits. Studies were selected based on the following criteria: (systematic reviews of) ≥ Phase III RCTs which compared the efficacy of thromboprophylaxis (DOAC, LMWH, fondaparinux) with placebo or no thromboprophylaxis in adult ambulatory patients with malignancy, initiating systemic anticancer treatment. 22 studies were initially selected based on title and abstract screening. After reading the full text, 21 studies were excluded (see the table with reasons for exclusion under the tab Methods), and one study was included (Cochrane Review of Rutjes, 2020).

Second search

An additional search was performed to complement the evidence in the Cochrane Review of Rutjes (2020). It was decided to omit the term ‘ambulatory’, in order to be sure that all relevant studies were found. The databases Medline (via OVID) and Embase (via Embase.com) were searched with relevant search terms until October 12^th, 2023. The systematic literature search resulted in 819 hits. Studies were selected based on the following criteria: (systematic reviews of) ≥ Phase III RCTs which compared the efficacy of thromboprophylaxis (DOAC, LMWH, fondaparinux) with placebo or no thromboprophylaxis in adult patients with malignancy, initiating systemic anticancer treatment. One study was initially selected based on title and abstract screening. After reading the full text, this study was included (Alexander, 2023).

The detailed search strategies are shown under the tab Methods.

Results

Two studies were included in the analysis of the literature (Rutjes, 2020 and Alexander, 2023). 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

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Altinbas M, Coskun HS, Er O, Ozkan M, Eser B, Unal A, Cetin M, Soyuer S. A randomized clinical trial of combination chemotherapy with and without low-molecular-weight heparin in small cell lung cancer. J Thromb Haemost. 2004 Aug;2(8):1266-71. doi: 10.1111/j.1538-7836.2004.00871.x. PMID: 15304029.
Bosch FTM, Mulder FI, Kamphuisen PW, Middeldorp S, Bossuyt PM, Büller HR, van Es N. Primary thromboprophylaxis in ambulatory cancer patients with a high Khorana score: a systematic review and meta-analysis. Blood Adv. 2020 Oct 27;4(20):5215-5225. Doi: 10.1182/bloodadvances.2020003115. PMID: 33104795; PMCID: PMC7594395.
Carrier M, Abou-Nassar K, Mallick R, Tagalakis V, Shivakumar S, Schattner A, Kuruvilla P, Hill D, Spadafora S, Marquis K, Trinkaus M, Tomiak A, Lee AYY, Gross PL, Lazo-Langner A, El-Maraghi R, Goss G, Le Gal G, Stewart D, Ramsay T, Rodger M, Witham D, Wells PS; AVERT Investigators. Apixaban to Prevent Venous Thromboembolism in Patients with Cancer. N Engl J Med. 2019 Feb 21;380(8):711-719. doi: 10.1056/NEJMoa1814468. Epub 2018 Dec 4. PMID: 30511879.
Kakkar AK, Levine MN, Kadziola Z, Lemoine NR, Low V, Patel HK, Rustin G, Thomas M, Quigley M, Williamson RC. Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: the fragmin advanced malignancy outcome study (FAMOUS). J Clin Oncol. 2004 May 15;22(10):1944-8. doi: 10.1200/JCO.2004.10.002. PMID: 15143088.
Kaptein FHJ, Guman NAM, van Es N, Kamphuisen PW, Klok FA, Mairuhu ATA, Huisman MV. Treatment and prevention of cancer-associated thrombosis in the Netherlands: A national survey. Res Pract Thromb Haemost. 2023 Jan 24;7(1):100057. Doi: 10.1016/j.rpth.2023.100057. PMID: 36846646; PMCID: PMC9943872.
Khorana AA, Soff GA, Kakkar AK, Vadhan-Raj S, Riess H, Wun T, Streiff MB, Garcia DA, Liebman HA, Belani CP, O'Reilly EM, Patel JN, Yimer HA, Wildgoose P, Burton P, Vijapurkar U, Kaul S, Eikelboom J, McBane R, Bauer KA, Kuderer NM, Lyman GH; CASSINI Investigators. Rivaroxaban for Thromboprophylaxis in High-Risk Ambulatory Patients with Cancer. N Engl J Med. 2019 Feb 21;380(8):720-728. doi: 10.1056/NEJMoa1814630. PMID: 30786186.
Kimpton M, Kumar S, Wells PS, Coyle D, Carrier M, Thavorn K. Cost-utility analysis of apixaban compared with usual care for primary thromboprophylaxis in ambulatory patients with cancer. CMAJ. 2021 Oct 12;193(40):E1551-E1560. Doi: 10.1503/cmaj.210523. PMID: 35040802; PMCID: PMC8568073.
Ladha D, Mallick R, Wang TF, Caiano L, Wells PS, Carrier M. Efficacy and safety of apixaban for primary prevention in gastrointestinal cancers: A post-hoc analysis of the AVERT trial. Thromb Res. 2021 Jun;202:151-154. doi: 10.1016/j.thromres.2021.03.013. Epub 2021 Mar 21. PMID: 33857789.
Li A, Carlson JJ, Kuderer NM, Schaefer JK, Li S, Garcia DA, Khorana AA, Carrier M, Lyman GH. Cost-effectiveness analysis of low-dose direct oral anticoagulant (DOAC) for the prevention of cancer-associated thrombosis in the United States. Cancer. 2020 Apr 15;126(8):1736-1748. Doi: 10.1002/cncr.32724. Epub 2020 Jan 30. PMID: 31999844.
Lyman GH, Carrier M, Ay C, Di Nisio M, Hicks LK, Khorana AA, Leavitt AD, Lee AYY, Macbeth F, Morgan RL, Noble S, Sexton EA, Stenehjem D, Wiercioch W, Kahale LA, Alonso-Coello P. American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer. Blood Adv. 2021 Feb 23;5(4):927-974. Doi: 10.1182/bloodadvances.2020003442. Erratum in: Blood Adv. 2021 Apr 13;5(7):1953. PMID: 33570602; PMCID: PMC7903232.
Macbeth F, Noble S, Evans J, Ahmed S, Cohen D, Hood K, Knoyle D, Linnane S, Longo M, Moore B, Woll PJ, Appel W, Dickson J, Ferry D, Brammer C, Griffiths G. Randomized Phase III Trial of Standard Therapy Plus Low Molecular Weight Heparin in Patients With Lung Cancer: FRAGMATIC Trial. J Clin Oncol. 2016 Feb 10;34(5):488-94. doi: 10.1200/JCO.2015.64.0268. Epub 2015 Dec 23. PMID: 26700124.
Mones JV, Streiff MB, Khorana AA, Bendheim GA, Damaraju CV, Wildgoose P, Burton P, Riess H, Soff GA. Rivaroxaban thromboprophylaxis for gastric/gastroesophageal junction tumors versus other tumors: A post hoc analysis of the randomized CASSINI trial. Res Pract Thromb Haemost. 2021 Jul 20;5(5):e12549. doi: 10.1002/rth2.12549. PMID: 34308096; PMCID: PMC8292144.
Mulder FI, Horváth-Puhó E, van Es N, van Laarhoven HWM, Pedersen L, Moik F, Ay C, Büller HR, Sørensen HT. Venous thromboembolism in cancer patients: a population-based cohort study. Blood. 2021 Apr 8;137(14):1959-1969. doi: 10.1182/blood.2020007338. PMID: 33171494.
Mulder FI, Candeloro M, Kamphuisen PW, Di Nisio M, Bossuyt PM, Guman N, Smit K, Büller HR, van Es N; CAT-prediction collaborators. The Khorana score for prediction of venous thromboembolism in cancer patients: a systematic review and meta-analysis. Haematologica. 2019 Jun;104(6):1277-1287. doi: 10.3324/haematol.2018.209114. Epub 2019 Jan 3. PMID: 30606788; PMCID: PMC6545838.
Muñoz AJ, Ortega L, Gutiérrez A, Gallardo E, Rubio-Rodríguez D, Rubio-Terrés C, Morón B, García-Alfonso P, Soria JM. Cost-effectiveness of apixaban and rivaroxaban in thromboprophylaxis of cancer patients treated with chemotherapy in Spain. J Med Econ. 2023 Jan-Dec;26(1):1145-1154. doi: 10.1080/13696998.2023.2248839. Epub 2023 Aug 21. PMID: 37602646.
Perry JR, Julian JA, Laperriere NJ, Geerts W, Agnelli G, Rogers LR, Malkin MG, Sawaya R, Baker R, Falanga A, Parpia S, Finch T, Levine MN. PRODIGE: a randomized placebo-controlled trial of dalteparin low-molecular-weight heparin thromboprophylaxis in patients with newly diagnosed malignant glioma. J Thromb Haemost. 2010 Sep;8(9):1959-65. doi: 10.1111/j.1538-7836.2010.03973.x. PMID: 20598077.
Potere N, Barco S, Mahé I, Cesarman-Maus G, Angchaisuksiri P, Leader A, Okoye HC, Olayemi E, Ay C, Carrier M, Connors JM, Farmakis IT, Fumagalli RM, Jing ZC, Lee LH, McLintock C, Ní Ainle F, Giannakoulas G, Goto S, Guillermo Esposito MC, Jara-Palomares L, Szlaszynska M, Tan CW, Van Es N, Wang TF, Hunt BJ, Di Nisio M. Awareness of venous thromboembolism among patients with cancer: Preliminary findings from a global initiative for World Thrombosis Day. J Thromb Haemost. 2022 Dec;20(12):2964-2971. doi: 10.1111/jth.15902. Epub 2022 Oct 21. PMID: 36201366; PMCID: PMC9828201.
Rutjes AW, Porreca E, Candeloro M, Valeriani E, Di Nisio M. Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy. Cochrane Database Syst Rev. 2020 Dec 18;12(12):CD008500. doi: 10.1002/14651858.CD008500.pub5. PMID: 33337539; PMCID: PMC8829903.
Schünemann HJ, Ventresca M, Crowther M, Briel M, Zhou Q, Noble S, Macbeth F, Griffiths G, Garcia D, Lyman GH, Di Nisio M, Iorio A, Mbuagbaw L, Neumann I, van Es N, Brouwers M, Guyatt G, Streiff MB, Marcucci M, Baldeh T, Florez ID, Alma OG, Solh Z, Bossuyt PM, Kahale LA, Ageno W, Bozas G, Büller HR, Lebeau B, Lecumberri R, Loprinzi C, McBane R, Sideras K, Maraveyas A, Pelzer U, Perry J, Klerk C, Agnelli G, Akl EA. Evaluating prophylactic heparin in ambulatory patients with solid tumours: a systematic review and individual participant data meta-analysis. Lancet Haematol. 2020 Oct;7(10):e746-e755. doi: 10.1016/S2352-3026(20)30293-3. PMID: 32976752.
Sideras K, Schaefer PL, Okuno SH, Sloan JA, Kutteh L, Fitch TR, Dakhil SR, Levitt R, Alberts SR, Morton RF, Rowland KM, Novotny PJ, Loprinzi CL. Low-molecular-weight heparin in patients with advanced cancer: a phase 3 clinical trial. Mayo Clin Proc. 2006 Jun;81(6):758-67. doi: 10.4065/81.6.758. PMID: 16770976.
Steffel J, Collins R, Antz M, Cornu P, Desteghe L, Haeusler KG, Oldgren J, Reinecke H, Roldan-Schilling V, Rowell N, Sinnaeve P, Vanassche T, Potpara T, Camm AJ, Heidbüchel H; External reviewers. 2021 European Heart Rhythm Association Practical Guide on the Use of Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation. Europace. 2021 Oct 9;23(10):1612-1676. doi: 10.1093/europace/euab065. Erratum in: Europace. 2021 Oct 9;23(10):1676. doi: 10.1093/europace/euab157. PMID: 33895845.

Evidence tabellen

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

Research question: What are the (un)desirable effects of thromboprophylaxis with Direct Oral Anticoagulants (DOAC), Low-Molecular-Weight Heparin (LMWH) or fondaparinux in adult ambulatory patients with malignancy in which systemic anticancer treatment was initiated, compared to placebo or standard of care?

Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Rutjes, 2020

Study characteristics and results are extracted from the SR, for details see study characteristics in Rutjes (2020).

SR and meta-analysis of RCTs

Literature search up to August 2020

A: Agnelli, 2009

D: Altinbas, 2004

E: Vadhan-Raj, 2013

F: Sideras, 2006

G: Kakkar, 2004

H: Perry, 2010

I: Macbeth, 2016

(TOPIC-2)

K: Khorana 2019

L: Carrier, 2019

Study design: Parallel RCT’s, all included studies

I: superiority trial

Setting and Country:

A: multicenter, EU

D: NR

E: NR, USA

F: multicenter, USA

G: multicenter, USA

H: multicenter, western countries

I: multicenter, UK

K: multicenter, USA

L: multicenter, Canada

Source of funding and conflicts of interest:

A: Commercial funding by pharmaceutical company, scientific director of pharmaceutical company was involved as author

D: Funding source not reported, no disclosure of potential COI

E: NR (commercial partner listed at clinicaltrials.gov)

F: Non-commercial funding, COI NR

G: Commercial funding by pharmaceutical company, several COI reported.

H: Commercial funding by pharmaceutical companies, lead author reported COI

I: Partial commercial funding by pharmaceutical company, some authors reported COI

K: Partial commercial funding by pharmaceutical companies, all authors reported COI.

L: Partial commercial funding by pharmaceutical companies, all authors reported COI

Inclusion criteria SR: RCT’s and quasi-RCT’s on participants who were ambulatory patients receiving chemotherapy at the time of randomisation or study entry. Intervention: Any type of oral or parenteral coagulation.

Exclusion criteria SR: Studies of participants receiving anticoagulation for a previous VTE or an indication other than VTE. Studies evaluating prophylaxis for catheter-related thrombosis.

Total of 32 studies included in qualitive analysis, 19 studies included in meta-analysis. Since part of these studies did not fulfil our inclusion criteria, we described 12 studies in this evidence table.

Important patient characteristics at baseline:

A: I: 779, C: 387

D: 83

E: I: 38, C: 37

F: first part: n=52, second part: n=86

G: I: 196, C: 189

H: I: 98, C: 88

I: I: 102, C: 1101

K: I: 436, C: 421

L: I: 291, C: 283

Age (mean years±SD)

A: I 62.1 (10.3)

C: 63.7 (9.2)

D: median 58 (IQR 34-75)

E: I: 59 (range 36-75), C: 64 (38-77)

F: First part: I: 64.5 (NR), C: 63.5 (NR)

Second part: I: 68.5 (NR), C: 70.5 (NR)

G: I: 62 (IQR 54-68), C: 60.9 (IQR 52-69))

H: I: 57 (range 30-81), C: 55 (range 26-77)

I: median I: 65 (IQR 59-71), C: 64 (IQR 58-71)

K: I: median 63(range 23-88), C: 62 (range 28-88)

L: I: 61.2 (12.4), C: 61.7 (11.3)

Sex (% male):

A: 48

D: 82

E: I: 52.6, C: 56.8

F: First part: I: 50, C: 42

Second part: I: 64, C: 70

G: I: 40.5, C: 45.7

H: I: 62, C: 57

I: I: 60, C: 59.6

K: I: 52.9, C: 48.9

L: I: 41.6, C: 42

Metastatic disease (%):

A: NR

D: I: n=19, C: n=17

E: NR

F: NR (all incurable cancer)

G: I: 85, C: 87.5

H: NR

I: I: 60.9, C: 60.5

K: NR (54.5) in those with solid tumour

L: I: 73 (25.1), C: 67 (23.7)

Previous VTE (n (%)):

A: I: 12 (1.6), C: 6 (1.6)

D: 0 (NA)

E: NR

F: First part: I: 4, C: 4

Second part: I: 5, C: 0

G: 0 (NA)

H: NR

I: NR

K: I: 13 (3.1), C: 2 (0.5)

L: 9 (3.1), 8 (2.8)

Disease characteristics

A: Ambulatory patients receiving chemotherapy for metastatic or locally advanced lung, gastrointestinal, pancreatic, breast, ovarian, or head and neck cancer

D: small-cell lung carcinoma patients with ECOG performance status of <3 and normal haematological, renal, and hepatic function tests

E: Patients with advanced stage adenocarcinoma

of the pancreas planning to initiate systemic chemotherapy within 2 weeks, ECOG performance status

0–2, adequate renal function.

F: Patients with advanced breast cancer who had failed first-line chemotherapy; advanced prostate cancer

who had failed primary hormonal therapy; advanced lung cancer; or advanced colorectal cancer.

G: patients with advanced stage III or IV malignant disease of the breast, lung, gastrointestinal tract, pancreas, liver, genitourinary tract, ovary, or uterus.

H: Patients with grade 3 or grade 4 Glioma

I: Patients with primary bronchial carcinoma of any stage and histology

K: High-risk ambulatory patients with solid cancer or lymphoma who had a Khorana score of ≥ 2, had a plan to start a new systemic regimen within 1 week before or after initiating the trial regimen and had

no DVT on screening ultrasonography.

L: Patients with a newly diagnosed cancer site or progression of the malignant disease after complete or partial remission who were initiating a new course of chemotherapy with a minimum intent of 3

months' therapy and who had a Khorana score of ≥ 2.

Groups comparable at baseline?

Yes

A: Nadroparin, 3800 IU SC, once daily for max. 120 days or for whole duration of chemotherapy

D: Dalteparin, 5000 IU SC, once daily for whole duration of therapy (was stopped with disease progression or at end of 18wks chemo)

E: Dalteparin, 5000 IU SC once daily for 16 weeks + standard care

F: Dalteparin, 5000 IU SC for 18 weeks or until disease progression

G: Dalteparin, 5000 IU SC, once daily for 1 year or until death

H: Dalteparin, 5000 IU SC, once daily, median duration 183 days.

I: Dalteparin, 5000 IU SC once daily for 24 weeks plus standard care

K: Rivaroxaban,10 mg once daily up to 180 days, mean treatment period was 4.3 months

L: Apixaban, 2.5 mg twice daily for 6 months

A: Placebo

D: no dalteparin

E: Standard care

F: First part placebo, second part standard care alone

G: Placebo

H: Placebo, median duration 157 days

I: Standard care

K: Placebo

L: Placebo

End-point of follow-up (median):

A: I 111 days, C: 113 days

D: 10 (2-33) months

E: NR

F: NR, 18 months was planned

G: I: 10 months, C: 9 months

H: NR, 12 months was planned

I: 23.1 (IQR 3.6-31.2) months

K: NR

L: 183 days

For how many participants were no complete outcome data available?

A: NR

D: NR

E: NR

F: NR

G: NR

H: NR

I: NR

K: NR

L: NR

For all analyses: pooled effect is NA (since not all of the studies in Rutjes (2020) will be included in our analysis.

Symptomatic VTE

Defined as objectively verified by means of Doppler

(compression) ultrasonography or venography for DVT, and

spiral computed tomography, ventilation/perfusion lung scan, or pulmonary angiography for PE.

DOAC (RR (95%CI))

K: 0.79 [0.41 , 1.54]

L: 0.39 [0.18 , 0.83]

LMWH (RR (95%CI))

F: 0.41 [0.08 , 2.05]

G: 2.91 [0.12 , 70.87]

H: 4.39 [0.52 , 36.89]

I: 1.50 [0.62 , 3.66]

Fondaparinux

Any VTE

Defined as symptomatic and incidental VTE

DOAC (RR (95%CI))

K: 0.68 [0.42 , 1.10]

L: 0.41 [0.21 , 0.79]

LMWH (RR (95%CI))

A: 0.56 [0.29 , 1.08]

E: 0.22 [0.05 , 0.94]

I: 0.57 [0.42 , 0.77]

Fondaparinux

Major bleed

Defined as overt bleeding associated with a decrease in haemoglobin of 2 g/dL or more, or leading to a transfusion of two or more units of packed red blood

cells or whole blood; bleeding that occurred at a critical site

(intracranial, intraspinal, intraocular, pericardial, intra-articular,intramuscular with compartment syndrome, retroperitoneal); or bleeding contributing to death.

DOAC (RR (95%CI))

K: 2.00 [0.61 , 6.57]

L: 1.91 [0.66 , 5.52]

LMWH (RR (95%CI))

F: 0.41 [0.08 , 2.05]

G: 2.91 [0.12 , 70.87]

H: 4.39 [0.52 , 36.89]

I: 1.50 [0.62 , 3.66]

Fondaparinux

Clinically relevant bleeding

Defined as major and clinically relevant nonmajor bleeding); typically defined as overt bleeding that does not meet the criteria for major bleeding, but is associated with the need for medical intervention, contact with a physician, or interruption of the study drug or with discomfort or impairment of activities of daily life

DOAC (RR (95%CI))

K: 1.58 [0.78 , 3.21]

LMWH (RR (95%CI))

I: 4.43 [2.49 , 7.86]

Fondaparinux

Mortality

Defined as 1 year overall mortality

DOAC (RR (95%CI))

LMWH (RR (95%CI))

D: 0.64 [0.43 , 0.97]

F: 1.13 [0.87 , 1.47]

G: 0.91 [0.76 , 1.08]

H: 1.24 [0.87 , 1.75]

Fondaparinux

Quality of life

Defined as

DOAC (RR (95%CI))

LMWH (RR (95%CI))

F: 1.06 [0.77 to 1.45]

LMWH (MD (95%CI))

I (6 months): 0.11 (-3.18 to 3.40)

I (12 months): –0.34 (–5.25 to 4.57)

Fondaparinux

Arterial thromboembolic events.

Defined as

DOAC (RR (95%CI))

K: 0.57 [0.17 , 1.94]

LMWH (RR (95%CI))

A: 0.50 [0.10 , 2.44]

I: 0.92 [0.53 , 1.60]

Fondaparinux

Author’s conclusion

In ambulatory cancer patients, primary thromboprophylaxis with direct factor Xa inhibitors may reduce the incidence of symptomatic venous thromboembolism (VTE) (low-certainty evidence) and

probably increases the risk major bleeding (moderate-certainty evidence) when compared with placebo. Low-molecular-weight heparin (LMWH) reduces symptomatic VTE with 37 participants

requiring prophylaxis to prevent one event (high-certainty evidence). This benefit comes at the cost of a higher incidence of major bleeding, where for each 144 participants treated, one

event is expected to occur when compared against placebo or no thromboprophylaxis (moderate-certainty evidence). When deciding whether to use primary antithrombotic prophylaxis in

ambulatory cancer patients receiving chemotherapy, clinicians need to determine the patient's baseline risk of VTE with the help of risk-stratification models and weigh the magnitude of benefit with antithrombotic prophylaxis, especially on major clinical endpoints,

against the risk of major bleeding complications. Evidence for the use of thromboprophylaxis with anticoagulants other than direct factor Xa inhibitors and LMWH is limited.

Remarks on individual studies

F: After 52 accrued participants, the study was modified because of concerns that the low accrual rate

was related to the requirements for placebo injections. The saline placebo injections were eliminated,

then, unblinded LMWH was compared with standard clinical care.

I: The trial did not reach its intended number of events for the primary analysis. Use of prophylactic anticoagulant outside of trial (short-term use, e.g. inpatient thromboprophylaxis,

and therapeutic anticoagulation were allowed if clinically indicated according to local guidelines), n

(%): 106 (9.7%) in LMWH group; 88 (8.0%) in control group.

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

Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size ⁴

Comments

Alexander, 2023

Type of study:

Open-label RCT

Setting and country:

Metropolitan (N=1) and regional (N=4) hospitals, Australia

Funding and conflicts of interest:

Several authors reported COI.

Inclusion criteria:

Adults with clinician-estimated life expectancy of ≤ 6 months, prior to commencement

of systemic anticancer therapies with or without

radiotherapy for gastrointestinal or lung cancer (newly

diagnosed or relapsed or progressive disease, curative or

palliative intent) at 5 hospitals in Australia.

Exclusion criteria:

Patients with contraindication to enoxaparin, including

conditions placing them at high risk of bleeding or requiring therapeutic anticoagulation.

N total at baseline:

Intervention: 100

Control: 100

Important prognostic factors²:

Age (median years (range))

I: 67 (30-87)

C: 66 (31-85)

Sex:

I: 62% M

C: 55% M

Metastatic disease (n (%)):

I: 52 (52%)

C: 44 (44%)

Previous thromboembolism (n (%))

I: 5 (5%)

C: 7 (7%)

Groups comparable at baseline?

Yes

Enoxaparin

40 mg, subcutaneously daily for a minimum of 90 days (extended up to 180 days according to ongoing risk)

No thromboprophylaxis

Length of follow-up:

180 days ± 30 days

Loss-to-follow-up:

Intervention:

However it was described that 41 (41%) patients discontinued treatment: patient choice (N=8, no reason (N=7), new contraindication (N=6), end of life care (N=6), CRNM bleeding (N=6), thromboembolism (N=3), major bleeding (N=1), other (N=4)) and 2 (2%) patients did not receive intervention.

Control:

0 (0%)

Reasons: NA

Incomplete outcome data:

Intervention:

Control:

All VTE

DVT must be confirmed by ultrasonography, venography or magnetic resonance angiography (cerebral events). PE must be confirmed by spiral CT, CT pulmonary angiography (CTPA) or lung ventilation/ perfusion scan.

I: 7/100 (7%)

C: 22/100 (22%)

aHR (95%CI): 0.28 (0.12-0.65)

P = NR

ATE

ATE must be confirmed by

relevant radiologic imaging, or specifically for myocardial

infarct (MI) must meet criteria outlined in the universal

definition of MI considering biomarker changes, ischemic

symptoms, ECG changes, cardiac imaging abnormalities, and cardiac death.

I: 1/100 (1%)

C: 2/100 (2%)

aHR (95%CI): 0.78 (0.05-13.20)

P = NR

All thromboembolism

Defined as DVT, PE and ATE.

I: 8/100 (8%) *

C: 23/100 (23%)

HR (95%CI): 0.30 (0.13-0.68)

P = 0.005

* 6/8 thromboembolic

events occurred without active enoxaparin

therapy.

Major bleeding

Defined as clinically overt bleeding meeting at least one of the following criteria: fatal bleeding; symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome; bleeding causing a fall in haemoglobin level of 20 g/L or more, or leading to

transfusion of two or more units of whole blood or red cells. Clinically overt was defined as new onset visible bleeding or signs and symptoms suggestive of bleeding which in the

absence of visible bleeding were confirmed by relevant imaging techniques.

I: 1/100 (1%)

C: 2/100 (2%)

aHR (95%CI): 2.63 (0.23-29.71)

P = NR

CRNMB

Defined as bleeding not meeting criteria for major

bleeding but that would be considered relevant and not trivial by a patient and physician.

I: 16/100 (16%)

C: 9/100 (9%)

aHR (95%CI): 0.68 (0.30-1.55)

P = NR

*one patient in the control group had both major bleeding and CRNMB.

Mortality

Defined as 6 month all cause mortality

I: 13/100 (13%)

C: 26/100 (26%)

aHR (95%CI): 0.45 (0.23-0.87))

P = NR

Quality of life

Not reported in this article yet.

Treatment adherence

*Adjusted for cancer diagnosis, cancer treatment, stage and hospital site.

ITT analysis was performed

Fibrinogen and d-dimer levels were used to identify patients with high risk on thromboembolism. In total 200 high-risk patients were randomized to receive either enoxaparin or no thromboprophylaxis. Other patients (low risk, N=128) were assigned to the observational group. These data were not taken into account in our literature analysis.

Of the 100 patients in the intervention group, N=41 discontinued treatment

Risk of bias table for intervention studies (randomized controlled trials; based on Cochrane risk of bias tool and suggestions by the CLARITY Group at McMaster University)

Study reference

(first author, publication year)

Was the allocation sequence adequately generated?

Definitely yes

Probably yes

Probably no

Definitely no

Was the allocation adequately concealed?

Definitely yes

Probably yes

Probably no

Definitely no

Blinding: Was knowledge of the allocated

interventions adequately prevented?

Were patients blinded?

Were healthcare providers blinded?

Were data collectors blinded?

Were outcome assessors blinded?

Were data analysts blinded?

Definitely yes

Probably yes

Probably no

Definitely no

Was loss to follow-up (missing outcome data) infrequent?

Definitely yes

Probably yes

Probably no

Definitely no

Are reports of the study free of selective outcome reporting?

Definitely yes

Probably yes

Probably no

Definitely no

Was the study apparently free of other problems that could put it at a risk of bias?

Definitely yes

Probably yes

Probably no

Definitely no

Overall risk of bias

If applicable/necessary, per outcome measure

LOW

Some concerns

HIGH

Alexander (2023)

Definitely yes;

Reason: Randomization was performed using the randomization module created by an independent statistician.

Definitely yes;

Reason: Randomization was performed blinded and in advance of patient recruitment.

Definitely no;

Reason: Open-label trial (after randomization the study team, treating clinician and patient

were unblinded to treatment allocation). TE and bleeding events were adjudicated by a committee unaware

of randomisation.

No information

Probably yes;

Reason: Not all relevant outcomes are reported yet, but might be reported in other (new) articles.

Definitely yes;

Reason: No other problems noted:

Some concerns (major bleeding, VTE, mortality, CRNMB, any thromboembolism)

HIGH (quality of life, discontinuation/ supplementation of oncological treatment, quality of dying and death)

Table of excluded studies

Excluded studies part I

Reference	Reason for exclusion
Carrier M, Abou-Nassar K, Mallick R, Tagalakis V, Shivakumar S, Schattner A, Kuruvilla P, Hill D, Spadafora S, Marquis K, Trinkaus M, Tomiak A, Lee AYY, Gross PL, Lazo-Langner A, El-Maraghi R, Goss G, Le Gal G, Stewart D, Ramsay T, Rodger M, Witham D, Wells PS; AVERT Investigators. Apixaban to Prevent Venous Thromboembolism in Patients with Cancer. N Engl J Med. 2019 Feb 21;380(8):711-719. doi: 10.1056/NEJMoa1814468. Epub 2018 Dec 4. PMID: 30511879.	Included in Rutjes (2020)
Khorana AA, Soff GA, Kakkar AK, Vadhan-Raj S, Riess H, Wun T, Streiff MB, Garcia DA, Liebman HA, Belani CP, O'Reilly EM, Patel JN, Yimer HA, Wildgoose P, Burton P, Vijapurkar U, Kaul S, Eikelboom J, McBane R, Bauer KA, Kuderer NM, Lyman GH; CASSINI Investigators. Rivaroxaban for Thromboprophylaxis in High-Risk Ambulatory Patients with Cancer. N Engl J Med. 2019 Feb 21;380(8):720-728. doi: 10.1056/NEJMoa1814630. PMID: 30786186	Included in Rutjes (2020)
Akl EA, Kahale LA, Ballout RA, Barba M, Yosuico VE, van Doormaal FF, Middeldorp S, Bryant A, Schünemann H. Parenteral anticoagulation in ambulatory patients with cancer. Cochrane Database Syst Rev. 2014 Dec 10;(12):CD006652. doi: 10.1002/14651858.CD006652.pub4. Update in: Cochrane Database Syst Rev. 2017 Sep 11;9:CD006652. PMID: 25491949.	Recent review available.
Bosch FTM, Mulder FI, Kamphuisen PW, Middeldorp S, Bossuyt PM, Büller HR, van Es N. Primary thromboprophylaxis in ambulatory cancer patients with a high Khorana score: a systematic review and meta-analysis. Blood Adv. 2020 Oct 27;4(20):5215-5225. doi: 10.1182/bloodadvances.2020003115. PMID: 33104795; PMCID: PMC7594395.	Included only studies in high-risk patients.
Agnelli G, Gussoni G, Bianchini C, Verso M, Mandalà M, Cavanna L, Barni S, Labianca R, Buzzi F, Scambia G, Passalacqua R, Ricci S, Gasparini G, Lorusso V, Bonizzoni E, Tonato M; PROTECHT Investigators. Nadroparin for the prevention of thromboembolic events in ambulatory patients with metastatic or locally advanced solid cancer receiving chemotherapy: a randomised, placebo-controlled, double-blind study. Lancet Oncol. 2009 Oct;10(10):943-9. doi: 10.1016/S1470-2045(09)70232-3. Epub 2009 Aug 31. PMID: 19726226.	Included in Rutjes (2020)
Carrier M, Abou-Nassar K, Mallick R, Tagalakis V, Shivakumar S, Schattner A, Kuruvilla P, Hill D, Spadafora S, Marquis K, Trinkaus M, Tomiak A, Lee AYY, Gross PL, Lazo-Langner A, El-Maraghi R, Goss G, Le Gal G, Stewart D, Ramsay T, Rodger M, Witham D, Wells PS; AVERT Investigators. Apixaban to Prevent Venous Thromboembolism in Patients with Cancer. N Engl J Med. 2019 Feb 21;380(8):711-719. doi: 10.1056/NEJMoa1814468. Epub 2018 Dec 4. PMID: 30511879.	Included in Rutjes (2020)
Khorana AA, Soff GA, Kakkar AK, Vadhan-Raj S, Riess H, Wun T, Streiff MB, Garcia DA, Liebman HA, Belani CP, O'Reilly EM, Patel JN, Yimer HA, Wildgoose P, Burton P, Vijapurkar U, Kaul S, Eikelboom J, McBane R, Bauer KA, Kuderer NM, Lyman GH; CASSINI Investigators. Rivaroxaban for Thromboprophylaxis in High-Risk Ambulatory Patients with Cancer. N Engl J Med. 2019 Feb 21;380(8):720-728. doi: 10.1056/NEJMoa1814630. PMID: 30786186	Included in Rutjes (2020)
Akl EA, Kahale LA, Ballout RA, Barba M, Yosuico VE, van Doormaal FF, Middeldorp S, Bryant A, Schünemann H. Parenteral anticoagulation in ambulatory patients with cancer. Cochrane Database Syst Rev. 2014 Dec 10;(12):CD006652. doi: 10.1002/14651858.CD006652.pub4. Update in: Cochrane Database Syst Rev. 2017 Sep 11;9:CD006652. PMID: 25491949.	Recent review available.
Bosch FTM, Mulder FI, Kamphuisen PW, Middeldorp S, Bossuyt PM, Büller HR, van Es N. Primary thromboprophylaxis in ambulatory cancer patients with a high Khorana score: a systematic review and meta-analysis. Blood Adv. 2020 Oct 27;4(20):5215-5225. doi: 10.1182/bloodadvances.2020003115. PMID: 33104795; PMCID: PMC7594395.	Included only studies in high-risk patients.

Studies excluded in Rutjes (2020)

Reference	Reason for exclusion
Campos-Cabrera G, Mendez-Garcia E, Campos-CabreraS, Campos-VillagomezJL, Campos-CabreraV. Rivaroxaban or aspirin as thromboprophylaxis in multiple myeloma. Blood 2018;132(Suppl 1):5068. [DOI: 10.1182/blood-2018-99-111579]	wrong comparison
Chahinian AP, Propert KJ, Ware JH, Zimmer B, Perry MC, Hirsh V, Skarin A, Kopel S, Holland JF, Comis RL, et al. A randomized trial of anticoagulation with warfarin and of alternating chemotherapy in extensive small-cell lung cancer by the Cancer and Leukemia Group B. J Clin Oncol. 1989 Aug;7(8):993-1002. doi: 10.1200/JCO.1989.7.8.993. PMID: 2547030.	wrong intervention
van Doormaal FF, Di Nisio M, Otten HM, Richel DJ, Prins M, Buller HR. Randomized trial of the effect of the low molecular weight heparin nadroparin on survival in patients with cancer. J Clin Oncol. 2011 May 20;29(15):2071-6. doi: 10.1200/JCO.2010.31.9293. Epub 2011 Apr 18. PMID: 21502549.	wrong intervention
Ek L, Gezelius E, Bergman B, Bendahl PO, Anderson H, Sundberg J, Wallberg M, Falkmer U, Verma S, Belting M; Swedish Lung Cancer Study Group (SLUSG). Randomized phase III trial of low-molecular-weight heparin enoxaparin in addition to standard treatment in small-cell lung cancer: the RASTEN trial. Ann Oncol. 2018 Feb 1;29(2):398-404. doi: 10.1093/annonc/mdx716. PMID: 29106448; PMCID: PMC5834130.	wrong intervention
Elit LM, Lee AY, Parpia S, Swystun LL, Liaw PC, Hoskins P, Julian DH, Julian JA, Levine MN. Dalteparin low molecular weight heparin (LMWH) in ovarian cancer: a phase II randomized study. Thromb Res. 2012 Dec;130(6):894-900. doi: 10.1016/j.thromres.2012.09.010. Epub 2012 Oct 7. PMID: 23046525.	wrong comparison
Greiner J, Schrappe M, Claviez A, Zimmermann M, Niemeyer C, Kolb R, Eberl W, Berthold F, Bergsträsser E, Gnekow A, Lassay E, Vorwerk P, Lauten M, Sauerbrey A, Rischewski J, Beilken A, Henze G, Korte W, Möricke A; THROMBOTECT Study Investigators. THROMBOTECT - a randomized study comparing low molecular weight heparin, antithrombin and unfractionated heparin for thromboprophylaxis during induction therapy of acute lymphoblastic leukemia in children and adolescents. Haematologica. 2019 Apr;104(4):756-765. doi: 10.3324/haematol.2018.194175. Epub 2018 Sep 27. PMID: 30262570; PMCID: PMC6442986.	wrong population
Haas SK, Freund M, Heigener D, HeilmannL, Kemkes- Matthes B, von TempelhoK GF, TOPIC Investigators. Lowmolecular- weight heparin versus placebo for the prevention of venous thromboembolism in metastatic breast cancer or stage III/IV lung cancer. Clinical and Applied Thrombosis Hemostasis 2012;18(2):159-65.	wrong intervention (TOPIC 1 and TOPIC 2), study terminated
Khorana AA, Francis CW, Kuderer NM, Carrier M, Ortel TL, Wun T, Rubens D, Hobbs S, Iyer R, Peterson D, Baran A, Kaproth-Joslin K, Lyman GH. Dalteparin thromboprophylaxis in cancer patients at high risk for venous thromboembolism: A randomized trial. Thromb Res. 2017 Mar;151:89-95. doi: 10.1016/j.thromres.2017.01.009. Epub 2017 Jan 26. PMID: 28139259.	study terminated
Klerk CP, Smorenburg SM, Otten HM, Lensing AW, Prins MH, Piovella F, Prandoni P, Bos MM, Richel DJ, van Tienhoven G, Büller HR. The effect of low molecular weight heparin on survival in patients with advanced malignancy. J Clin Oncol. 2005 Apr 1;23(10):2130-5. doi: 10.1200/JCO.2005.03.134. Epub 2005 Feb 7. PMID: 15699479.	wrong intervention
Larocca A, Cavallo F, Bringhen S, Di Raimondo F, Falanga A, Evangelista A, Cavalli M, Stanevsky A, Corradini P, Pezzatti S, Patriarca F, Cavo M, Peccatori J, Catalano L, Carella AM, Cafro AM, Siniscalchi A, Crippa C, Petrucci MT, Yehuda DB, Beggiato E, Di Toritto TC, Boccadoro M, Nagler A, Palumbo A. Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide. Blood. 2012 Jan 26;119(4):933-9; quiz 1093. doi: 10.1182/blood-2011-03-344333. Epub 2011 Aug 11. PMID: 21835953.	wrong comparison
Lebeau B, Chastang C, Brechot JM, Capron F, Dautzenberg B, Delaisements C, Mornet M, Brun J, Hurdebourcq JP, Lemarie E. Subcutaneous heparin treatment increases survival in small cell lung cancer. "Petites Cellules" Group. Cancer. 1994 Jul 1;74(1):38-45. doi: 10.1002/1097-0142(19940701)74:1<38::aid-cncr2820740108>3.0.co;2-e. PMID: 8004580.	wrong intervention
Lecumberri R, López Vivanco G, Font A, González Billalabeitia E, Gúrpide A, Gómez Codina J, Isla D, Galán A, Bover I, Domine M, Vicente V, Rosell R, Rocha E. Adjuvant therapy with bemiparin in patients with limited-stage small cell lung cancer: results from the ABEL study. Thromb Res. 2013;132(6):666-70. doi: 10.1016/j.thromres.2013.09.026. Epub 2013 Sep 27. PMID: 24491267.	wrong intervention
Levine M, Hirsh J, Gent M, Arnold A, Warr D, Falanga A, Samosh M, Bramwell V, Pritchard KI, Stewart D, et al. Double-blind randomised trial of a very-low-dose warfarin for prevention of thromboembolism in stage IV breast cancer. Lancet. 1994 Apr 9;343(8902):886-9. doi: 10.1016/s0140-6736(94)90008-6. PMID: 7908358.	wrong intervention
Levine MN, Gu C, Liebman HA, Escalante CP, Solymoss S, Deitchman D, Ramirez L, Julian J. A randomized phase II trial of apixaban for the prevention of thromboembolism in patients with metastatic cancer. J Thromb Haemost. 2012 May;10(5):807-14. doi: 10.1111/j.1538-7836.2012.04693.x. PMID: 22409262.	wrong comparison, Phase II trial
Maraveyas A, Waters J, Roy R, Fyfe D, Propper D, Lofts F, Sgouros J, Gardiner E, Wedgwood K, Ettelaie C, Bozas G. Gemcitabine versus gemcitabine plus dalteparin thromboprophylaxis in pancreatic cancer. Eur J Cancer. 2012 Jun;48(9):1283-92. doi: 10.1016/j.ejca.2011.10.017. Epub 2011 Nov 17. PMID: 22100906.	phase II trial, wrong intervention
Maurer LH, Herndon JE 2nd, Hollis DR, Aisner J, Carey RW, Skarin AT, Perry MC, Eaton WL, Zacharski LL, Hammond S, Green MR. Randomized trial of chemotherapy and radiation therapy with or without warfarin for limited-stage small-cell lung cancer: a Cancer and Leukemia Group B study. J Clin Oncol. 1997 Nov;15(11):3378-87. doi: 10.1200/JCO.1997.15.11.3378. PMID: 9363869.	wrong intervention
Meyer G, Besse B, Doubre H, Charles-Nelson A, Aquilanti S, Izadifar A, Azarian R, Monnet I, Lamour C, Descourt R, Oliviero G, Taillade L, Chouaid C, Giraud F, Falcoz PE, Revel MP, Westeel V, Dixmier A, Tredaniel J, Dehette S, Decroisette C, Prevost A, Pichon E, Fabre E, Soria JC, Friard S, Stern JB, Jabot L, Dennewald G, Pavy G, Petitpretz P, Tourani JM, Alifano M, Chatellier G, Girard P. Anti-tumour effect of low molecular weight heparin in localised lung cancer: a phase III clinical trial. Eur Respir J. 2018 Oct 4;52(4):1801220. doi: 10.1183/13993003.01220-2018. PMID: 30262574.	wrong intervention
Mitchell L, Andrew M, Hanna K, Abshire T, Halton J, Wu J, Anderson R, Cherrick I, Desai S, Mahoney D, McCusker P, Chait P, Abdolell M, de Veber G, Mikulis D. Trend to efficacy and safety using antithrombin concentrate in prevention of thrombosis in children receiving l-asparaginase for acute lymphoblastic leukemia. Results of the PAARKA study. Thromb Haemost. 2003 Aug;90(2):235-44. doi: 10.1160/TH02-11-0283. PMID: 12888870.	wrong intervention, wrong population, Phase II trial
Palumbo A, Cavo M, Bringhen S, Zamagni E, Romano A, Patriarca F, Rossi D, Gentilini F, Crippa C, Galli M, Nozzoli C, Ria R, Marasca R, Montefusco V, Baldini L, Elice F, Callea V, Pulini S, Carella AM, Zambello R, Benevolo G, Magarotto V, Tacchetti P, Pescosta N, Cellini C, Polloni C, Evangelista A, Caravita T, Morabito F, Offidani M, Tosi P, Boccadoro M. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol. 2011 Mar 10;29(8):986-93. doi: 10.1200/JCO.2010.31.6844. Epub 2011 Jan 31. PMID: 21282540.	wrong comparison
Pelzer U, Opitz B, Deutschinoff G, Stauch M, Reitzig PC, Hahnfeld S, Müller L, Grunewald M, Stieler JM, Sinn M, Denecke T, Bischoff S, Oettle H, Dörken B, Riess H. Efficacy of Prophylactic Low-Molecular Weight Heparin for Ambulatory Patients With Advanced Pancreatic Cancer: Outcomes From the CONKO-004 Trial. J Clin Oncol. 2015 Jun 20;33(18):2028-34. doi: 10.1200/JCO.2014.55.1481. Epub 2015 May 18. PMID: 25987694.	wrong intervention
Zacharski LR, Henderson WG, Rickles FR, Forman WB, Cornell CJ Jr, Forcier RJ, Edwards R, Headley E, Kim SH, O'Donnell JR, O'Dell R, Tornyos K, Kwaan HC. Effect of warfarin on survival in small cell carcinoma of the lung. Veterans Administration Study No. 75. JAMA. 1981 Feb 27;245(8):831-5. PMID: 6257941.	wrong intervention
Zwicker JI, Liebman HA, Bauer KA, Caughey T, Campigotto F, Rosovsky R, Mantha S, Kessler CM, Eneman J, Raghavan V, Lenz HJ, Bullock A, Buchbinder E, Neuberg D, Furie B. Prediction and prevention of thromboembolic events with enoxaparin in cancer patients with elevated tissue factor-bearing microparticles: a randomized-controlled phase II trial (the Microtec study). Br J Haematol. 2013 Feb;160(4):530-7. doi: 10.1111/bjh.12163. Epub 2012 Dec 13. PMID: 23240761; PMCID: PMC3609903.	phase II trial, wrong intervention
Vadhan-Raj S, Zhou_X, Varadhachary_GR, Milind_J, Fogelman_D, ShroK_R, et al. Randomized controlled trial of dalteparin for primary thromboprophylaxis for venous thromboembolism (VTE) in patients with advanced pancreatic cancer (APC): risk factors predictive of VTE. 55th Annual Meeting of the American Society of Hematology; 2013 Dec 7-10; New Orleans, LA.	abstract

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
Tromboseprofylaxe volwassenen met maligniteit	geen financiële gevolgen	Hoewel uit de toetsing volgt dat de aanbevelingen breed toepasbaar zijn (>40.000 patiënten), volgt ook uit de toetsing dat het geen nieuwe manier van zorgverlening of andere organisatie van zorgverlening betreft, het geen toename in het aantal in te zetten voltijdsequivalenten aan zorgverleners betreft en het geen wijziging in het opleidingsniveau van zorgpersoneel betreft. Er worden daarom geen substantiële financiële gevolgen verwacht.

Zoekverantwoording

Algemene informatie

Richtlijn: Cluster antitrombotische beleid
Uitgangsvraag: UV3 Moeten poliklinische patiënten met kanker tijdens systemische kankerbehandeling farmacologische tromboseprofylaxe krijgen als primaire preventie voor veneuze tromboembolie?
Database(s): Ovid/Medline, Embase	Datum: 4-7-2023 en 14-9-2023
Periode: nvt	Talen: nvt
Literatuurspecialist: Ingeborg van Dusseldorp en Esther van der Bijl
BMI zoekblokken: voor verschillende opdrachten wordt (deels) gebruik gemaakt van de zoekblokken van BMI-Online https://blocks.bmi-online.nl/ Bij gebruikmaking van een volledig zoekblok zal naar de betreffende link op de website worden verwezen.
Toelichting: 14-9-2023 Na de selectie is geconstateerd dat niet alle relevante literatuur wordt gevonden. Naar aanleiding van gevonden evidence in 2020 wordt gevraagd om een update van de zoekstrategie, waarin de setting ambulante patiënten achterwege wordt gelaten en gezocht wordt vanaf 2020. Het resultaat wordt ontdubbeld t.o.v. het eerder gevonden resultaat op 4 juli. 4-7-2023 Voor deze vraag is gezocht met de volgende concepten: Systeemtherapie EN farmacologische tromboseprofylaxe EN ambulante patiënten Er is geen onderscheid gemaakt tussen volwassenen en kinderen. De drie sleutelartikelen worden gevonden.

Zoekopbrengst

Zoekopbrengst 12-10-2023	EMBASE vanaf 2023	OVID/MEDLINE vanaf 2020	Ontdubbeld t.o.v. Rayyan 14-9-2023
SRs	81	24	7
RCTs	61	37	1
Observationele studies
Totaal			819
*Zoekopbrengst 14-9-2023*	EMBASE	OVID/MEDLINE	Ontdubbeld t.o.v. Rayyan 4-7-2023
SRs	513	24	485
RCTs	338	35	326
Observationele studies
Totaal	851	59	811

4-7-2023

	EMBASE	OVID/MEDLINE	Ontdubbeld
SRs	67	21	62
RCTs	38	22	42
Observationele studies
Totaal	105	43	104

Zoekstrategie

Embase 14-9-2023

#16	#12 AND [2020-2023]py RCT	338
#15	#11 AND [2020-2023]py SR	513
#14	#4 AND #13 sleutelartikelen gevonden	3
#13	#11 OR #12	2215
#12	#8 AND #10 NOT #11	988
#11	#8 AND #9	1227
#10	'randomized controlled trial'/exp OR random:ti,ab OR (((pragmatic OR practical) NEAR/1 'clinical trial'):ti,ab) OR ((('non inferiority' OR noninferiority OR superiority OR equivalence) NEAR/3 trial*):ti,ab) OR rct:ti,ab,kw	2099619
#9	'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	961476
#8	#7 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)	15307
#7	#5 AND #6	20071
#6	'low molecular weight heparin'/exp OR 'dalteparin'/exp OR 'enoxaparin'/exp OR 'nadroparin'/exp OR 'tinzaparin'/exp OR 'fondaparinux'/exp OR 'apixaban'/exp OR 'dabigatran'/exp OR 'rivaroxaban'/exp OR 'bm 2123':ti,ab,kw OR 'bm2123':ti,ab,kw OR 'choay':ti,ab,kw OR 'depolymerized heparin':ti,ab,kw OR 'ebpm 1':ti,ab,kw OR 'ebpm 2':ti,ab,kw OR 'ebpm 3':ti,ab,kw OR 'ebpm1':ti,ab,kw OR 'ebpm2':ti,ab,kw OR 'ebpm3':ti,ab,kw OR 'ff 1034':ti,ab,kw OR 'ff1034':ti,ab,kw OR 'fr 860':ti,ab,kw OR 'low molecular heparin':ti,ab,kw OR 'low molecular weight heparin':ti,ab,kw OR 'nm heparin':ti,ab,kw OR 'pk 007':ti,ab,kw OR 'sandoz 5100':ti,ab,kw OR 'sandoz 6700':ti,ab,kw OR 'traxyparine':ti,ab,kw OR lmwh:ti,ab,kw OR 'assubex':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 OR 'bibr 953':ti,ab,kw OR 'bibr953':ti,ab,kw OR 'dabigatran':ti,ab,kw OR 'aboxoma':ti,ab,kw OR 'apixaban':ti,ab,kw OR 'apixaben':ti,ab,kw OR 'bms 562247':ti,ab,kw OR 'bms562247':ti,ab,kw OR 'bms562247 01':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 'arixtra':ti,ab,kw OR 'fondaparin':ti,ab,kw OR 'gsk 576428':ti,ab,kw OR 'gsk576428':ti,ab,kw OR 'ic 851589':ti,ab,kw OR 'ic851589':ti,ab,kw OR 'org 31540':ti,ab,kw OR 'org31540':ti,ab,kw OR 'quixidar':ti,ab,kw OR 'sr 90107':ti,ab,kw OR 'sr 90107a':ti,ab,kw OR 'sr90107':ti,ab,kw OR 'sr90107a':ti,ab,kw OR 'xantidar':ti,ab,kw OR 'innohep':ti,ab,kw OR 'lhn1':ti,ab,kw OR 'logiparin':ti,ab,kw OR 'tinzaparin':ti,ab,kw OR 'dalteparin':ti,ab,kw OR 'fragmin':ti,ab,kw OR 'fragmine':ti,ab,kw OR 'k 2165':ti,ab,kw OR 'k2165':ti,ab,kw OR 'kabi 2165':ti,ab,kw OR 'low liquemin':ti,ab,kw OR 'arovi':ti,ab,kw OR 'clexan':ti,ab,kw OR 'clexane':ti,ab,kw OR 'colevance':ti,ab,kw OR 'crusia':ti,ab,kw OR 'decipar':ti,ab,kw OR 'enoxaparin':ti,ab,kw OR 'ghemaxan':ti,ab,kw OR 'hepaxane':ti,ab,kw OR 'inhixa':ti,ab,kw OR 'klexane':ti,ab,kw OR 'ledraxen':ti,ab,kw OR 'losima':ti,ab,kw OR 'lovenox':ti,ab,kw OR 'neoparin':ti,ab,kw OR 'percolozin':ti,ab,kw OR 'pk 10169':ti,ab,kw OR 'pk10169':ti,ab,kw OR 'qualiop klinik':ti,ab,kw OR 'rovinadil':ti,ab,kw OR 'rp 54563':ti,ab,kw OR 'rp54563':ti,ab,kw OR 'thorinane':ti,ab,kw OR 'cy 216':ti,ab,kw OR 'cy 216d':ti,ab,kw OR 'cy216':ti,ab,kw OR 'cy216d':ti,ab,kw OR 'fraxiparin':ti,ab,kw OR 'fraxodi':ti,ab,kw OR 'nadroparin':ti,ab,kw OR 'seledie':ti,ab,kw OR 'seleparina':ti,ab,kw OR 'seleparine':ti,ab,kw OR 'tedegliparin':ti,ab,kw	118112
#5	'systemic therapy'/exp AND ('neoplasm'/exp OR neoplas:ti,ab,kw OR carcinom:ti,ab,kw OR cancer:ti,ab,kw OR malignan:ti,ab,kw OR tumor:ti,ab,kw OR tumour:ti,ab,kw OR metasta) OR 'cancer immunotherapy'/exp OR 'cancer hormone therapy'/exp OR 'molecularly targeted therapy'/exp OR 'multimodality cancer therapy'/exp OR 'chemotherapy'/exp OR 'antineoplastic agent'/exp OR 'checkpoint inhibitor therapy'/exp OR 'protein kinase inhibitor'/exp OR ((((hormon OR endocrin* OR 'combined modalit' OR multimodal OR 'multiple modalit' OR target OR immun* OR systemic* OR checkpoint OR 'check point') NEAR/3 (therap* OR treat)):ti,ab,kw) AND ('neoplasm'/exp OR neoplas:ti,ab,kw OR carcinom:ti,ab,kw OR cancer:ti,ab,kw OR malignan:ti,ab,kw OR tumor:ti,ab,kw OR tumour:ti,ab,kw OR metasta:ti,ab,kw)) OR 'biologic response modifier therapy':ti,ab,kw OR 'biological response modifier therapy':ti,ab,kw OR 'chemoradiotherapy'/exp OR 'chemoradi':ti,ab,kw OR 'radiochemo':ti,ab,kw OR chemotherap:ti,ab,kw OR ((antineoplastic NEAR/3 (drug OR agent)):ti,ab,kw) OR 'protein kinase inhibitor':ti,ab,kw	3982517
#4	#1 OR #2 OR #3 sleutelartikelen	3
#3	'primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy' AND [2020]/py AND rutjes	1
#2	'rivaroxaban for thromboprophylaxis in high-risk ambulatory patients with cancer' AND khorana	1
#1	'apixaban to prevent venous thromboembolism in patients with cancer'	1

Embase 4-7-2023

#15	#4 AND #14 sleutelartikelen gevonden	3
#14	#12 OR #13	105
#13	#9 AND #11 NOT #12 RCT	38
#12	#9 AND #10 SR	67
#11	'randomized controlled trial'/exp OR random:ti,ab OR (((pragmatic OR practical) NEAR/1 'clinical trial'):ti,ab) OR ((('non inferiority' OR noninferiority OR superiority OR equivalence) NEAR/3 trial*):ti,ab) OR rct:ti,ab,kw	2070573
#10	'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	940686
#9	#8 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)	217
#8	#5 AND #6 AND #7	437
#7	'outpatient department'/exp OR 'ambulatory care'/exp OR 'outpatient'/exp OR 'outpatient care'/exp OR ambulator:ti,ab,kw OR dispensar:ti,ab,kw OR extramural:ti,ab,kw OR oupatient:ti,ab,kw OR 'out patient':ti,ab,kw OR 'outward patient':ti,ab,kw OR policlinic:ti,ab,kw OR polyclinic:ti,ab,kw	462561
#6	'low molecular weight heparin'/exp OR 'dalteparin'/exp OR 'enoxaparin'/exp OR 'nadroparin'/exp OR 'tinzaparin'/exp OR 'fondaparinux'/exp OR 'apixaban'/exp OR 'dabigatran'/exp OR 'rivaroxaban'/exp OR 'bm 2123':ti,ab,kw OR 'bm2123':ti,ab,kw OR 'choay':ti,ab,kw OR 'depolymerized heparin':ti,ab,kw OR 'ebpm 1':ti,ab,kw OR 'ebpm 2':ti,ab,kw OR 'ebpm 3':ti,ab,kw OR 'ebpm1':ti,ab,kw OR 'ebpm2':ti,ab,kw OR 'ebpm3':ti,ab,kw OR 'ff 1034':ti,ab,kw OR 'ff1034':ti,ab,kw OR 'fr 860':ti,ab,kw OR 'low molecular heparin':ti,ab,kw OR 'low molecular weight heparin':ti,ab,kw OR 'nm heparin':ti,ab,kw OR 'pk 007':ti,ab,kw OR 'sandoz 5100':ti,ab,kw OR 'sandoz 6700':ti,ab,kw OR 'traxyparine':ti,ab,kw OR lmwh:ti,ab,kw OR 'assubex':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 OR 'bibr 953':ti,ab,kw OR 'bibr953':ti,ab,kw OR 'dabigatran':ti,ab,kw OR 'aboxoma':ti,ab,kw OR 'apixaban':ti,ab,kw OR 'apixaben':ti,ab,kw OR 'bms 562247':ti,ab,kw OR 'bms562247':ti,ab,kw OR 'bms562247 01':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 'arixtra':ti,ab,kw OR 'fondaparin':ti,ab,kw OR 'gsk 576428':ti,ab,kw OR 'gsk576428':ti,ab,kw OR 'ic 851589':ti,ab,kw OR 'ic851589':ti,ab,kw OR 'org 31540':ti,ab,kw OR 'org31540':ti,ab,kw OR 'quixidar':ti,ab,kw OR 'sr 90107':ti,ab,kw OR 'sr 90107a':ti,ab,kw OR 'sr90107':ti,ab,kw OR 'sr90107a':ti,ab,kw OR 'xantidar':ti,ab,kw OR 'innohep':ti,ab,kw OR 'lhn1':ti,ab,kw OR 'logiparin':ti,ab,kw OR 'tinzaparin':ti,ab,kw OR 'dalteparin':ti,ab,kw OR 'fragmin':ti,ab,kw OR 'fragmine':ti,ab,kw OR 'k 2165':ti,ab,kw OR 'k2165':ti,ab,kw OR 'kabi 2165':ti,ab,kw OR 'low liquemin':ti,ab,kw OR 'arovi':ti,ab,kw OR 'clexan':ti,ab,kw OR 'clexane':ti,ab,kw OR 'colevance':ti,ab,kw OR 'crusia':ti,ab,kw OR 'decipar':ti,ab,kw OR 'enoxaparin':ti,ab,kw OR 'ghemaxan':ti,ab,kw OR 'hepaxane':ti,ab,kw OR 'inhixa':ti,ab,kw OR 'klexane':ti,ab,kw OR 'ledraxen':ti,ab,kw OR 'losima':ti,ab,kw OR 'lovenox':ti,ab,kw OR 'neoparin':ti,ab,kw OR 'percolozin':ti,ab,kw OR 'pk 10169':ti,ab,kw OR 'pk10169':ti,ab,kw OR 'qualiop klinik':ti,ab,kw OR 'rovinadil':ti,ab,kw OR 'rp 54563':ti,ab,kw OR 'rp54563':ti,ab,kw OR 'thorinane':ti,ab,kw OR 'cy 216':ti,ab,kw OR 'cy 216d':ti,ab,kw OR 'cy216':ti,ab,kw OR 'cy216d':ti,ab,kw OR 'fraxiparin':ti,ab,kw OR 'fraxodi':ti,ab,kw OR 'nadroparin':ti,ab,kw OR 'seledie':ti,ab,kw OR 'seleparina':ti,ab,kw OR 'seleparine':ti,ab,kw OR 'tedegliparin':ti,ab,kw	116390
#5	'systemic therapy'/exp AND ('neoplasm'/exp OR neoplas:ti,ab,kw OR carcinom:ti,ab,kw OR cancer:ti,ab,kw OR malignan:ti,ab,kw OR tumor:ti,ab,kw OR tumour:ti,ab,kw OR metasta) OR 'cancer immunotherapy'/exp OR 'cancer hormone therapy'/exp OR 'molecularly targeted therapy'/exp OR 'multimodality cancer therapy'/exp OR 'chemotherapy'/exp OR 'antineoplastic agent'/exp OR 'checkpoint inhibitor therapy'/exp OR 'protein kinase inhibitor'/exp OR ((((hormon OR endocrin* OR 'combined modalit' OR multimodal OR 'multiple modalit' OR target OR immun* OR systemic* OR checkpoint OR 'check point') NEAR/3 (therap* OR treat)):ti,ab,kw) AND ('neoplasm'/exp OR neoplas:ti,ab,kw OR carcinom:ti,ab,kw OR cancer:ti,ab,kw OR malignan:ti,ab,kw OR tumor:ti,ab,kw OR tumour:ti,ab,kw OR metasta:ti,ab,kw)) OR 'biologic response modifier therapy':ti,ab,kw OR 'biological response modifier therapy':ti,ab,kw OR 'chemoradiotherapy'/exp OR 'chemoradi':ti,ab,kw OR 'radiochemo':ti,ab,kw OR chemotherap:ti,ab,kw OR ((antineoplastic NEAR/3 (drug OR agent)):ti,ab,kw) OR 'protein kinase inhibitor':ti,ab,kw	3912136
#4	#1 OR #2 OR #3 sleutelartikelen	3
#3	'primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy' AND [2020]/py AND rutjes	1
#2	'rivaroxaban for thromboprophylaxis in high-risk ambulatory patients with cancer' AND khorana	1
#1	'apixaban to prevent venous thromboembolism in patients with cancer'	1

Ovid/Medline 14-9-2023

#	Searches	Results
11	limit 8 to yr="2020 - 2024" RCT	35
10	limit 7 to yr="2020 - 2024" SR	24
9	7 or 8	264
8	4 and 6 (not 7)	180
7	4 and 5	84
6	exp randomized controlled trial/ or randomized controlled trials as topic/ or random.ti,ab. or rct?.ti,ab. or ((pragmatic or practical) adj "clinical trial").ti,ab,kf. or ((non-inferiority or noninferiority or superiority or equivalence) adj3 trial*).ti,ab,kf.	1644900
5	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.	693090
4	3 not ((exp animals/ or exp models, animal/) not humans/) not (letter/ or comment/ or editorial/)	1165
3	1 and 2	1335
2	exp Heparin, Low-Molecular-Weight/ or Dalteparin/ or Enoxaparin/ or Nadroparin/ or Tinzaparin/ or Dabigatran/ or Rivaroxaban/ or bm 2123.ti,ab,kf. or bm2123.ti,ab,kf. or choay.ti,ab,kf. or depolymerized heparin.ti,ab,kf. or ebpm 1.ti,ab,kf. or ebpm 2.ti,ab,kf. or ebpm 3.ti,ab,kf. or ebpm1.ti,ab,kf. or ebpm2.ti,ab,kf. or ebpm3.ti,ab,kf. or ff 1034.ti,ab,kf. or ff1034.ti,ab,kf. or fr 860.ti,ab,kf. or low molecular heparin.ti,ab,kf. or low molecular weight heparin.ti,ab,kf. or nm heparin.ti,ab,kf. or "pk 007".ti,ab,kf. or sandoz 5100.ti,ab,kf. or sandoz 6700.ti,ab,kf. or traxyparine.ti,ab,kf. or lmwh.ti,ab,kf. or assubex.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. or bibr 953.ti,ab,kf. or bibr953.ti,ab,kf. or dabigatran.ti,ab,kf. or aboxoma.ti,ab,kf. or apixaban.ti,ab,kf. or apixaben.ti,ab,kf. or bms 562247.ti,ab,kf. or bms562247.ti,ab,kf. or "bms562247 01".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 arixtra.ti,ab,kf. or fondaparin.ti,ab,kf. or gsk 576428.ti,ab,kf. or gsk576428.ti,ab,kf. or ic 851589.ti,ab,kf. or ic851589.ti,ab,kf. or org 31540.ti,ab,kf. or org31540.ti,ab,kf. or quixidar.ti,ab,kf. or sr 90107.ti,ab,kf. or sr 90107a.ti,ab,kf. or sr90107.ti,ab,kf. or sr90107a.ti,ab,kf. or xantidar.ti,ab,kf. or innohep.ti,ab,kf. or lhn1.ti,ab,kf. or logiparin.ti,ab,kf. or tinzaparin.ti,ab,kf. or dalteparin.ti,ab,kf. or fragmin.ti,ab,kf. or fragmine.ti,ab,kf. or k 2165.ti,ab,kf. or k2165.ti,ab,kf. or kabi 2165.ti,ab,kf. or low liquemin.ti,ab,kf. or arovi.ti,ab,kf. or clexan.ti,ab,kf. or clexane.ti,ab,kf. or colevance.ti,ab,kf. or crusia.ti,ab,kf. or decipar.ti,ab,kf. or enoxaparin.ti,ab,kf. or ghemaxan.ti,ab,kf. or hepaxane.ti,ab,kf. or inhixa.ti,ab,kf. or klexane.ti,ab,kf. or ledraxen.ti,ab,kf. or losima.ti,ab,kf. or lovenox.ti,ab,kf. or neoparin.ti,ab,kf. or percolozin.ti,ab,kf. or pk 10169.ti,ab,kf. or pk10169.ti,ab,kf. or qualiop klinik.ti,ab,kf. or rovinadil.ti,ab,kf. or rp 54563.ti,ab,kf. or rp54563.ti,ab,kf. or thorinane.ti,ab,kf. or cy 216.ti,ab,kf. or cy 216d.ti,ab,kf. or cy216.ti,ab,kf. or cy216d.ti,ab,kf. or fraxiparin.ti,ab,kf. or fraxodi.ti,ab,kf. or nadroparin.ti,ab,kf. or seledie.ti,ab,kf. or seleparina.ti,ab,kf. or seleparine.ti,ab,kf. or tedegliparin.ti,ab,kf.	34414
1	Chemoradiotherapy/ or Chemotherapy, Adjuvant/ or Consolidation Chemotherapy/ or Electrochemotherapy/ or Induction Chemotherapy/ or Maintenance Chemotherapy/ or Molecular Targeted Therapy/ or Orthomolecular Therapy/ or Photochemotherapy/ or (Immunotherapy/ and (exp Neoplasms/ or (neoplas* or carcinom* or cancer* or malignan* or tumor* or tumour* or metasta).ti,ab,kf.)) or exp Antineoplastic Agents/ or Immune Checkpoint Inhibitors/ or Protein Kinase Inhibitors/ or (((hormon or endocrin* or combined modalit* or multimodal* or multiple modalit* or target* or immun* or systemic* or checkpoint or "check point") adj3 (therap* or treat)).ti,ab,kf. and (exp Neoplasms/ or neoplas.ti,ab,kf. or carcinom.ti,ab,kf. or cancer.ti,ab,kf. or malignan.ti,ab,kf. or tumor.ti,ab,kf. or tumour.ti,ab,kf. or metasta.ti,ab,kf.)) or biologic response modifier therapy.ti,ab,kf. or biological response modifier therapy.ti,ab,kf. or chemoradi.ti,ab,kf. or radiochemo.ti,ab,kf. or chemotherap.ti,ab,kf. or (antineoplastic adj3 (drug or agent)).ti,ab,kf. or protein kinase inhibitor.ti,ab,kf.	1871870

Ovid/Medline 144-7-2023

#	Searches	Results
11	9 or 10	43
10	6 and 8 not 9 RCT	22
9	6 and 7 SR	21
8	exp randomized controlled trial/ or randomized controlled trials as topic/ or random.ti,ab. or rct?.ti,ab. or ((pragmatic or practical) adj "clinical trial").ti,ab,kf. or ((non-inferiority or noninferiority or superiority or equivalence) adj3 trial*).ti,ab,kf.	1625962
7	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.	678494
6	5 not ((exp animals/ or exp models, animal/) not humans/) not (letter/ or comment/ or editorial/)	75
5	3 and 4	81
4	Ambulatory Care/ or exp Outpatient Clinics, Hospital/ or Ambulatory Care Facilities/ or ambulator.ti,ab,kf. or dispensar.ti,ab,kf. or extramural.ti,ab,kf. or oupatient.ti,ab,kf. or out patient.ti,ab,kf. or outward patient.ti,ab,kf. or policlinic.ti,ab,kf. or polyclinic.ti,ab,kf.	179576
3	1 and 2	1327
2	exp Heparin, Low-Molecular-Weight/ or Dalteparin/ or Enoxaparin/ or Nadroparin/ or Tinzaparin/ or Dabigatran/ or Rivaroxaban/ or bm 2123.ti,ab,kf. or bm2123.ti,ab,kf. or choay.ti,ab,kf. or depolymerized heparin.ti,ab,kf. or ebpm 1.ti,ab,kf. or ebpm 2.ti,ab,kf. or ebpm 3.ti,ab,kf. or ebpm1.ti,ab,kf. or ebpm2.ti,ab,kf. or ebpm3.ti,ab,kf. or ff 1034.ti,ab,kf. or ff1034.ti,ab,kf. or fr 860.ti,ab,kf. or low molecular heparin.ti,ab,kf. or low molecular weight heparin.ti,ab,kf. or nm heparin.ti,ab,kf. or "pk 007".ti,ab,kf. or sandoz 5100.ti,ab,kf. or sandoz 6700.ti,ab,kf. or traxyparine.ti,ab,kf. or lmwh.ti,ab,kf. or assubex.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. or bibr 953.ti,ab,kf. or bibr953.ti,ab,kf. or dabigatran.ti,ab,kf. or aboxoma.ti,ab,kf. or apixaban.ti,ab,kf. or apixaben.ti,ab,kf. or bms 562247.ti,ab,kf. or bms562247.ti,ab,kf. or "bms562247 01".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 arixtra.ti,ab,kf. or fondaparin.ti,ab,kf. or gsk 576428.ti,ab,kf. or gsk576428.ti,ab,kf. or ic 851589.ti,ab,kf. or ic851589.ti,ab,kf. or org 31540.ti,ab,kf. or org31540.ti,ab,kf. or quixidar.ti,ab,kf. or sr 90107.ti,ab,kf. or sr 90107a.ti,ab,kf. or sr90107.ti,ab,kf. or sr90107a.ti,ab,kf. or xantidar.ti,ab,kf. or innohep.ti,ab,kf. or lhn1.ti,ab,kf. or logiparin.ti,ab,kf. or tinzaparin.ti,ab,kf. or dalteparin.ti,ab,kf. or fragmin.ti,ab,kf. or fragmine.ti,ab,kf. or k 2165.ti,ab,kf. or k2165.ti,ab,kf. or kabi 2165.ti,ab,kf. or low liquemin.ti,ab,kf. or arovi.ti,ab,kf. or clexan.ti,ab,kf. or clexane.ti,ab,kf. or colevance.ti,ab,kf. or crusia.ti,ab,kf. or decipar.ti,ab,kf. or enoxaparin.ti,ab,kf. or ghemaxan.ti,ab,kf. or hepaxane.ti,ab,kf. or inhixa.ti,ab,kf. or klexane.ti,ab,kf. or ledraxen.ti,ab,kf. or losima.ti,ab,kf. or lovenox.ti,ab,kf. or neoparin.ti,ab,kf. or percolozin.ti,ab,kf. or pk 10169.ti,ab,kf. or pk10169.ti,ab,kf. or qualiop klinik.ti,ab,kf. or rovinadil.ti,ab,kf. or rp 54563.ti,ab,kf. or rp54563.ti,ab,kf. or thorinane.ti,ab,kf. or cy 216.ti,ab,kf. or cy 216d.ti,ab,kf. or cy216.ti,ab,kf. or cy216d.ti,ab,kf. or fraxiparin.ti,ab,kf. or fraxodi.ti,ab,kf. or nadroparin.ti,ab,kf. or seledie.ti,ab,kf. or seleparina.ti,ab,kf. or seleparine.ti,ab,kf. or tedegliparin.ti,ab,kf.	34104
1	Chemoradiotherapy/ or Chemotherapy, Adjuvant/ or Consolidation Chemotherapy/ or Electrochemotherapy/ or Induction Chemotherapy/ or Maintenance Chemotherapy/ or Molecular Targeted Therapy/ or Orthomolecular Therapy/ or Photochemotherapy/ or (Immunotherapy/ and (exp Neoplasms/ or (neoplas* or carcinom* or cancer* or malignan* or tumor* or tumour* or metasta).ti,ab,kf.)) or exp Antineoplastic Agents/ or Immune Checkpoint Inhibitors/ or Protein Kinase Inhibitors/ or (((hormon or endocrin* or combined modalit* or multimodal* or multiple modalit* or target* or immun* or systemic* or checkpoint or "check point") adj3 (therap* or treat)).ti,ab,kf. and (exp Neoplasms/ or neoplas.ti,ab,kf. or carcinom.ti,ab,kf. or cancer.ti,ab,kf. or malignan.ti,ab,kf. or tumor.ti,ab,kf. or tumour.ti,ab,kf. or metasta.ti,ab,kf.)) or biologic response modifier therapy.ti,ab,kf. or biological response modifier therapy.ti,ab,kf. or chemoradi.ti,ab,kf. or radiochemo.ti,ab,kf. or chemotherap.ti,ab,kf. or (antineoplastic adj3 (drug or agent)).ti,ab,kf. or protein kinase inhibitor.ti,ab,kf.	1856533

Richtlijnendatabase

Antitrombotisch beleid

Antitrombotisch beleid

Tromboseprofylaxe volwassenen met maligniteit

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