Background: Oral anticoagulants may improve the survival of people with cancer through an antithrombotic effect, yet increase the risk of bleeding. Objectives: To evaluate the efficacy and safety of oral anticoagulants in ambulatory people with cancer undergoing chemotherapy, targeted therapy, immunotherapy, or radiotherapy (either alone or in combination), with no standard therapeutic or prophylactic indication for anticoagulation. Search methods: We conducted comprehensive searches on 14 June 2021, following the original electronic searches performed in February 2016 (last major search). We electronically searched the following databases: CENTRAL, MEDLINE, Embase. In addition, we handsearched conference proceedings, checked references of included studies, and searched for ongoing studies. As part of the living systematic review approach, we are running continual searches and will incorporate new evidence rapidly after it is identified. Selection criteria: We included randomised controlled trials (RCTs) assessing the benefits and harms of vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs) in ambulatory people with cancer (i.e., not hospital inpatients during the time of their participation in trials) These people are typically undergoing systemic anticancer therapy, possibly including chemotherapy, targeted therapy, immunotherapy, or radiotherapy, but otherwise have no standard therapeutic or prophylactic indication for anticoagulation. Data collection and analysis: Using a standardised form, two review authors independently extracted data on study design, participants, intervention outcomes of interest, and risk of bias. Outcomes of interest included all-cause mortality, pulmonary embolism, symptomatic deep vein thrombosis (DVT), major bleeding, minor bleeding and health-related quality of life. We assessed the certainty of evidence for each outcome using the GRADE approach. Main results: Of 12,620 identified citations, 10 RCTs fulfilled the inclusion criteria. The oral anticoagulant was a vitamin K antagonist (VKA) in six of these RCTs, and a direct oral anticoagulant (DOAC) in the remaining four RCTs (three studies used apixaban; one used rivaroxaban). The comparator was either placebo or no prophylaxis. Compared to no prophylaxis, vitamin K antagonists (VKAs) probably reduce mortality at six months slightly (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.77 to 1.13; risk difference (RD) 22 fewer per 1000, 95% CI 72 fewer to 41 more; moderate-certainty evidence), and probably reduce mortality at 12 months slightly (RR 0.95, 95% CI 0.87 to 1.03; RD 29 fewer per 1000, 95% CI 75 fewer to 17 more; moderate-certainty evidence). One study assessed the effect of a VKA compared to no prophylaxis on thrombosis; the evidence was very uncertain about the effect of VKA compared to no VKA on pulmonary embolism and symptomatic DVT (RR 1.05, 95% CI 0.07 to 16.58; RD 0 fewer per 1000, 95% CI 6 fewer to 98 more; very low-certainty evidence; RR 0.08, 95% CI 0.01 to 1.42; RD 35 fewer per 1000, 95% CI 37 fewer to 16 more; very low-certainty evidence, respectively). Also, VKAs probably increase major and minor bleeding at 12 months (RR 2.93, 95% CI 1.86 to 4.62; RD 107 more per 1000, 95% CI 48 more to 201 more; moderate-certainty evidence for major bleeding, and RR 3.14, 95% CI 1.85 to 5.32; RD 167 more per 1000, 95% CI 66 more to 337 more; moderate-certainty evidence for minor bleeding). Compared to no prophylaxis, at three to six months, direct oral anticoagulants (DOACs) probably reduce mortality slightly (RR 0.94, 95% CI 0.64 to 1.38, RD 11 fewer per 1000, 95% CI 67 fewer to 70 more; moderate-certainty evidence), probably reduce the risk of pulmonary embolism slightly compared to no prophylaxis (RR 0.48, 95% CI 0.24 to 0.98; RD 24 fewer per 1000, 95% CI 35 fewer to 1 fewer; moderate-certainty evidence), probably reduce symptomatic DVT slightly (RR 0.58, 95% CI 0.30 to 1.15; RD 21 fewer per 1000, 95% CI 35 fewer to 8 more; moderate-certainty evidence), probably do not increase major bleeding (RR 1.65, 95% CI 0.72 to 3.80; RD 9 more per 1000, 95% CI 4 fewer to 40 more; moderate-certainty evidence), and may increase minor bleeding (RR 3.58, 95% CI 0.55 to 23.44; RD 55 more per 1000, 95% CI 10 fewer to 482 more; low-certainty evidence). Authors' conclusions: In ambulatory people with cancer undergoing chemotherapy, targeted therapy, immunotherapy, or radiotherapy (either alone or in combination), the current evidence on VKA thromboprophylaxis suggests that the harm of major bleeding might outweigh the benefit of reduction in venous thromboembolism. With DOACs, the benefit of reduction in venous thromboembolic events outweighs the risk of major bleeding. Editorial note: this is a living systematic review. Living systematic reviews offer a new approach to review updating in which the review is continually updated, incorporating relevant new evidence, as it becomes available. Please refer to the 'What's new' section in the Cochrane Database of Systematic Reviews for the current status of this review.
BACKGROUND: Venous thromboembolism (VTE) often complicates the clinical course of cancer. The risk is further increased by chemotherapy, but the trade-off between safety and efficacy of primary thromboprophylaxis in cancer patients treated with chemotherapy is uncertain. This is the third update of a review first published in February 2012.
OBJECTIVES: To assess the efficacy and safety of primary thromboprophylaxis for VTE in ambulatory cancer patients receiving chemotherapy compared with placebo or no thromboprophylaxis, or an active control intervention.
SEARCH METHODS: For this update, the Cochrane Vascular Information Specialist searched the Cochrane Vascular, CENTRAL, MEDLINE, Embase and CINAHL databases and World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 3 August 2020. We also searched the reference lists of identified studies and contacted content experts and trialists for relevant references.
SELECTION CRITERIA: Randomised controlled trials comparing any oral or parenteral anticoagulant or mechanical intervention to no thromboprophylaxis or placebo, or comparing two different anticoagulants.
DATA COLLECTION AND ANALYSIS: We extracted data on risk of bias, participant characteristics, interventions, and outcomes including symptomatic VTE and major bleeding as the primary effectiveness and safety outcomes, respectively. We applied GRADE to assess the certainty of evidence.
MAIN RESULTS: We identified six additional randomised controlled trials (3326 participants) for this update, bringing the included study total to 32 (15,678 participants), all evaluating pharmacological interventions and performed mainly in people with locally advanced or metastatic cancer. The certainty of the evidence ranged from high to very low across the different outcomes and comparisons. The main limiting factors were imprecision and risk of bias. Thromboprophylaxis with direct oral anticoagulants (direct factor Xa inhibitors apixaban and rivaroxaban) may decrease the incidence of symptomatic VTE (risk ratio (RR) 0.43, 95% confidence interval (CI) 0.18 to 1.06; 3 studies, 1526 participants; low-certainty evidence); and probably increases the risk of major bleeding compared with placebo (RR 1.74, 95% CI 0.82 to 3.68; 3 studies, 1494 participants; moderate-certainty evidence). When compared with no thromboprophylaxis, low-molecular-weight heparin (LMWH) reduced the incidence of symptomatic VTE (RR 0.62, 95% CI 0.46 to 0.83; 11 studies, 3931 participants; high-certainty evidence); and probably increased the risk of major bleeding events (RR 1.63, 95% CI 1.12 to 2.35; 15 studies, 7282 participants; moderate-certainty evidence). In participants with multiple myeloma, LMWH resulted in lower symptomatic VTE compared with the vitamin K antagonist warfarin (RR 0.33, 95% CI 0.14 to 0.83; 1 study, 439 participants; high-certainty evidence), while LMWH probably lowers symptomatic VTE more than aspirin (RR 0.51, 95% CI 0.22 to 1.17; 2 studies, 781 participants; moderate-certainty evidence). Major bleeding was observed in none of the participants with multiple myeloma treated with LMWH or warfarin and in less than 1% of those treated with aspirin. Only one study evaluated unfractionated heparin against no thromboprophylaxis, but did not report on VTE or major bleeding. When compared with placebo or no thromboprophylaxis, warfarin may importantly reduce symptomatic VTE (RR 0.15, 95% CI 0.02 to 1.20; 1 study, 311 participants; low-certainty evidence) and may result in a large increase in major bleeding (RR 3.82, 95% CI 0.97 to 15.04; 4 studies, 994 participants; low-certainty evidence). One study evaluated antithrombin versus no antithrombin in children. This study did not report on symptomatic VTE but did report any VTE (symptomatic and incidental VTE). The effect of antithrombin on any VTE and major bleeding is uncertain (any VTE.: RR 0.84, 95% CI 0.41 to 1.73; major bleeding: RR 0.78, 95% CI 0.03 to 18.57; 1 study, 85 participants; very low-certainty evidence).
AUTHORS' CONCLUSIONS: In ambulatory cancer patients, primary thromboprophylaxis with direct factor Xa inhibitors may reduce the incidence of symptomatic VTE (low-certainty evidence) and probably increases the risk of major bleeding (moderate-certainty evidence) when compared with placebo. LMWH decreases the incidence of symptomatic VTE (high-certainty evidence), but increases the risk of major bleeding (moderate-certainty evidence) when compared with placebo or no thromboprophylaxis. Evidence for the use of thromboprophylaxis with anticoagulants other than direct factor Xa inhibitors and LMWH is limited. More studies are warranted to evaluate the efficacy and safety of primary prophylaxis in specific types of chemotherapeutic agents and types of cancer, such as gastrointestinal or genitourinary cancer.
Background: Venous thromboembolism (VTE) is a common complication in cancer patients. We aim to evaluate the effect and safety of direct oral anticoagulants (DOACs) as primary prophylaxis in ambulatory cancer patients.Methods: We conducted a literature search in PubMed, EMBASE and ClinicalTrials for studies that evaluated DOACs for thromboprophylaxis in cancer patients. RevMan 5.3 software was used for this meta-analysis.Results: Three randomized controlled trials (RCTs) with a total of 1465 patients were pooled in the meta-analysis. DOACs significantly reduced the symptomatic VTE incidence during intervention period (RR 0.23, CI 0.11-0.47, P<0.0001, I2=9%). Significantly lower total VTE incidence (RR 0.53, CI 0.36-0.78, P = 0.001, I2 =30%) and PE incidence (RR 0.50, CI 0.28-0.89, P = 0.02, I2 =5%) were found during the observation period, and a trend for less symptomatic DVT events was found in the DOACs group (RR 0.62, CI 0.37-1.04, P = 0.07, I2 =5%). No differences for all-cause mortality were found between groups (RR 0.92, CI 0.74-1.15, P = 0.47, I2 =14%). DOACs did not significantly increase major bleeding risks (RR 1.66, CI 0.72-3.83, P = 0.24, I2 =0%) during the intervention period or clinically relevant non-major bleeding events (RR 1.50, CI 0.90-2.49, P = 0.12, I2 =0%) and total bleeding events during the observation period (RR 1.50, CI 0.98-2.29, P = 0.06, I2 =0%).Conclusion: DOACs are effective for thromboprophylaxis in ambulatory cancer patients, but there is a potential risk of bleeding. DOACs may be recommended in selected patients at high risk of VTE. More high-quality studies are needed to further validate our results.Abbreviations: CAT: cancer-associated thrombosis; CI: confidence interval; DOAC: direct oral anticoagulant; DVT: deep vein thrombosis; LMWH: low molecular weight heparin; NNH: number needed to harm; NNT: number needed to treat; PE: pulmonary embolism; RCT: randomized controlled trials; RR: risk ratio; RD: rate difference; VTE: venous thromboembolism.
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.
It is not well understood the efficacy and safety of primary deep vein thrombosis (DVT) prophylaxis of anticoagulants in patients with solid tumors. This systematic review and meta-analysis of randomized controlled trials (RCT) determines the relative ratio of primary DVT, survival rate and bleeding events among patients with solid tumors treated with anticoagulants or placebo. Comprehensive literature searches were conducted through the Pubmed, Ovid MEDLINE and EMBASE databases published from January 1st, 1993 to December 31st, 2015. Statistical analysis was performed by RevMan 5.0 software. For DVT events, the risk ratio in 16 trials between the prophylactic and control patients was statistically significant at 0.45 [0.36-0.58]; for major bleeding events, the risk ratio in 18 trials between the prophylactic and control patients was not statistically significant at 1.33 [0.99-1.79], while that in 15 trials with clinically relevant non-major bleeding was statistically significant at 1.83 [1.46-2.30]; the risk ratio for the mortality rate of patients with solid tumors in 16 trials was not statistically significant at 0.97 [0.93-1.02]. In conclusion, the risk ratio in this meta-analysis showed a significantly reduced incidence of DVT with anticoagulant use. Treatment to patients who had solid tumors with prophylactic anticoagulants enhanced the incidence rate of non-major bleeding but has no significant impact on the incidence rate of major bleeding. No significant differences were found in the mortality outcomes between anticoagulant and non-anticoagulant groups.
Effectiveness of new oral anticoagulants (NOAC) in patients with cancer is not clearly defined. There remain concerns of doubtful benefit and chances of potential harm with newer agents. In this meta-analysis, we evaluated the efficacy and safety of NOAC in patients with cancer. PubMed, Cochrane Library, EMBASE, Web of Science, and CINAHL databases were searched from January 01, 2001 through February 28, 2013. Randomized controlled trials reporting efficacy and safety data of NOACs (rivaroxaban, dabigatran, and apixaban) with control (low-molecular-weight heparin/vitamin K antagonists/placebo) for patients with cancer were included. Primary efficacy outcome was venous thromboembolism (VTE) or VTE-related death, and primary safety outcome was clinically relevant bleeding. We used random-effects models. Six trials randomized 19,832 patients, and 1197 patients had cancer. Risk of VTE or VTE-related death was not significantly different with NOAC versus control [odds ratio (OR), 0.80; 95% confidence interval (CI), 0.39-1.65] in patients with cancer. Separate analysis for individual effects showed similar results for rivaroxaban (OR, 1.08; 95% CI, 0.60-1.94) and dabigatran (OR, 0.91; 95% CI, 0.21-3.91). Clinically relevant bleeding was not higher with NOAC compared with control (OR, 1.49; 95% CI, 0.82-2.71); individual effect of rivaroxaban showed similar results. No statistically significant difference of efficacy and safety with NOAC was found between patients with and without cancer. Rivaroxaban might be equally effective and safe as vitamin K antagonist in patients with cancer. Dabigatran is as effective as comparator; however, safety profile of dabigatran is unknown. Randomized trials of new anticoagulants specific to the cancer population are necessary, and NOAC also need to be evaluated against low-molecular-weight heparin.
CONTEXTE ET OBJECTIFS: Une nouvelle génération d'anticoagulants oraux (AOMC), qui comprend la thrombine et le facteur Xa inhibiteurs, a été montré pour être efficace, mais on sait peu de savoir si ces médicaments augmentent le risque de saignement gastro-intestinal (GIB) des patients. Les patients qui ont besoin d'une thérapie OAC ont souvent des comorbidités significatives et peuvent aussi prendre de l'aspirine et / ou thienopyridines. Nous avons effectué une revue systématique et une méta-analyse du risque de GIB et des saignements cliniquement pertinents chez les patients prenant AOMC.
MÉTHODES: Nous avons interrogé Medline, Embase et la bibliothèque Cochrane (à Juillet 2012) sans restriction de langue. Nous avons analysé les données de 43 essais contrôlés randomisés (151 578 patients) par rapport AOMC (peu d'indication) au traitement standard pour le risque de saignement (19 essais sur GIB). Les odds ratios (OR) ont été estimées en utilisant un modèle à effets aléatoires. L'hétérogénéité a été évaluée avec le test Q de Cochran et le Higgins I (2) test.
RÉSULTATS: Le GIB ensemble, soit pour chez les patients prenant noac était de 1,45 (intervalle de confiance à 95% [IC], 1,07 à 1,97), mais il y avait une grande hétérogénéité entre les études (I2, 61%). Les analyses de sous-groupes ont montré que l'OR pour la fibrillation auriculaire était de 1,21 (IC 95% 0,91 à 1,61), pour la thromboprophylaxie après une chirurgie orthopédique, le RC était de 0,78 (IC 95% 0,31 à 1,96), pour le traitement de la thrombose veineuse l'OR était de 1,59 ( IC 95%, 1,03 à 2,44), et pour le syndrome coronarien aigu OR était de 5,21 (IC 95%, 2,58 à 10,53). Parmi les médicaments étudiés, l'OR pour apixaban était de 1,23 (IC 95% 0,56 à 2,73), l'OR pour le dabigatran était de 1,58 (IC 95% 1,29 à 1,93), l'OR était de 0,31 pour edoxaban (IC de 0,01 à 95% 7,69), et l'OR pour le rivaroxaban était de 1,48 (IC 1,21 à 1,82 95%). Le saignement pertinente ensemble, soit pour clinique chez les patients prenant noac était de 1,16 (IC 95% 1,00 à 1,34), avec des tendances similaires entre les sous-groupes.
CONCLUSIONS: Les études sur le traitement de la thrombose veineuse ou d'un syndrome coronarien aigu ont montré que les patients traités avec AOMC ont un risque accru de GIB, comparativement à ceux qui reçoivent des soins standard. Mieux rendre compte des événements GIB dans les essais futurs pourraient permettre la stratification des patients pour le traitement avec des agents gastriques.
Background: Oral anticoagulants may improve the survival of people with cancer through an antithrombotic effect, yet increase the risk of bleeding. Objectives: To evaluate the efficacy and safety of oral anticoagulants in ambulatory people with cancer undergoing chemotherapy, targeted therapy, immunotherapy, or radiotherapy (either alone or in combination), with no standard therapeutic or prophylactic indication for anticoagulation. Search methods: We conducted comprehensive searches on 14 June 2021, following the original electronic searches performed in February 2016 (last major search). We electronically searched the following databases: CENTRAL, MEDLINE, Embase. In addition, we handsearched conference proceedings, checked references of included studies, and searched for ongoing studies. As part of the living systematic review approach, we are running continual searches and will incorporate new evidence rapidly after it is identified. Selection criteria: We included randomised controlled trials (RCTs) assessing the benefits and harms of vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs) in ambulatory people with cancer (i.e., not hospital inpatients during the time of their participation in trials) These people are typically undergoing systemic anticancer therapy, possibly including chemotherapy, targeted therapy, immunotherapy, or radiotherapy, but otherwise have no standard therapeutic or prophylactic indication for anticoagulation. Data collection and analysis: Using a standardised form, two review authors independently extracted data on study design, participants, intervention outcomes of interest, and risk of bias. Outcomes of interest included all-cause mortality, pulmonary embolism, symptomatic deep vein thrombosis (DVT), major bleeding, minor bleeding and health-related quality of life. We assessed the certainty of evidence for each outcome using the GRADE approach. Main results: Of 12,620 identified citations, 10 RCTs fulfilled the inclusion criteria. The oral anticoagulant was a vitamin K antagonist (VKA) in six of these RCTs, and a direct oral anticoagulant (DOAC) in the remaining four RCTs (three studies used apixaban; one used rivaroxaban). The comparator was either placebo or no prophylaxis. Compared to no prophylaxis, vitamin K antagonists (VKAs) probably reduce mortality at six months slightly (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.77 to 1.13; risk difference (RD) 22 fewer per 1000, 95% CI 72 fewer to 41 more; moderate-certainty evidence), and probably reduce mortality at 12 months slightly (RR 0.95, 95% CI 0.87 to 1.03; RD 29 fewer per 1000, 95% CI 75 fewer to 17 more; moderate-certainty evidence). One study assessed the effect of a VKA compared to no prophylaxis on thrombosis; the evidence was very uncertain about the effect of VKA compared to no VKA on pulmonary embolism and symptomatic DVT (RR 1.05, 95% CI 0.07 to 16.58; RD 0 fewer per 1000, 95% CI 6 fewer to 98 more; very low-certainty evidence; RR 0.08, 95% CI 0.01 to 1.42; RD 35 fewer per 1000, 95% CI 37 fewer to 16 more; very low-certainty evidence, respectively). Also, VKAs probably increase major and minor bleeding at 12 months (RR 2.93, 95% CI 1.86 to 4.62; RD 107 more per 1000, 95% CI 48 more to 201 more; moderate-certainty evidence for major bleeding, and RR 3.14, 95% CI 1.85 to 5.32; RD 167 more per 1000, 95% CI 66 more to 337 more; moderate-certainty evidence for minor bleeding). Compared to no prophylaxis, at three to six months, direct oral anticoagulants (DOACs) probably reduce mortality slightly (RR 0.94, 95% CI 0.64 to 1.38, RD 11 fewer per 1000, 95% CI 67 fewer to 70 more; moderate-certainty evidence), probably reduce the risk of pulmonary embolism slightly compared to no prophylaxis (RR 0.48, 95% CI 0.24 to 0.98; RD 24 fewer per 1000, 95% CI 35 fewer to 1 fewer; moderate-certainty evidence), probably reduce symptomatic DVT slightly (RR 0.58, 95% CI 0.30 to 1.15; RD 21 fewer per 1000, 95% CI 35 fewer to 8 more; moderate-certainty evidence), probably do not increase major bleeding (RR 1.65, 95% CI 0.72 to 3.80; RD 9 more per 1000, 95% CI 4 fewer to 40 more; moderate-certainty evidence), and may increase minor bleeding (RR 3.58, 95% CI 0.55 to 23.44; RD 55 more per 1000, 95% CI 10 fewer to 482 more; low-certainty evidence). Authors' conclusions: In ambulatory people with cancer undergoing chemotherapy, targeted therapy, immunotherapy, or radiotherapy (either alone or in combination), the current evidence on VKA thromboprophylaxis suggests that the harm of major bleeding might outweigh the benefit of reduction in venous thromboembolism. With DOACs, the benefit of reduction in venous thromboembolic events outweighs the risk of major bleeding. Editorial note: this is a living systematic review. Living systematic reviews offer a new approach to review updating in which the review is continually updated, incorporating relevant new evidence, as it becomes available. Please refer to the 'What's new' section in the Cochrane Database of Systematic Reviews for the current status of this review.
