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.
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.
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).
CONTEXTE: Les patients atteints de tumeurs malignes ont une augmentation de 4 fois du risque de développer une thrombose veineuse et une augmentation de 3 fois le risque de saignement. Les deux bas-poids moléculaire de l'héparine (HBPM) et antivitamines K (AVK) ont été utilisés pour le traitement du cancer associée à une thrombose. Cependant, la meilleure approche anticoagulation reste un sujet de débat. OBJECTIF: Chez les patients adultes atteints de cancer et un événement thrombo-embolique veineuse aiguë nous avons cherché à déterminer les taux de thrombo-embolie veineuse (TEV) récurrente et d'une hémorragie majeure lorsqu'ils sont traités avec traitement par HBPM prolongée par rapport à antivitamines K. Les patients et méthodes: Une stratégie de recherche systématique de la littérature a été utilisé pour identifier les essais potentiels sur MEDLINE, EMBASE, le Registre Cochrane Controlled Trials et en cours MEDLINE à l'aide d'une interface OVID. L'évaluation des risques de partialité d'essais contrôlés randomisés (ECR) a été effectuée en fonction de la Cochrane Collaboration Cochrane-Manuel de revues systématiques des interventions. Le critère de jugement principal était le taux de récidive symptomatique TEV au cours de la période de l'anticoagulation. Le risque relatif (RR) a été utilisé comme mesure primaire avec des intervalles de confiance à 95% (IC). Mesures mises en commun ont été calculées à l'aide à effets aléatoires et effets fixes du modèle. Résultats: Cinq articles répondaient à nos critères d'inclusion. Tous les HBPM par rapport et AVK pour la prévention secondaire de la TEV. Le RR de récidive TEV était de 0,53 (IC 95%: 0.36 à 0,76, p = 0,007). Le RR de saignement majeur était de 0,98 (IC 95%: 0,49 à 1,93, p = 0,95). Événements hémorragiques mineures et mortalité toutes causes confondues étaient similaires entre les 2 bras d'intervention. CONCLUSIONS: Les résultats de notre étude suggèrent que l'utilisation à long terme des HBPM après la semaine aiguë traitement de première intention est supérieure aux AVK pour la prévention secondaire de la thromboembolie veineuse chez les patients adultes atteints de cancer.
CONTEXTE: Le cancer et ses traitements augmentent le risque de thrombo-embolie veineuse. Comparativement aux patients sans cancer, les patients atteints du cancer sous traitement anticoagulant de thromboembolie veineuse sont plus susceptibles de développer récurrent de thromboses et les saignements majeurs. S'adressant à tous les résultats importants, y compris le préjudice est d'une grande importance à faire preuve des décisions fondées sur des soins de santé. L'objectif de cette étude était de comparer l'héparine de bas poids moléculaire (HBPM) et des anticoagulants oraux (antivitamine K (AVK) et ximélagatran) pour le traitement à long terme de la maladie thromboembolique veineuse chez les patients atteints d'un cancer. MÉTHODES: Une revue systématique de la littérature médicale. Nous avons suivi la méthodologie Cochrane Collaboration pour effectuer des examens systématiques. Nous avons évalué la qualité méthodologique de chaque résultat en classant la qualité des preuves en utilisant la classification des recommandations d'évaluation, de développement et de l'évaluation (GRADE) la méthodologie. RÉSULTATS: Huit essais contrôlés randomisés (ECR) étaient admissibles et ont communiqué des données pour les patients atteints d'un cancer. La qualité de la preuve était faible en cas de décès et modérée pour la maladie thromboembolique veineuse récidivante. HBPM, par rapport à AVK n'apporte aucun bénéfice survie statistiquement significatif (Hazard Ratio (HR) = 0,96, IC 95% 0,81 à 1,14), mais une réduction statistiquement significative de la thrombo-embolie veineuse (HR = 0,47; 95% (Intervalle de confiance (IC) = 0.32 à 0,71). Il n'y avait pas de différence statistiquement significative entre les HBPM et AVK dans les résultats de saignement (RR = 0,91, IC 95% = 0,64 à 1,31) ou une thrombopénie (RR = 1,02, IC 95% = 0,60 à 1,74). CONCLUSION: Pour le traitement à long terme de la maladie thromboembolique veineuse chez les patients atteints d'un cancer, les HBPM par rapport à AVK réduit la maladie thromboembolique veineuse, mais pas la mort.
La thromboembolie veineuse est fréquente chez les patients atteints d'un cancer. Cependant, pas de lignes directrices de gestion existent pour la maladie thromboembolique veineuse spécifique aux patients atteints d'un cancer avancé progressive. Pour aider à élaborer des recommandations pour la pratique, nous avons fait un examen complet de traitement anticoagulant chez les patients atteints d'un cancer, avec un accent particulier sur les études incluant des patients ayant une maladie avancée. Les données de 19 publications, y compris les études randomisées, prospectives, et rétrospectives suggèrent que: à long terme à faible dose à plein-héparine de poids moléculaire (HBPM) est plus efficace que la warfarine dans la prévention secondaire de la thromboembolie veineuse chez les patients atteints d'un cancer de n'importe quel stade , le performance status, ou le pronostic; la warfarine ne devrait pas être utilisé chez les patients avec une maladie progressive avancer, et chez les patients à haut risque de saignement, à pleine dose HBPM pendant 7 jours, suivie d'une longue durée a diminué à dose fixe à long terme peut être considéré. La durée optimale de traitement n'est pas claire, mais parce que la tendance prothrombotique va persister dans les patients atteints de cancer avancé, le traitement de longue durée est généralement recommandé. Pour les patients présentant des contre-anticoagulation, inférieure-cave-caves filtres peuvent être considérés, mais leur utilisation doit sélection rigoureuse des patients. En fin de compte, la décision d'engager, de poursuivre et arrêter l'anticoagulation devra être faite sur une base individuelle, guidée par les éléments de preuve disponibles, la situation du patient, et de leurs préférences éclairées.
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.
