Cancer-associated venous thromboembolism (VTE) is associated with high VTE recurrence and bleeding. We included all randomized clinical trials that evaluated the efficacy and safety of various anticoagulants in cancer-associated VTE. Trial-level data were extracted from 13 trials. Aggregate odds ratios (ORs) were calculated using direct and network meta-analysis. The primary outcome was VTE (pulmonary embolism and/or deep vein thrombosis) recurrence. Secondary outcomes were major bleeding and all-cause mortality. We identified 13 trials with 4869 patient-years of follow-up (6595 total patients; mean age 62.4 ± 12.2; 50.4 % female; 17.7 % hematological malignancies). The most common cancer type was colorectal and 48 % had metastatic cancer at baseline. Compared to vitamin-K-antagonists (VKAs), non-vitamin-K-antagonist-oral-anticoagulants (NOACs) were associated with significantly reduced VTE recurrence (OR, 0.58; 95 % CI, 0.40-0.83) and reduced major bleeding risks (OR, 0.56; 95 % CI, 0.35-0.91). However, no differences were observed in the subgroup analysis of patients with active cancer. Although NOACs were associated with reduced VTE recurrence compared with low-molecular-weight-heparin (LMWHs) (OR, 0.46; 95 % CI, 0.25- 0.85), there was a significant increased major bleeding in high-quality trials. LMWHs were associated with significantly reduced VTE recurrence compared with VKAs (OR, 0.52; 95 % CI, 0.39-0.71) and similar bleeding risks. Conclusions: Among patients with cancer-associated VTE, NOACs were associated with significantly reduced VTE recurrence and bleeding compared with VKAs, however, with similar outcomes in the active cancer population. NOACs were associated with reduced VTE recurrence but higher bleeding risks compared with LMWHs. LMWHs were associated with significantly reduced VTE recurrence and similar bleeding compared with VKAs.
PURPOSE: To provide updated recommendations about prophylaxis and treatment of venous thromboembolism (VTE) in patients with cancer.
METHODS: PubMed and the Cochrane Library were searched for randomized controlled trials (RCTs) and meta-analyses of RCTs published from August 1, 2014, through December 4, 2018. ASCO convened an Expert Panel to review the evidence and revise previous recommendations as needed.
RESULTS: The systematic review included 35 publications on VTE prophylaxis and treatment and 18 publications on VTE risk assessment. Two RCTs of direct oral anticoagulants (DOACs) for the treatment of VTE in patients with cancer reported that edoxaban and rivaroxaban are effective but are linked with a higher risk of bleeding compared with low-molecular-weight heparin (LMWH) in patients with GI and potentially genitourinary cancers. Two additional RCTs reported on DOACs for thromboprophylaxis in ambulatory patients with cancer at increased risk of VTE.
RECOMMENDATIONS: Changes to previous recommendations: Clinicians may offer thromboprophylaxis with apixaban, rivaroxaban, or LMWH to selected high-risk outpatients with cancer; rivaroxaban and edoxaban have been added as options for VTE treatment; patients with brain metastases are now addressed in the VTE treatment section; and the recommendation regarding long-term postoperative LMWH has been expanded. Re-affirmed recommendations: Most hospitalized patients with cancer and an acute medical condition require thromboprophylaxis throughout hospitalization. Thromboprophylaxis is not routinely recommended for all outpatients with cancer. Patients undergoing major cancer surgery should receive prophylaxis starting before surgery and continuing for at least 7 to 10 days. Patients with cancer should be periodically assessed for VTE risk, and oncology professionals should provide patient education about the signs and symptoms of VTE.Additional information is available at www.asco.org/supportive-care-guidelines.
Efficacy and safety of direct oral anticoagulants (DOACs) for preventing primary and recurrent venous thromboembolism (VTE) in patients with cancer remain unclear. In this study, we conducted a systematic review to summarize the most up-to-date evidence from randomized controlled trials (RCTs). Our primary outcomes included the benefit outcome (VTE) and safety outcome (major bleeding). A random-effects model was used to pool the relative risks (RRs) for data syntheses. The Grading of Recommendations Assessment, Development and Evaluation tool was used to evaluate the quality of the entire body of evidence across studies. We included 11 RCTs with a total of 3741 patients with cancer for analyses. The DOACs were significantly related with a reduced risk of VTE when compared with non-DOACs: RR = 0.77, 95% confidence interval [CI]: 0.61-0.99, P = .04. Nonsignificant trend towards a higher risk of major bleeding was found in DOACs: RR = 1.28 95% CI: 0.81-2.02, P = .29. The quality of the entire body of evidence was graded as moderate for risk of VTE, and low for risk of major bleeding. To summarize, DOACs were found to have a favorable effect on risk of VTE but a nonsignificant higher risk of major bleeding compared with non-DOACs in patients with cancer. The safety effect of DOACs in patients with cancer requires further evaluation in adequately powered and designed studies.
BACKGROUND: Cancer increases the risk of thromboembolic events, especially in people receiving anticoagulation treatments.
OBJECTIVES: To compare the efficacy and safety of low molecular weight heparins (LMWHs), direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) for the long-term treatment of venous thromboembolism (VTE) in people with cancer.
SEARCH METHODS: We conducted a literature search including a major electronic search of the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 1), MEDLINE (Ovid), and Embase (Ovid); handsearching conference proceedings; checking references of included studies; use of the 'related citation' feature in PubMed and a search for ongoing studies in trial registries. As part of the living systematic review approach, we run searches continually, incorporating new evidence after it is identified. Last search date 14 May 2018.
SELECTION CRITERIA: Randomized controlled trials (RCTs) assessing the benefits and harms of long-term treatment with LMWHs, DOACs or VKAs in people with cancer and symptomatic VTE.
DATA COLLECTION AND ANALYSIS: We extracted data in duplicate on study characteristics and risk of bias. Outcomes included: all-cause mortality, recurrent VTE, major bleeding, minor bleeding, thrombocytopenia, and health-related quality of life (QoL). We assessed the certainty of the evidence at the outcome level following the GRADE approach (GRADE handbook).
MAIN RESULTS: Of 15,785 citations, including 7602 unique citations, 16 RCTs fulfilled the eligibility criteria. These trials enrolled 5167 people with cancer and VTE.Low molecular weight heparins versus vitamin K antagonistsEight studies enrolling 2327 participants compared LMWHs with VKAs. Meta-analysis of five studies probably did not rule out a beneficial or harmful effect of LMWHs compared to VKAs on mortality up to 12 months of follow-up (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.88 to 1.13; risk difference (RD) 0 fewer per 1000, 95% CI 45 fewer to 48 more; moderate-certainty evidence). Meta-analysis of four studies did not rule out a beneficial or harmful effect of LMWHs compared to VKAs on major bleeding (RR 1.09, 95% CI 0.55 to 2.12; RD 4 more per 1000, 95% CI 19 fewer to 48 more, moderate-certainty evidence) or minor bleeding (RR 0.78, 95% CI 0.47 to 1.27; RD 38 fewer per 1000, 95% CI 92 fewer to 47 more; low-certainty evidence), or thrombocytopenia (RR 0.94, 95% CI 0.52 to 1.69). Meta-analysis of five studies showed that LMWHs probably reduced the recurrence of VTE compared to VKAs (RR 0.58, 95% CI 0.43 to 0.77; RD 53 fewer per 1000, 95% CI 29 fewer to 72 fewer, moderate-certainty evidence).Direct oral anticoagulants versus vitamin K antagonistsFive studies enrolling 982 participants compared DOACs with VKAs. Meta-analysis of four studies may not rule out a beneficial or harmful effect of DOACs compared to VKAs on mortality (RR 0.93, 95% CI 0.71 to 1.21; RD 12 fewer per 1000, 95% CI 51 fewer to 37 more; low-certainty evidence), recurrent VTE (RR 0.66, 95% CI 0.33 to 1.31; RD 14 fewer per 1000, 95% CI 27 fewer to 12 more; low-certainty evidence), major bleeding (RR 0.77, 95% CI 0.38 to 1.57, RD 8 fewer per 1000, 95% CI 22 fewer to 20 more; low-certainty evidence), or minor bleeding (RR 0.84, 95% CI 0.58 to 1.22; RD 21 fewer per 1000, 95% CI 54 fewer to 28 more; low-certainty evidence). One study reporting on DOAC versus VKA was published as abstract so is not included in the main analysis.Direct oral anticoagulants versus low molecular weight heparinsTwo studies enrolling 1455 participants compared DOAC with LMWH. The study by Raskob did not rule out a beneficial or harmful effect of DOACs compared to LMWH on mortality up to 12 months of follow-up (RR 1.07, 95% CI 0.92 to 1.25; RD 27 more per 1000, 95% CI 30 fewer to 95 more; low-certainty evidence). The data also showed that DOACs may have shown a likely reduction in VTE recurrence up to 12 months of follow-up compared to LMWH (RR 0.69, 95% CI 0.47 to 1.01; RD 36 fewer per 1000, 95% CI 62 fewer to 1 more; low-certainty evidence). DOAC may have increased major bleeding at 12 months of follow-up compared to LMWH (RR 1.71, 95% CI 1.01 to 2.88; RD 29 more per 1000, 95% CI 0 fewer to 78 more; low-certainty evidence) and likely increased minor bleeding up to 12 months of follow-up compared to LMWH (RR 1.31, 95% CI 0.95 to 1.80; RD 35 more per 1000, 95% CI 6 fewer to 92 more; low-certainty evidence). The second study on DOAC versus LMWH was published as an abstract and is not included in the main analysis.Idraparinux versus vitamin K antagonistsOne RCT with 284 participants compared once-weekly subcutaneous injection of idraparinux versus standard treatment (parenteral anticoagulation followed by warfarin or acenocoumarol) for three or six months. The data probably did not rule out a beneficial or harmful effect of idraparinux compared to VKAs on mortality at six months (RR 1.11, 95% CI 0.78 to 1.59; RD 31 more per 1000, 95% CI 62 fewer to 167 more; moderate-certainty evidence), VTE recurrence at six months (RR 0.46, 95% CI 0.16 to 1.32; RD 42 fewer per 1000, 95% CI 65 fewer to 25 more; low-certainty evidence) or major bleeding (RR 1.11, 95% CI 0.35 to 3.56; RD 4 more per 1000, 95% CI 25 fewer to 98 more; low-certainty evidence).
AUTHORS' CONCLUSIONS: For the long-term treatment of VTE in people with cancer, evidence shows that LMWHs compared to VKAs probably produces an important reduction in VTE and DOACs compared to LMWH, may likely reduce VTE but may increase risk of major bleeding. Decisions for a person with cancer and VTE to start long-term LMWHs versus oral anticoagulation should balance benefits and harms and integrate the person's values and preferences for the important outcomes and alternative management strategies.Editorial note: this is a living systematic review (LSR). LSRs offer new approaches to review updating in which the review is continually updated, incorporating relevant new evidence as it becomes available. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.
Venous thromboembolism (VTE) is highly prevalent in patients with cancer. Non-vitamin K antagonist oral anticoagulants (NOACs), directly targeting the enzymatic activity of thrombin or factor Xa, have been shown to be as effective as and safer than traditional anticoagulation for VTE prophylaxis in no-cancer patients. However, related studies that focused on the anticoagulation in cancer patients are lacked, and almost no net clinical benefit (NCB) analyses that quantified both VTE events and bleeding events have been addressed in this fragile population. Therefore, we aim to investigate this issue using a systematic review and NCB analysis. A comprehensive search of Medline, Embase, and Cochrane Library were performed for randomized controlled trials (RCTs) that reported the VTE events and major bleeding of NOACs and traditional anticoagulants in patients with or without cancer. Odds ratios (ORs) and 95% confidence intervals (CIs) of VTE and bleeding events were calculated using a random-effects model. The primacy outcome of narrow NCB was calculated by pooling ORs of VTE and major bleeding, with a weighting of 1.0. Similarly, the broad NCB was calculated by pooling ORs of VTE and clinically relevant bleeding. Heterogeneity was assessed through I2 test and Q statistic, and subgroup analyses were performed on the basis of different patients (VTE patients or acutely ill patients), comparators (vitamin-K antagonists or low-molecular-weight heparin), and follow-up duration (≤6 months or >6 months). Overall, 9 RCTs including 41,454 patients were enrolled, of which 2,902 (7%) were cancer patients, and 38,552 (93%) were no-cancer patients; 20,712 (50%) were administrated with NOACs and 20,742 (50%) were administrated with traditional anticoagulants. The use of NOACs had a superior NCB than traditional anticoagulation in both cancer patients (OR: 0.68, 95%CI: 0.50-0.85 for narrow NCB; OR: 0.76, 95%CI: 0.61-0.91 for broad NCB) and no-cancer patients (OR: 0.75, 95%CI: 0.54-0.96 for narrow NCB; OR: 0.85, 95%CI: 0.67-1.04 for broad NCB), with the estimates mainly from VTE patients receiving long-term warfarin treatment. In conclusion, NOACs may represent a better NCB property compared to traditional anticoagulants in cancer patients who need long-term anticoagulation treatment.
OBJECTIVE: To review the published literature for evidence of the efficacy and safety of direct oral anticoagulants (DOACs) when used in the management of atypical thrombosis-related conditions.
DATA SOURCES: A comprehensive MEDLINE database search (1948 to July 2017) and EMBASE search (1980 to July 2017) were conducted using the search terms direct oral anticoagulant in combination with acute coronary syndrome (ACS), antiphospholipid antibody syndrome (APLAS), and cancer-associated thrombosis (CAT).
STUDY SELECTION AND DATA EXTRACTION: The literature search was limited to studies that were conducted in humans and published in English. Clinical trials, observational studies, and case series were selected.
DATA SYNTHESIS: A total of 20 published studies were selected from the literature. Only 1 randomized controlled study showed a significant reduction in cardiovascular outcomes on DOAC use in ACS patients but at the expense of increased bleeding. For the use of DOACs in APLAS, the evidence from case series seems to suggest low incidence of thromboembolic events or recurrent thrombosis in low-risk patients. Finally, in cancer patients, DOACs were comparable to warfarin in preventing CAT in 8 studies of different designs. Major bleeding with DOACs was not significantly lower than in patients who received an enoxaparin/warfarin regimen.
CONCLUSIONS: Until more evidence from the ongoing clinical trials is available, DOACs may not be favorable add-on therapy in ACS patients receiving standard antiplatelet therapy but may be alternative to warfarin in preventing or treating thrombosis in low-risk APLAS patients as well as in cases of CAT in which patients have to be managed with warfarin.
CONTEXTE: Les personnes développant des thromboembolies veineuses (TEV) sont généralement traitées pendant cinq jours par héparine non fractionnée intraveineuse ou par héparine de bas poids moléculaire (HBPM) par voie sous-cutanée, puis au moyen d'antagonistes de la vitamine K (AVK) pendant trois mois. Le traitement aux AVK nécessite des examens de laboratoire réguliers et comporte un risque de saignement ; certaines personnes présentent des contre-indications pour ce type de traitement. Le traitement par HBPM a été proposé comme option pour minimiser le risque de complications hémorragiques. Cet article est la deuxième mise à jour d'une revue publiée pour la première fois en 2001.
OBJECTIFS: L'objectif de cette revue était d'évaluer l'efficacité et l'innocuité du traitement à long terme (trois mois) au moyen d'HBPM par rapport à un traitement à long terme (trois mois) avec des AVK pour les TEV symptomatiques.
STRATÉGIE DE RECHERCHE DOCUMENTAIRE: Pour cette mise à jour, le spécialiste Cochrane de l'information dans le domaine vasculaire a réalisé des recherches dans son registre spécialisé (dernière recherche en novembre 2016) et dans le registre Cochrane des essais contrôlés (CENTRAL, 2016, numéro 10), le spécialiste Cochrane de l'information dans le domaine vasculaire a également réalisé des recherches dans des registres d'essais cliniques pour identifier des études en cours.
CRITÈRES DE SÉLECTION: Les essais contrôlés randomisés comparant l'HBPM par rapport aux AVK pour le traitement à long-terme (trois mois) des TEV symptomatiques. Deux auteurs de la revue ont indépendamment évalué les essais à inclure ainsi que leur qualité méthodologique.
RECUEIL ET ANALYSE DES DONNÉES: Les auteurs de la revue ont indépendamment extrait les données et évalué le risque de biais. Nous avons résolu les désaccords par la discussion et effectué une méta-analyse en utilisant des modèles à effets fixes avec des rapports de cotes de Peto (RC de Peto) et des intervalles de confiance à 95 % (IC). Les critères de jugement d'intérêt étaient les récurrences des TEV, les hémorragies majeures, et la mortalité. Nous avons utilisé l'approche GRADE pour évaluer la qualité globale des preuves étayant ces critères de jugement.
RÉSULTATS PRINCIPAUX: Seize essais, avec un total combiné de 3299 participants ont rempli nos critères d'inclusion. Conformément à l'approche GRADE, la qualité des preuves était modérée pour les récurrences des TEV, faible pour les hémorragies majeures, et modérée pour la mortalité. Nous avons rabaissé la qualité des preuves en raison des imprécisions (récurrences des TEV, mortalité) et du risque de biais et du manque de cohérence (hémorragies majeures).Nous n'avons trouvé aucune différence claire au niveau des récurrences des TEV entre l'HBPM et les AVK (RC de Peto 0,83, intervalle de confiance à 95 % (IC) 0,60 à 1,15 ; P = 0,27 ; 3299 participants ; 16 études ; preuves de qualité modérée). Nous avons trouvé moins de saignements avec l'HBPM par rapport aux AVK (RC de Peto 0,51, IC à 95 % 0,32 à 0,80 ; P = 0,004 ; 3299 participants ; 16 études ; preuves de faible qualité). Toutefois, dans la comparaison portant seulement sur les études de haute qualité, nous n'avons observé aucune différence claire au niveau des saignements entre l'HBPM et les AVK (RC de Peto 0,62, IC à 95 % 0,36 à 1,07 ; P = 0,08 ; 1872 participants ; sept études). Nous n'avons identifié aucune différence notable entre l'HBPM et les AVK en termes de mortalité (RC de Peto 1,08, IC à 95 % 0,75 à 1,56 ; P = 0,68 ; 3299 participants ; 16 études ; preuves de qualité modérée).
CONCLUSIONS DES AUTEURS: Des données de qualité modérée ne montrent aucune différence claire entre l'HBPM et les AVK dans la prévention des TEV symptomatiques et des décès après un épisode de TVP symptomatique. Des preuves de faible qualité suggèrent moins de cas d'hémorragies majeures avec l'HBPM par rapport aux AVK. Cependant, dans la comparaison portant seulement sur les études de haute qualité il n'y avait aucune différence claire entre l'HBPM et les AVK au niveau des saignements. Les HBPM peuvent faire office d'alternative pour certaines personnes, par exemple, celles résidant dans des zones géographiquement inaccessibles, celles qui ne sont pas en mesure de se rendre régulièrement dans des services ou ne souhaitent pas le faire, et celles ayant des contre-indications à la prise d'un AVK.
NOTES DE TRADUCTION: Traduction réalisée par Martin Vuillème et révisée par Cochrane France
INTRODUCTION: Low-molecular-weight heparin (LMWH) and vitamin K antagonists (VKA) are current treatment options for cancer patients suffering from acute venous thromboembolism (VTE). The role of direct-acting oral anticoagulants (DOACs) for the treatment of VTE in cancer patients, particular in comparison with the current standard of care which is LMWH, remains unclear. In this network meta-analysis, we compared the relative efficacy and safety of LMWH, VKA, and DOAC for the treatment of cancer-associated VTE.
METHODS: A pre-specified search protocol identified 10 randomized controlled trials including 3242 cancer patients. Relative risks (RR) of recurrent VTE (efficacy) and major bleeding (safety) were analyzed using a random-effects meta-regression model.
RESULTS: LMWH emerged as significantly superior to VKA with respect to risk reduction of recurrent VTE (RR=0.60, 95%CI:0.45-0.79, p<0.001), and its safety was comparable to VKA (RR=1.08, 95%CI:0.70-1.66, p=0.74). For the DOAC vs. VKA efficacy and safety comparison, the relative risk estimates were in favor of DOAC, but had confidence intervals that still included equivalence (RR for recurrent VTE=0.65, 95%CI:0.38-1.09, p=0.10; RR for major bleeding=0.72, 95%CI:0.39-1.37, p=0.32). In the indirect network comparison between DOAC and LMWH, the results indicated comparable efficacy (RR=1.08, 95%CI:0.59-1.95, p=0.81), and a non-significant relative risk towards improved safety with DOAC (RR=0.67, 95%CI:0.31-1.46, p=0.31). The results prevailed after adjusting for different risk of recurrent VTE and major bleeding between LMWH vs. VKA and DOAC vs. VKA studies.
CONCLUSION: The efficacy and safety of LMWH and DOACs for the treatment of VTE in cancer patients may be comparable.
FUNDING: Austrian Science Fund (FWF-SFB-54).
IMPORTANCE: De nombreuses stratégies anticoagulantes sont disponibles pour le traitement de la thromboembolie veineuse aiguë, mais peu d'indications existe au sujet de laquelle le médicament est le plus efficace et sécuritaire.
OBJECTIF: Pour résumer et de comparer les résultats d'efficacité et de sécurité associés aux options 8 anticoagulation (héparine non fractionnée [HNF], à faible poids moléculaire héparine [HBPM], ou fondaparinux en combinaison avec des antagonistes de la vitamine K); HBPM avec dabigatran ou edoxaban; rivaroxaban; apixaban; et HBPM seule) pour le traitement de la thromboembolie veineuse.
SOURCES DE DONNÉES: Une recherche systématique de la littérature a été réalisée en utilisant MEDLINE, EMBASE, et les examens de médecine fondée sur des données probantes de création au 28 Février 2014.
SÉLECTION DES ÉTUDES: Les études admissibles ont été randomisés essais faisant état de taux de thromboembolie veineuse récurrente et saignements majeurs chez les patients atteints de thromboembolie veineuse aiguë. Parmi les 1197 études identifiées, 45 essais dont 44,989 patients ont été inclus dans les analyses.
EXTRACTION DE DONNÉES ET SYNTHÈSE: Deux auteurs ont extrait indépendamment les données au niveau du procès, y compris nombre de patients, la durée du suivi, et les résultats. Les données ont été rassemblées en utilisant le réseau méta-analyse.
LES RÉSULTATS ET MESURES PRINCIPALES: Les résultats cliniques et de sécurité primaires étaient la thromboembolie veineuse récurrente et saignement majeur, respectivement.
RÉSULTATS: Par rapport à la combinaison K antagoniste HBPM-vitamine, une stratégie de traitement utilisant la combinaison K antagoniste HNF-vitamine a été associée à un risque accru de thromboembolie veineuse récurrente (risque relatif [RR], 1,42; 95% intervalle de crédibilité [ICr], 1,15 à 1,79). La proportion de patients ayant présenté une thromboembolie veineuse récurrente pendant 3 mois de traitement était de 1,84% (95% ICr, 1,33% -2,51%) pour la K combinaison antagoniste UFH-vitamine et 1,30% (95% ICr, 1,02% -1,62%) pour la combinaison K antagoniste HBPM-vitamine. Rivaroxaban (HR, 0,55; 95% ICr, de 0,35 à 0,89) et apixaban (HR, 0,31; 95% ICr, de 0,15 à 0,62) ont été associés à un risque moindre de saignements que était la combinaison K antagoniste HBPM-vitaminique, avec une plus faible proportion de patients ayant présenté un événement de saignement majeur pendant 3 mois de anticoagulation: 0,49% (95% ICr, 0,29% -0,85%) pour rivaroxaban, 0,28% (95% ICr, 0,14% -0,50%) pour apixaban, et 0,89% ( 95% ICr, 0,66% -1,16%) pour la K combinaison antagoniste HBPM-vitamine.
CONCLUSIONS ET PERTINENCE: Utilisation de la mise en commun méta-analyse, il n'y avait pas de différence statistiquement significative pour l'efficacité et la sécurité associée à la plupart des stratégies de traitement utilisés pour traiter la maladie thromboembolique veineuse aiguë par rapport à la K combinaison antagoniste HBPM-vitamine. Toutefois, les résultats suggèrent que la combinaison K antagoniste UFH-vitamine est associée à la stratégie moins efficace et que le rivaroxaban et l'apixaban peut être associé au risque le plus faible pour le saignement.
Cancer-associated venous thromboembolism (VTE) is associated with high VTE recurrence and bleeding. We included all randomized clinical trials that evaluated the efficacy and safety of various anticoagulants in cancer-associated VTE. Trial-level data were extracted from 13 trials. Aggregate odds ratios (ORs) were calculated using direct and network meta-analysis. The primary outcome was VTE (pulmonary embolism and/or deep vein thrombosis) recurrence. Secondary outcomes were major bleeding and all-cause mortality. We identified 13 trials with 4869 patient-years of follow-up (6595 total patients; mean age 62.4 ± 12.2; 50.4 % female; 17.7 % hematological malignancies). The most common cancer type was colorectal and 48 % had metastatic cancer at baseline. Compared to vitamin-K-antagonists (VKAs), non-vitamin-K-antagonist-oral-anticoagulants (NOACs) were associated with significantly reduced VTE recurrence (OR, 0.58; 95 % CI, 0.40-0.83) and reduced major bleeding risks (OR, 0.56; 95 % CI, 0.35-0.91). However, no differences were observed in the subgroup analysis of patients with active cancer. Although NOACs were associated with reduced VTE recurrence compared with low-molecular-weight-heparin (LMWHs) (OR, 0.46; 95 % CI, 0.25- 0.85), there was a significant increased major bleeding in high-quality trials. LMWHs were associated with significantly reduced VTE recurrence compared with VKAs (OR, 0.52; 95 % CI, 0.39-0.71) and similar bleeding risks. Conclusions: Among patients with cancer-associated VTE, NOACs were associated with significantly reduced VTE recurrence and bleeding compared with VKAs, however, with similar outcomes in the active cancer population. NOACs were associated with reduced VTE recurrence but higher bleeding risks compared with LMWHs. LMWHs were associated with significantly reduced VTE recurrence and similar bleeding compared with VKAs.
