Antithrombotic therapy for ambulatory patients with multiple myeloma receiving immunomodulatory agents.

BACKGROUND: Multiple myeloma is a malignant plasma cell disorder characterised by clonal plasma cells that cause end-organ damage such as renal failure, lytic bone lesions, hypercalcaemia and/or anaemia. People with multiple myeloma are treated with immunomodulatory agents including lenalidomide, pomalidomide, and thalidomide. Multiple myeloma is associated with an increased risk of thromboembolism, which appears to be further increased in people receiving immunomodulatory agents. OBJECTIVES: (1) To systematically review the evidence for the relative efficacy and safety of aspirin, oral anticoagulants, or parenteral anticoagulants in ambulatory patients with multiple myeloma receiving immunomodulatory agents who otherwise have no standard therapeutic or prophylactic indication for anticoagulation. (2) To maintain this review as a living systematic review by continually running the searches and incorporating newly identified studies. SEARCH METHODS: We conducted a comprehensive literature search that included (1) a major electronic search (14 June 2021) of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE via Ovid, and Embase via Ovid; (2) hand-searching of conference proceedings; (3) checking of reference lists of included studies; and (4) a search for ongoing studies in trial registries. As part of the living systematic review approach, we are running continual searches, and we will incorporate new evidence rapidly after it is identified. SELECTION CRITERIA: Randomised controlled trials (RCTs) assessing the benefits and harms of oral anticoagulants such as vitamin K antagonist (VKA) and direct oral anticoagulants (DOAC), anti-platelet agents such as aspirin (ASA), and parenteral anticoagulants such as low molecular weight heparin (LMWH)in ambulatory patients with multiple myeloma receiving immunomodulatory agents. DATA COLLECTION AND ANALYSIS: Using a standardised form, we extracted data in duplicate on study design, participants, interventions, outcomes of interest, and risk of bias. Outcomes of interest included all-cause mortality, symptomatic deep vein thrombosis (DVT), pulmonary embolism (PE), major bleeding, and minor bleeding. For each outcome we calculated the risk ratio (RR) with its 95% confidence interval (CI) and the risk difference (RD) with its 95% CI. We then assessed the certainty of evidence at the outcome level following the GRADE approach (GRADE Handbook). MAIN RESULTS: We identified 1015 identified citations and included 11 articles reporting four RCTs that enrolled 1042 participants. The included studies made the following comparisons: ASA versus VKA (one study); ASA versus LMWH (two studies); VKA versus LMWH (one study); and ASA versus DOAC (two studies, one of which was an abstract). ASA versus VKA One RCT compared ASA to VKA at six months follow-up. The data did not confirm or exclude a beneficial or detrimental effect of ASA relative to VKA on all-cause mortality (RR 3.00, 95% CI 0.12 to 73.24; RD 2 more per 1000, 95% CI 1 fewer to 72 more; very low-certainty evidence); symptomatic DVT (RR 0.57, 95% CI 0.24 to 1.33; RD 27 fewer per 1000, 95% CI 48 fewer to 21 more; very low-certainty evidence); PE (RR 1.00, 95% CI 0.25 to 3.95; RD 0 fewer per 1000, 95% CI 14 fewer to 54 more; very low-certainty evidence); major bleeding (RR 7.00, 95% CI 0.36 to 134.72; RD 6 more per 1000, 95% CI 1 fewer to 134 more; very low-certainty evidence); and minor bleeding (RR 6.00, 95% CI 0.73 to 49.43; RD 23 more per 1000, 95% CI 1 fewer to 220 more; very low-certainty evidence). One RCT compared ASA to VKA at two years follow-up. The data did not confirm or exclude a beneficial or detrimental effect of ASA relative to VKA on all-cause mortality (RR 0.50, 95% CI 0.05 to 5.47; RD 5 fewer per 1000, 95% CI 9 fewer to 41 more; very low-certainty evidence); symptomatic DVT (RR 0.71, 95% CI 0.35 to 1.44; RD 22 fewer per 1000, 95% CI 50 fewer to 34 more; very low-certainty evidence); and PE (RR 1.00, 95% CI 0.25 to 3.95; RD 0 fewer per 1000, 95% CI 14 fewer to 54 more; very low-certainty evidence). ASA versus LMWH Two RCTs compared ASA to LMWH at six months follow-up. The pooled data did not confirm or exclude a beneficial or detrimental effect of ASA relative to LMWH on all-cause mortality (RR 1.00, 95% CI 0.06 to 15.81; RD 0 fewer per 1000, 95% CI 2 fewer to 38 more; very low-certainty evidence); symptomatic DVT (RR 1.23, 95% CI 0.49 to 3.08; RD 5 more per 1000, 95% CI 11 fewer to 43 more; very low-certainty evidence); PE (RR 7.71, 95% CI 0.97 to 61.44; RD 7 more per 1000, 95% CI 0 fewer to 60 more; very low-certainty evidence); major bleeding (RR 6.97, 95% CI 0.36 to 134.11; RD 6 more per 1000, 95% CI 1 fewer to 133 more; very low-certainty evidence); and minor bleeding (RR 1.42, 95% CI 0.35 to 5.78; RD 4 more per 1000, 95% CI 7 fewer to 50 more; very low-certainty evidence). One RCT compared ASA to LMWH at two years follow-up. The pooled data did not confirm or exclude a beneficial or detrimental effect of ASA relative to LMWH on all-cause mortality (RR 1.00, 95% CI 0.06 to 15.89; RD 0 fewer per 1000, 95% CI 4 fewer to 68 more; very low-certainty evidence); symptomatic DVT (RR 1.20, 95% CI 0.53 to 2.72; RD 9 more per 1000, 95% CI 21 fewer to 78 more; very low-certainty evidence); and PE (RR 9.00, 95% CI 0.49 to 166.17; RD 8 more per 1000, 95% CI 1 fewer to 165 more; very low-certainty evidence). VKA versus LMWH One RCT compared VKA to LMWH at six months follow-up. The data did not confirm or exclude a beneficial or detrimental effect of VKA relative to LMWH on all-cause mortality (RR 0.33, 95% CI 0.01 to 8.10; RD 3 fewer per 1000, 95% CI 5 fewer to 32 more; very low-certainty evidence); symptomatic DVT (RR 2.32, 95% CI 0.91 to 5.93; RD 36 more per 1000, 95% CI 2 fewer to 135 more; very low-certainty evidence); PE (RR 8.96, 95% CI 0.49 to 165.42; RD 8 more per 1000, 95% CI 1 fewer to 164 more; very low-certainty evidence); and minor bleeding (RR 0.33, 95% CI 0.03 to 3.17; RD 9 fewer per 1000, 95% CI 13 fewer to 30 more; very low-certainty evidence). The study reported that no major bleeding occurred in either arm. One RCT compared VKA to LMWH at two years follow-up. The data did not confirm or exclude a beneficial or detrimental effect of VKA relative to LMWH on all-cause mortality (RR 2.00, 95% CI 0.18 to 21.90; RD 5 more per 1000, 95% CI 4 fewer to 95 more; very low-certainty evidence); symptomatic DVT (RR 1.70, 95% CI 0.80 to 3.63; RD 32 more per 1000, 95% CI 9 fewer to 120 more; very low-certainty evidence); and PE (RR 9.00, 95% CI 0.49 to 166.17; RD 8 more per 1000, 95% CI 1 fewer to 165 more; very low-certainty evidence). ASA versus DOAC One RCT compared ASA to DOAC at six months follow-up. The data did not confirm or exclude a beneficial or detrimental effect of ASA relative to DOAC on DVT, PE, and major bleeding and minor bleeding (minor bleeding: RR 5.00, 95% CI 0.31 to 79.94; RD 4 more per 1000, 95% CI 1 fewer to 79 more; very low-certainty evidence). The study reported that no DVT, PE, or major bleeding events occurred in either arm. These results did not change in a meta-analysis including the study published as an abstract. AUTHORS' CONCLUSIONS: The certainty of the available evidence for the comparative effects of ASA, VKA, LMWH, and DOAC on all-cause mortality, DVT, PE, or bleeding was either low or very low. People with multiple myeloma considering antithrombotic agents should balance the possible benefits of reduced thromboembolic complications with the possible harms and burden of anticoagulants. 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 Cochrane Database of Systematic Reviews for the current status of this review.

Oral anticoagulation in people with cancer who have no therapeutic or prophylactic indication for anticoagulation.

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.

Anticoagulation for the initial treatment of venous thromboembolism in people with cancer.

BACKGROUND: Compared with people without cancer, people with cancer who receive anticoagulant treatment for venous thromboembolism (VTE) are more likely to develop recurrent VTE. OBJECTIVES: To compare the efficacy and safety of three types of parenteral anticoagulants (i.e. fixed-dose low molecular weight heparin (LMWH), adjusted-dose unfractionated heparin (UFH), and fondaparinux) for the initial treatment of VTE in people with cancer. SEARCH METHODS: We performed a comprehensive search in the following major databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (via Ovid) and Embase (via Ovid). We also handsearched conference proceedings, checked references of included studies, and searched for ongoing studies. This update of the systematic review is based on the findings of a literature search conducted on 14 August 2021. SELECTION CRITERIA: Randomised controlled trials (RCTs) assessing the benefits and harms of LMWH, UFH, and fondaparinux in people with cancer and objectively confirmed VTE. DATA COLLECTION AND ANALYSIS: Using a standardised form, we extracted data - in duplicate - on study design, participants, interventions, outcomes of interest, and risk of bias. Outcomes of interest included all-cause mortality, symptomatic VTE, major bleeding, minor bleeding, postphlebitic syndrome, quality of life, and thrombocytopenia. We assessed the certainty of evidence for each outcome using the GRADE approach. MAIN RESULTS: Of 11,484 identified citations, 3073 were unique citations and 15 RCTs fulfilled the eligibility criteria, none of which were identified in the latest search. These trials enrolled 1615 participants with cancer and VTE: 13 compared LMWH with UFH; one compared fondaparinux with UFH and LMWH; and one compared dalteparin with tinzaparin, two different types of low molecular weight heparin. The meta-analyses showed that LMWH may reduce mortality at three months compared to UFH (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.40 to 1.10; risk difference (RD) 57 fewer per 1000, 95% CI 101 fewer to 17 more; low certainty evidence) and may reduce VTE recurrence slightly (RR 0.69, 95% CI 0.27 to 1.76; RD 30 fewer per 1000, 95% CI 70 fewer to 73 more; low certainty evidence). There were no data available for bleeding outcomes, postphlebitic syndrome, quality of life, or thrombocytopenia. The study comparing fondaparinux with heparin (UFH or LMWH) found that fondaparinux may increase mortality at three months (RR 1.25, 95% CI 0.86 to 1.81; RD 43 more per 1000, 95% CI 24 fewer to 139 more; low certainty evidence), may result in little to no difference in recurrent VTE (RR 0.93, 95% CI 0.56 to 1.54; RD 8 fewer per 1000, 95% CI 52 fewer to 63 more; low certainty evidence), may result in little to no difference in major bleeding (RR 0.82, 95% CI 0.40 to 1.66; RD 12 fewer per 1000, 95% CI 40 fewer to 44 more; low certainty evidence), and probably increases minor bleeding (RR 1.53, 95% CI 0.88 to 2.66; RD 42 more per 1000, 95% CI 10 fewer to 132 more; moderate certainty evidence). There were no data available for postphlebitic syndrome, quality of life, or thrombocytopenia. The study comparing dalteparin with tinzaparin found that dalteparin may reduce mortality slightly (RR 0.86, 95% CI 0.43 to 1.73; RD 33 fewer per 1000, 95% CI 135 fewer to 173 more; low certainty evidence), may reduce recurrent VTE (RR 0.44, 95% CI 0.09 to 2.16; RD 47 fewer per 1000, 95% CI 77 fewer to 98 more; low certainty evidence), may increase major bleeding slightly (RR 2.19, 95% CI 0.20 to 23.42; RD 20 more per 1000, 95% CI 14 fewer to 380 more; low certainty evidence), and may reduce minor bleeding slightly (RR 0.82, 95% CI 0.30 to 2.21; RD 24 fewer per 1000, 95% CI 95 fewer to 164 more; low certainty evidence). There were no data available for postphlebitic syndrome, quality of life, or thrombocytopenia. AUTHORS' CONCLUSIONS: Low molecular weight heparin (LMWH) is probably superior to UFH in the initial treatment of VTE in people with cancer. Additional trials focusing on patient-important outcomes will further inform the questions addressed in this review. The decision for a person with cancer to start LMWH therapy should balance the benefits and harms and consider the person's values and preferences.

Contextual differences considered in the Tunisian ADOLOPMENT of the European guidelines on breast cancer screening.

BACKGROUND: Breast cancer is a common disease in Tunisia and is associated with high mortality rates. The "Instance Nationale de l'Evaluation et de l'Accréditation en Santé" (INEAS) and the Tunisian Society of Oncology decided to develop practice guidelines on the subject. While the development of de novo guidelines on breast cancer screening is a demanding process, guideline adaptation appears more appropriate and context sensitive. The objective of this paper is to describe the adaptation process of the European Guidelines on Breast Cancer Screening and Diagnosis to the Tunisian setting in terms of the methodological process, contextual differences between the source and adoloped guideline, and changes in the recommendations. METHODS: We used the 'Grading of Recommendations Assessment, Development and Evaluation' (GRADE)-ADOLOPMENT methodology to prioritize the topic, select the source guideline, and prioritize the questions and the outcomes. Once the source guideline was selected-the European Breast Cancer Guidelines-the European Commission´s Joint Research Centre shared with the project team in Tunisia all relevant documents and files. In parallel, the project team searched for local studies on the disease prevalence, associated outcomes' baseline risks, patients' values and preferences, cost, cost-effectiveness, acceptability, and feasibility. Then, the adoloping panel reviewed the GRADE evidence tables and the Evidence to Decision tables and discussed whether their own judgments were consistent with those from the source guideline or not. They based their judgments on the evidence on health effects, the contextual evidence, and their own experiences. RESULTS: The most relevant contextual differences between the source and adoloped guidelines were related to the perspective, scope, prioritized questions, rating of outcome importance, baseline risks, and indirectness of the evidence. The ADOLOPMENT process resulted in keeping 5 out of 6 recommendations unmodified. One recommendation addressing "screening versus no screening with ultrasound in women with high breast density on mammography screening" was modified from 'conditional against' to 'conditional for either' due to more favorable ratings by the adoloping panel in terms of equity and feasibility. CONCLUSION: This process illustrates both the feasibility of GRADE-ADOLOPMENT approach and the importance of consideration of contextual evidence. It also highlights the value of collaboration with the organization that developed the source guideline.

Anticoagulation for perioperative thromboprophylaxis in people with cancer.

BACKGROUND: The choice of the appropriate perioperative thromboprophylaxis for people with cancer depends on the relative benefits and harms of different anticoagulants. OBJECTIVES: To systematically review the evidence for the relative efficacy and safety of anticoagulants for perioperative thromboprophylaxis in people with cancer. SEARCH METHODS: This update of the systematic review was based on the findings of a comprehensive literature search conducted on 14 June 2018 that included a major electronic search of Cochrane Central Register of Controlled Trials (CENTRAL, 2018, Issue 6), MEDLINE (Ovid), and Embase (Ovid); handsearching of conference proceedings; checking of references of included studies; searching for ongoing studies; and using the 'related citation' feature in PubMed. SELECTION CRITERIA: Randomized controlled trials (RCTs) that enrolled people with cancer undergoing a surgical intervention and assessed the effects of low-molecular weight heparin (LMWH) to unfractionated heparin (UFH) or to fondaparinux on mortality, deep venous thrombosis (DVT), pulmonary embolism (PE), bleeding outcomes, and thrombocytopenia. DATA COLLECTION AND ANALYSIS: Using a standardized form, we extracted data in duplicate on study design, participants, interventions outcomes of interest, and risk of bias. Outcomes of interest included all-cause mortality, PE, symptomatic venous thromboembolism (VTE), asymptomatic DVT, major bleeding, minor bleeding, postphlebitic syndrome, health related quality of life, and thrombocytopenia. We assessed the certainty of evidence for each outcome using the GRADE approach (GRADE Handbook). MAIN RESULTS: Of 7670 identified unique citations, we included 20 RCTs with 9771 randomized people with cancer receiving preoperative prophylactic anticoagulation. We identified seven reports for seven new RCTs for this update.The meta-analyses did not conclusively rule out either a beneficial or harmful effect of LMWH compared with UFH for the following outcomes: mortality (risk ratio (RR) 0.82, 95% confidence interval (CI) 0.63 to 1.07; risk difference (RD) 9 fewer per 1000, 95% CI 19 fewer to 4 more; moderate-certainty evidence), PE (RR 0.49, 95% CI 0.17 to 1.47; RD 3 fewer per 1000, 95% CI 5 fewer to 3 more; moderate-certainty evidence), symptomatic DVT (RR 0.67, 95% CI 0.27 to 1.69; RD 3 fewer per 1000, 95% CI 7 fewer to 7 more; moderate-certainty evidence), asymptomatic DVT (RR 0.86, 95% CI 0.71 to 1.05; RD 11 fewer per 1000, 95% CI 23 fewer to 4 more; low-certainty evidence), major bleeding (RR 1.01, 95% CI 0.69 to 1.48; RD 0 fewer per 1000, 95% CI 10 fewer to 15 more; moderate-certainty evidence), minor bleeding (RR 1.01, 95% CI 0.76 to 1.33; RD 1 more per 1000, 95% CI 34 fewer to 47 more; moderate-certainty evidence), reoperation for bleeding (RR 0.93, 95% CI 0.57 to 1.50; RD 4 fewer per 1000, 95% CI 22 fewer to 26 more; moderate-certainty evidence), intraoperative transfusion (mean difference (MD) -35.36 mL, 95% CI -253.19 to 182.47; low-certainty evidence), postoperative transfusion (MD 190.03 mL, 95% CI -23.65 to 403.72; low-certainty evidence), and thrombocytopenia (RR 3.07, 95% CI 0.32 to 29.33; RD 6 more per 1000, 95% CI 2 fewer to 82 more; moderate-certainty evidence). LMWH was associated with lower incidence of wound hematoma (RR 0.70, 95% CI 0.54 to 0.92; RD 26 fewer per 1000, 95% CI 39 fewer to 7 fewer; moderate-certainty evidence). The meta-analyses found the following additional results: outcomes intraoperative blood loss (MD -6.75 mL, 95% CI -85.49 to 71.99; moderate-certainty evidence); and postoperative drain volume (MD 30.18 mL, 95% CI -36.26 to 96.62; moderate-certainty evidence).In addition, the meta-analyses did not conclusively rule out either a beneficial or harmful effect of LMWH compared with Fondaparinux for the following outcomes: any VTE (DVT or PE, or both; RR 2.51, 95% CI 0.89 to 7.03; RD 57 more per 1000, 95% CI 4 fewer to 228 more; low-certainty evidence), major bleeding (RR 0.74, 95% CI 0.45 to 1.23; RD 8 fewer per 1000, 95% CI 16 fewer to 7 more; low-certainty evidence), minor bleeding (RR 0.83, 95% CI 0.34 to 2.05; RD 8fewer per 1000, 95% CI 33 fewer to 52 more; low-certainty evidence), thrombocytopenia (RR 0.35, 95% CI 0.04 to 3.30; RD 14 fewer per 1000, 95% CI 20 fewer to 48 more; low-certainty evidence), any PE (RR 3.13, 95% CI 0.13 to 74.64; RD 2 more per 1000, 95% CI 1 fewer to 78 more; low-certainty evidence) and postoperative drain volume (MD -20.00 mL, 95% CI -114.34 to 74.34; low-certainty evidence) AUTHORS' CONCLUSIONS: We found no difference between perioperative thromboprophylaxis with LMWH versus UFH and LMWH compared with fondaparinux in their effects on mortality, thromboembolic outcomes, major bleeding, or minor bleeding in people with cancer. There was a lower incidence of wound hematoma with LMWH compared to UFH.

Anticoagulation for the long-term treatment of venous thromboembolism in people with cancer.

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.

Anticoagulation for people with cancer and central venous catheters.

BACKGROUND: Central venous catheter (CVC) placement increases the risk of thrombosis in people with cancer. Thrombosis often necessitates the removal of the CVC, resulting in treatment delays and thrombosis-related morbidity and mortality. This is an update of the Cochrane Review published in 2014. OBJECTIVES: To evaluate the efficacy and safety of anticoagulation for thromboprophylaxis in people with cancer with a CVC. SEARCH METHODS: We conducted a comprehensive literature search in May 2018 that included a major electronic search of Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid), and Embase (Ovid); handsearching of conference proceedings; checking of references of included studies; searching for ongoing studies; and using the 'related citation' feature in PubMed. This update of the systematic review was based on the findings of a literature search conducted on 14 May 2018. SELECTION CRITERIA: Randomized controlled trials (RCTs) assessing the benefits and harms of unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), vitamin K antagonists (VKA), or fondaparinux or comparing the effects of two of these anticoagulants in people with cancer and a CVC. DATA COLLECTION AND ANALYSIS: Using a standardized form, we extracted data and assessed risk of bias. Outcomes included all-cause mortality, symptomatic catheter-related venous thromboembolism (VTE), pulmonary embolism (PE), major bleeding, minor bleeding, catheter-related infection, thrombocytopenia, and health-related quality of life (HRQoL). We assessed the certainty of evidence for each outcome using the GRADE approach (Balshem 2011). MAIN RESULTS: Thirteen RCTs (23 papers) fulfilled the inclusion criteria. These trials enrolled 3420 participants. Seven RCTs compared LMWH to no LMWH (six in adults and one in children), six RCTs compared VKA to no VKA (five in adults and one in children), and three RCTs compared LMWH to VKA in adults.LMWH versus no LMWHSix RCTs (1537 participants) compared LMWH to no LMWH in adults. The meta-analyses showed that LMWH probably decreased the incidence of symptomatic catheter-related VTE up to three months of follow-up compared to no LMWH (risk ratio (RR) 0.43, 95% confidence interval (CI) 0.22 to 0.81; risk difference (RD) 38 fewer per 1000, 95% CI 13 fewer to 52 fewer; moderate-certainty evidence). However, the analysis did not confirm or exclude a beneficial or detrimental effect of LMWH on mortality at three months of follow-up (RR 0.82, 95% CI 0.53 to 1.26; RD 14 fewer per 1000, 95% CI 36 fewer to 20 more; low-certainty evidence), major bleeding (RR 1.49, 95% CI 0.06 to 36.28; RD 0 more per 1000, 95% CI 1 fewer to 35 more; very low-certainty evidence), minor bleeding (RR 1.35, 95% CI 0.62 to 2.92; RD 14 more per 1000, 95% CI 16 fewer to 79 more; low-certainty evidence), and thrombocytopenia (RR 1.03, 95% CI 0.80 to 1.33; RD 5 more per 1000, 95% CI 35 fewer to 58 more; low-certainty evidence).VKA versus no VKAFive RCTs (1599 participants) compared low-dose VKA to no VKA in adults. The meta-analyses did not confirm or exclude a beneficial or detrimental effect of low-dose VKA compared to no VKA on mortality (RR 0.99, 95% CI 0.64 to 1.55; RD 1 fewer per 1000, 95% CI 34 fewer to 52 more; low-certainty evidence), symptomatic catheter-related VTE (RR 0.61, 95% CI 0.23 to 1.64; RD 31 fewer per 1000, 95% CI 62 fewer to 51 more; low-certainty evidence), major bleeding (RR 7.14, 95% CI 0.88 to 57.78; RD 12 more per 1000, 95% CI 0 fewer to 110 more; low-certainty evidence), minor bleeding (RR 0.69, 95% CI 0.38 to 1.26; RD 15 fewer per 1000, 95% CI 30 fewer to 13 more; low-certainty evidence), premature catheter removal (RR 0.82, 95% CI 0.30 to 2.24; RD 29 fewer per 1000, 95% CI 114 fewer to 202 more; low-certainty evidence), and catheter-related infection (RR 1.17, 95% CI 0.74 to 1.85; RD 71 more per 1000, 95% CI 109 fewer to 356; low-certainty evidence).LMWH versus VKAThree RCTs (641 participants) compared LMWH to VKA in adults. The available evidence did not confirm or exclude a beneficial or detrimental effect of LMWH relative to VKA on mortality (RR 0.94, 95% CI 0.56 to 1.59; RD 6 fewer per 1000, 95% CI 41 fewer to 56 more; low-certainty evidence), symptomatic catheter-related VTE (RR 1.83, 95% CI 0.44 to 7.61; RD 15 more per 1000, 95% CI 10 fewer to 122 more; very low-certainty evidence), PE (RR 1.70, 95% CI 0.74 to 3.92; RD 35 more per 1000, 95% CI 13 fewer to 144 more; low-certainty evidence), major bleeding (RR 3.11, 95% CI 0.13 to 73.11; RD 2 more per 1000, 95% CI 1 fewer to 72 more; very low-certainty evidence), or minor bleeding (RR 0.95, 95% CI 0.20 to 4.61; RD 1 fewer per 1000, 95% CI 21 fewer to 95 more; very low-certainty evidence). The meta-analyses showed that LMWH probably increased the risk of thrombocytopenia compared to VKA at three months of follow-up (RR 1.69, 95% CI 1.20 to 2.39; RD 149 more per 1000, 95% CI 43 fewer to 300 more; moderate-certainty evidence). AUTHORS' CONCLUSIONS: The evidence was not conclusive for the effect of LMWH on mortality, the effect of VKA on mortality and catheter-related VTE, and the effect of LMWH compared to VKA on mortality and catheter-related VTE. We found moderate-certainty evidence that LMWH reduces catheter-related VTE compared to no LMWH. People with cancer with CVCs considering anticoagulation should balance the possible benefit of reduced thromboembolic complications with the possible harms and burden of anticoagulants.

Anticoagulation for the initial treatment of venous thromboembolism in people with cancer.

BACKGROUND: Compared with people without cancer, people with cancer who receive anticoagulant treatment for venous thromboembolism (VTE) are more likely to develop recurrent VTE. OBJECTIVES: To compare the efficacy and safety of three types of parenteral anticoagulants (i.e. fixed-dose low molecular weight heparin (LMWH), adjusted-dose unfractionated heparin (UFH), and fondaparinux) for the initial treatment of VTE in people with cancer. SEARCH METHODS: A comprehensive search included a major electronic search of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL) (2018, Issue 1), MEDLINE (via Ovid) and Embase (via Ovid); handsearching of conference proceedings; checking of references of included studies; use of the 'related citation' feature in PubMed; and a search for ongoing studies. This update of the systematic review was based on the findings of a literature search conducted on 14 January 2018. SELECTION CRITERIA: Randomized controlled trials (RCTs) assessing the benefits and harms of LMWH, UFH, and fondaparinux in people with cancer and objectively confirmed VTE. DATA COLLECTION AND ANALYSIS: Using a standardized form, we extracted data in duplicate on study design, participants, interventions outcomes of interest, and risk of bias. Outcomes of interested included all-cause mortality, symptomatic VTE, major bleeding, minor bleeding, postphlebitic syndrome, quality of life, and thrombocytopenia. We assessed the certainty of evidence for each outcome using the GRADE approach. MAIN RESULTS: Of 15440 identified citations, 7387 unique citations, 15 RCTs fulfilled the eligibility criteria. These trials enrolled 1615 participants with cancer and VTE: 13 compared LMWH with UFH enrolling 1025 participants, one compared fondaparinux with UFH and LMWH enrolling 477 participants, and one compared dalteparin with tinzaparin enrolling 113 participants. The meta-analysis of mortality at three months included 418 participants from five studies and that of recurrent VTE included 422 participants from 3 studies. The findings showed that LMWH likely decreases mortality at three months compared to UFH (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.40 to 1.10; risk difference (RD) 57 fewer per 1000, 95% CI 101 fewer to 17 more; moderate certainty evidence), but did not rule out a clinically significant increase or decrease in VTE recurrence (RR 0.69, 95% CI 0.27 to 1.76; RD 30 fewer per 1000, 95% CI 70 fewer to 73 more; moderate certainty evidence).The study comparing fondaparinux with heparin (UFH or LMWH) did not exclude a beneficial or detrimental effect of fondaparinux on mortality at three months (RR 1.25, 95% CI 0.86 to 1.81; RD 43 more per 1000, 95% CI 24 fewer to 139 more; moderate certainty evidence), recurrent VTE (RR 0.93, 95% CI 0.56 to 1.54; RD 8 fewer per 1000, 95% CI 52 fewer to 63 more; moderate certainty evidence), major bleeding (RR 0.82, 95% CI 0.40 to 1.66; RD 12 fewer per 1000, 95% CI 40 fewer to 44 more; moderate certainty evidence), or minor bleeding (RR 1.53, 95% CI 0.88 to 2.66; RD 42 more per 1000, 95% CI 10 fewer to 132 more; moderate certainty evidence)The study comparing dalteparin with tinzaparin did not exclude a beneficial or detrimental effect of dalteparin on mortality (RR 0.86, 95% CI 0.43 to 1.73; RD 33 fewer per 1000, 95% CI 135 fewer to 173 more; low certainty evidence), recurrent VTE (RR 0.44, 95% CI 0.09 to 2.16; RD 47 fewer per 1000, 95% CI 77 fewer to 98 more; low certainty evidence), major bleeding (RR 2.19, 95% CI 0.20 to 23.42; RD 20 more per 1000, 95% CI 14 fewer to 380 more; low certainty evidence), or minor bleeding (RR 0.82, 95% CI 0.30 to 2.21; RD 24 fewer per 1000, 95% CI 95 fewer to 164 more; low certainty evidence). AUTHORS' CONCLUSIONS: LMWH is possibly superior to UFH in the initial treatment of VTE in people with cancer. Additional trials focusing on patient-important outcomes will further inform the questions addressed in this review. The decision for a person with cancer to start LMWH therapy should balance the benefits and harms and consider the person's values and preferences.

Extent of physician-pharmaceutical industry interactions in low- and middle-income countries: a systematic review.

Background: Pharmaceutical companies spend large amounts of money promoting their products to physicians. There is evidence that physicians' interactions with pharmaceutical companies negatively affect their prescribing patterns. The objective of this study was to systematically review the extent of the relationship between physicians and pharmaceutical companies in low- and middle-income countries (LMICs). Methods: Studies assessing the extent of any type of interaction between practicing physicians and pharmaceutical companies were eligible. We searched MEDLINE and EMBASE databases in July 2016. Reviewers worked in duplicate and independently to complete study selection, data abstraction and assessment of methodological features. We summarized the findings narratively. Results: We included 11 eligible studies (7 quantitative and 4 qualitative). Quantitative studies found that pharmaceutical company representatives visited at least 90% of physicians. Printed material, stationery items and drug samples were the most frequently received gifts. Two of the studies assessing direct payment found percentages of 16 and 5%, respectively. Findings of qualitative studies were consistent with those of quantitative studies. In addition, they revealed an increasing tendency for pharmaceutical companies to provide expensive personal gifts, sponsor social events and offer cash as inducements to physicians based on their demands. They also identified building personal relationships, creating a sense of indebtedness and emotional blackmailing as commonly used techniques to influence physicians. Conclusion: A relatively high percentage of physicians in LMICs interact with pharmaceutical companies. Findings have implications for policy and practice, given the current extent of interaction is likely affecting the prescribing habits and professional behaviour of physicians.

Body positioning for spontaneously breathing preterm infants with apnoea.

BACKGROUND: It has been proposed that body positioning in preterm infants, as compared with other, more invasive measures, may be an effective method of reducing clinically significant apnoea. OBJECTIVES: To determine effects of body positioning on cardiorespiratory parameters in spontaneously breathing preterm infants with clinically significant apnoea.Subgroup analyses examined effects of body positioning of spontaneously breathing preterm infants with apnoea from the following subgroups.• Gestational age < 28 weeks or birth weight less than 1000 grams.• Apnoea managed with methylxanthines.• Frequent apnoea (> 10 events/d).• Type of apnoea measured (central vs mixed vs obstructive) SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group (CNRG) to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 10), MEDLINE via PubMed (1966 to 14 November 2016), Embase (1980 to 14 November 2016) and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 2016 November 14). We also searched clinical trials databases and conference proceedings for randomised controlled trials and quasi-randomised trials. SELECTION CRITERIA: Randomised and quasi-randomised controlled clinical trials with parallel, factorial or cross-over design comparing the impact of different body positions on apnoea in spontaneously breathing preterm infants were eligible for our review. DATA COLLECTION AND ANALYSIS: We assessed trial quality, data extraction and synthesis of data using standard methods of the CNRG. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess the quality of evidence. MAIN RESULTS: The search conducted in November 2016 identified no new studies. Five studies (N = 114) were eligible for inclusion. None of the individual studies nor meta-analyses showed a reduction in apnoea, bradycardia, oxygen desaturation or oxygen saturation with body positioning (supine vs prone; prone vs right lateral; prone vs left lateral; right lateral vs left lateral; prone horizontal vs prone head elevated; right lateral horizontal vs right lateral head elevated, left lateral horizontal vs left lateral head elevated). AUTHORS' CONCLUSIONS: We found insufficient evidence to determine effects of body positioning on apnoea, bradycardia and oxygen saturation in preterm infants. No new studies have been conducted since the original review was published. Large, multi-centre studies are warranted to provide conclusive evidence, but it may be plausible to conclude that positioning of spontaneously breathing preterm infants has no effect on their cardiorespiratory parameters.

Parenteral anticoagulation in ambulatory patients with cancer.

BACKGROUND: Anticoagulation may improve survival in patients with cancer through a speculated anti-tumour effect, in addition to the antithrombotic effect, although may increase the risk of bleeding. OBJECTIVES: To evaluate the efficacy and safety of parenteral anticoagulants in ambulatory patients with cancer who, typically, are undergoing chemotherapy, hormonal therapy, immunotherapy or radiotherapy, but otherwise have no standard therapeutic or prophylactic indication for anticoagulation. SEARCH METHODS: A comprehensive search included (1) a major electronic search (February 2016) of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL) (2016, Issue 1), MEDLINE (1946 to February 2016; accessed via OVID) and Embase (1980 to February 2016; accessed via OVID); (2) handsearching of conference proceedings; (3) checking of references of included studies; (4) use of the 'related citation' feature in PubMed and (5) a search for ongoing studies in trial registries. As part of the living systematic review approach, we are running searches continually and we will incorporate new evidence rapidly after it is identified. This update of the systematic review is based on the findings of a literature search conducted on 14 August, 2017. SELECTION CRITERIA: Randomized controlled trials (RCTs) assessing the benefits and harms of parenteral anticoagulation in ambulatory patients with cancer. Typically, these patients are undergoing chemotherapy, hormonal therapy, immunotherapy or radiotherapy, but otherwise have no standard therapeutic or prophylactic indication for anticoagulation. DATA COLLECTION AND ANALYSIS: Using a standardized form we extracted data in duplicate on study design, participants, interventions outcomes of interest, and risk of bias. Outcomes of interested included all-cause mortality, symptomatic venous thromboembolism (VTE), symptomatic deep vein thrombosis (DVT), pulmonary embolism (PE), major bleeding, minor bleeding, and quality of life. We assessed the certainty of evidence for each outcome using the GRADE approach (GRADE handbook). MAIN RESULTS: Of 6947 identified citations, 18 RCTs fulfilled the eligibility criteria. These trials enrolled 9575 participants. Trial registries' searches identified nine registered but unpublished trials, two of which were labeled as 'ongoing trials'. In all included RCTs, the intervention consisted of heparin (either unfractionated heparin or low molecular weight heparin). Overall, heparin appears to have no effect on mortality at 12 months (risk ratio (RR) 0.98; 95% confidence interval (CI) 0.93 to 1.03; risk difference (RD) 10 fewer per 1000; 95% CI 35 fewer to 15 more; moderate certainty of evidence) and mortality at 24 months (RR 0.99; 95% CI 0.96 to 1.01; RD 8 fewer per 1000; 95% CI 31 fewer to 8 more; moderate certainty of evidence). Heparin therapy reduces the risk of symptomatic VTE (RR 0.56; 95% CI 0.47 to 0.68; RD 30 fewer per 1000; 95% CI 36 fewer to 22 fewer; high certainty of evidence), while it increases in the risks of major bleeding (RR 1.30; 95% 0.94 to 1.79; RD 4 more per 1000; 95% CI 1 fewer to 11 more; moderate certainty of evidence) and minor bleeding (RR 1.70; 95% 1.13 to 2.55; RD 17 more per 1000; 95% CI 3 more to 37 more; high certainty of evidence). Results failed to confirm or to exclude a beneficial or detrimental effect of heparin on thrombocytopenia (RR 0.69; 95% CI 0.37 to 1.27; RD 33 fewer per 1000; 95% CI 66 fewer to 28 more; moderate certainty of evidence); quality of life (moderate certainty of evidence). AUTHORS' CONCLUSIONS: Heparin appears to have no effect on mortality at 12 months and 24 months. It reduces symptomatic VTE and likely increases major and minor bleeding. Future research should further investigate the survival benefit of different types of anticoagulants in patients with different types and stages of cancer. The decision for a patient with cancer to start heparin therapy should balance the benefits and downsides, and should integrate the patient's values and preferences.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 Cochrane Database of Systematic Reviews for the current status of this review.

Oral anticoagulation in people with cancer who have no therapeutic or prophylactic indication for anticoagulation.

BACKGROUND: Oral anticoagulants may improve the survival of people with cancer through both an antitumor effect and 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, hormonal therapy, immunotherapy or radiotherapy, but otherwise have no standard therapeutic or prophylactic indication for anticoagulation. SEARCH METHODS: We conducted a comprehensive literature search in February 2016 that included a major electronic search of Cochrane Central Register of Controlled Trials (CENTRAL) (2016, Issue 1), MEDLINE (Ovid) and Embase (Ovid); handsearching of conference proceedings; checking of references of included studies; a search for ongoing studies; and using the 'related citation' feature in PubMed. As part of the living systematic review approach, we are running continual searches and will incorporate new evidence rapidly after it is identified. This update of the systematic review is based on the findings of a literature search conducted on 14 December 2017. SELECTION CRITERIA: Randomized controlled trials (RCTs) assessing the benefits and harms of vitamin K antagonist (VKA) or direct oral anticoagulants (DOAC) in ambulatory people with cancer. These participants are typically undergoing systemic anticancer therapy, possibly including chemotherapy, target therapy, immunotherapy or radiotherapy, but otherwise have no standard therapeutic or prophylactic indication for anticoagulation. DATA COLLECTION AND ANALYSIS: Using a standardized form, we extracted data in duplicate on study design, participants, intervention outcomes of interest and risk of bias. Outcomes of interest included all-cause mortality, symptomatic venous thromboembolism (VTE), symptomatic deep vein thrombosis (DVT), pulmonary embolism (PE), major bleeding, minor bleeding and health-related quality of life (HRQoL). We assessed the certainty of evidence for each outcome using the GRADE approach (GRADE Handbook). MAIN RESULTS: Of 8545 identified citations, including 7668 unique citations, 16 papers reporting on 7 RCTs fulfilled the inclusion criteria. These trials enrolled 1486 participants. The oral anticoagulant was warfarin in six of these RCTs and apixaban in the seventh RCT. The comparator was either placebo or no intervention. The meta-analysis of the studies comparing VKA to no VKA did not rule out a clinically significant increase or decrease in mortality at one year (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.87 to 1.03; risk difference (RD) 29 fewer per 1000, 95% CI 75 fewer to 17 more; moderate certainty evidence). One study assessed the effect of VKA on thrombotic outcomes. The study did not rule out a clinically significant increase or decrease in PE when comparing VKA to no VKA (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), but found that VKA compared to no VKA likely decreases the incidence of DVT (RR 0.08, 95% CI 0.00 to 1.42; RD 35 fewer per 1000, 95% CI 38 fewer to 16 more; low certainty evidence). VKA increased both major bleeding (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) and minor bleeding (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).The study assessing the effect of DOAC compared to no DOAC did not rule out a clinically significant increase or decrease in mortality at three months (RR 0.24, 95% CI 0.02 to 2.56; RD 51 fewer per 1000, 95% CI 65 fewer to 104 more; low certainty evidence), PE (RR 0.16, 95% CI 0.01 to 3.91; RD 28 fewer per 1000, 95% CI 33 fewer to 97 more; low certainty evidence), symptomatic DVT (RR 0.07, 95% CI 0.00 to 1.32; RD 93 fewer per 1000, 95% CI 100 fewer to 32 more; low certainty evidence), major bleeding (RR 0.16, 95% CI 0.01 to 3.91; RD 28 fewer per 1000, 95% CI 33 fewer to 97 more; low certainty evidence); and minor bleeding (RR 4.43, 95% CI 0.25 to 79.68; RD 0 fewer per 1000, 95% CI 0 fewer to 8 more; low certainty evidence). AUTHORS' CONCLUSIONS: The existing evidence does not show a mortality benefit from oral anticoagulation in people with cancer but suggests an increased risk for 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 Cochrane Database of Systematic Reviews for the current status of this review.

Knowledge, beliefs and attitudes of physicians in low and middle-income countries regarding interacting with pharmaceutical companies: a systematic review.

BACKGROUND: Understanding the perceptions and attitudes of physicians is important. This knowledge assists in the efforts to reduce the impact of their interactions with the pharmaceutical industry on clinical practice. It appears that most studies on such perceptions and attitudes have been conducted in high-income countries. The objective was to systematically review the knowledge, beliefs and attitudes of physicians in low and middle-income countries regarding interactions with pharmaceutical companies. METHODS: Eligible studies addressed any type of interaction between physicians and pharmaceutical companies. The outcomes of interest included knowledge, beliefs and attitudes of practicing physicians. The search strategy covered MEDLINE and EMBASE databases. Two reviewers completed in duplicate and independently study selection, data abstraction, and assessment of methodological features. The data synthesis consisted of a narrative summary of the findings stratified by knowledge, beliefs and attitudes. RESULTS: We included ten reports from nine eligible studies, each of which had a number of methodological limitations. Four studies found that the top perceived benefits of this interaction were receiving information and rewards. In five out of eight studies assessing the perception regarding the impact of the interaction on the behavior of physician prescription, the majority of participants believed it to be minor. In one of these studies, participants perceived that impact to be lesser when asked about their own behavior. The attitudes of physicians towards information and rewards provided by pharmaceutical company representatives (PCRs) (assessed in 5 and 2 studies respectively) varied across studies. In the only study assessing their attitudes towards pharmaceutical-sponsored Continuing Medical Education, physicians considered local conferences to have higher impact. Their attitudes towards developing policies restricting physicians' interactions with PCRs were positive in two studies. In one study, the majority of participants did not mind the public knowing that physicians were receiving gifts and awards from drug companies. CONCLUSIONS: This review identified few studies conducted in low and middle-income countries. While physicians generally perceived the impact of interactions on their behavior to be minor, their attitudes toward receiving information and rewards varied across studies.

Association between perioperative low-molecular-weight heparin vs unfractionated heparin and clinical outcomes in patients with cancer undergoing surgery.

CLINICAL QUESTION: In patients with cancer undergoing surgery, what is the association between perioperative thromboprophylaxis with low-molecular-weight heparin (LMWH) or unfractionated heparin and mortality, pulmonary embolism, deep venous thrombosis, thrombocytopenia, and bleeding outcomes? BOTTOM LINE: When used for perioperative thromboprophylaxis, there are no differences in the association of LMWH vs unfractionated heparin for preventing mortality, pulmonary embolism, deep venous thrombosis, bleeding outcomes, or thrombocytopenia in patients with cancer.

Anticoagulation for the initial treatment of venous thromboembolism in patients with cancer.

BACKGROUND: Compared with patients without cancer, patients with cancer who receive anticoagulant treatment for venous thromboembolism (VTE) are more likely to develop recurrent VTE. OBJECTIVES: To compare the efficacy and safety of three types of parenteral anticoagulants (i.e. fixed-dose low molecular weight heparin (LMWH), adjusted-dose unfractionated heparin (UFH), and fondaparinux) for the initial treatment of VTE in patients with cancer. SEARCH METHODS: A comprehensive search for studies of anticoagulation in patients with cancer including a February 2013 electronic search of: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and ISI Web of Science. SELECTION CRITERIA: Randomized clinical trials (RCTs) comparing LMWH, UFH, and fondaparinux in patients with cancer and objectively confirmed VTE. DATA COLLECTION AND ANALYSIS: Using a standardized data form, review authors extracted data in duplicate on methodologic quality, participants, interventions, and outcomes of interest that included mortality, recurrent VTE, major bleeding, minor bleeding, postphlebitic syndrome, quality of life, and thrombocytopenia. MAIN RESULTS: Of 9559 identified citations, 16 RCTs were eligible: 13 compared LMWH with UFH, two compared fondaparinux with heparin, and one compared dalteparin with tinzaparin. Meta-analysis of 11 studies showed a statistically significant reduction in mortality at three months of follow-up with LMWH compared with UFH (risk ratio (RR) 0.71; 95% confidence interval (CI) 0.52 to 0.98). There was little change in the effect estimate after excluding studies of lower methodologic quality (RR 0.72; 95% CI 0.52 to 1.00). A meta-analysis of three studies comparing LMWH with UFH showed no statistically significant reduction in VTE recurrence (RR 0.78; 95% CI 0.29 to 2.08). The overall quality of evidence was low for LMWH versus UFH due to imprecision and likely publication bias. There were no statistically significant differences between heparin and fondaparinux for the outcomes of mortality (RR 1.27; 95% CI 0.88 to 1.84), recurrent VTE (RR 0.95; 95% CI 0.57 to 1.60), major bleeding (RR 0.79; 95% CI 0.39 to1.63), or minor bleeding (RR 1.50; 95% CI 0.87 to 2.59). The one study comparing dalteparin with tinzaparin found no statistically significant difference in mortality (RR 0.86; 95% CI 0.43 to 1.73). AUTHORS' CONCLUSIONS: LMWH is possibly superior to UFH in the initial treatment of VTE in patients with cancer. Additional trials focusing on patient-important outcomes will further inform the questions addressed in this review.

Anticoagulation for people with cancer and central venous catheters.

BACKGROUND: Central venous catheter (CVC) placement increases the risk of thrombosis in people with cancer. Thrombosis often necessitates the removal of the CVC, resulting in treatment delays and thrombosis-related morbidity and mortality. OBJECTIVES: To evaluate the relative efficacy and safety of anticoagulation for thromboprophylaxis in people with cancer with a CVC. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 12, 2012), MEDLINE Ovid (January 1966 to February 2013), and EMBASE Ovid (1980 to February 2013). We handsearched conference proceedings, checked references of included studies, used the 'related citations' feature within PubMed, and searched clinicaltrials.gov for ongoing studies. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing the effects of any dose of unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), vitamin K antagonists (VKA), or fondaparinux with no intervention or placebo or comparing the effects of two different anticoagulants in people with cancer and a CVC. DATA COLLECTION AND ANALYSIS: Teams of two review authors independently used a standardized form to extract data in duplicate. They resolved any disagreements by discussion. They extracted data on risk of bias, participants, interventions, and outcomes. Outcomes of interest included mortality, symptomatic deep venous thrombosis (DVT), asymptomatic DVT, major bleeding, minor bleeding, infection, and thrombocytopenia. Where possible, we conducted meta-analyses using the random-effects model. MAIN RESULTS: Of 9559 identified citations, we included 12 RCTs (17 publications) reporting follow-up data on 2823 participants. Two of the RCTs included children. Of the 10 RCTs including 2564 adults, one compared prophylactic dose heparin with low-dose VKA. Three RCTs compared VKA with no VKA and four RCTs compared heparin with no heparin. Two additional trials had three separate arms comparing heparin, VKA, and no intervention. Prophylactic-dose heparin, compared with no heparin, was associated with a statistically significant reduction in symptomatic DVT (risk ratio (RR) 0.48; 95% confidence interval (CI) 0.27 to 0.86; moderate-quality evidence). However, results did not confirm or exclude a beneficial or detrimental effect of heparin on mortality (RR 0.82; 95% CI 0.53 to 1.26; moderate-quality evidence), major bleeding (RR 0.49; 95% CI 0.03 to 7.84; low-quality evidence), infection (RR 1.00; 95% CI 0.54 to 1.85; moderate-quality evidence); thrombocytopenia (RR 1.03; 95% CI 0.80 to 1.33; moderate-quality evidence), or minor bleeding (RR 1.35; 95% CI: 0.62 to 2.92). Low-dose VKAs, compared with no VKAs, were associated with a statistically significant reduction in asymptomatic DVT (RR 0.43; 95% CI 0.30 to 0.62). Results did not confirm or exclude a beneficial or detrimental effect of VKAs on mortality (RR 1.04; 95% CI 0.89 to 1.22; low-quality evidence), symptomatic DVT (RR 0.51; 95% CI 0.21 to 1.22; low-quality evidence), major bleeding (RR 7.60; 95% CI 0.94 to 61.49; very-low-quality evidence), or minor bleeding (RR 3.14; 95% CI 0.14 to 71.51). The use of heparin, compared with VKA was associated with a statistically significant increase in thrombocytopenia (RR 3.73; 95% CI 2.26 to 6.16; low-quality evidence) and asymptomatic DVT (RR 1.74; 95% CI 1.20 to 2.52). However, results did not show or exclude a beneficial or detrimental effect on any of the other outcomes of interest (very-low-quality evidence). AUTHORS' CONCLUSIONS: Compared with no anticoagulation, we found a statistically significant reduction of symptomatic DVT with heparin and asymptomatic DVT with VKA. Heparin was associated with a higher risk of thrombocytopenia and asymptomatic DVT when compared with VKA. However, the findings did not rule out other clinically important benefits and harms. People with cancer with CVCs considering anticoagulation should balance the possible benefit of reduced thromboembolic complications with the possible harms and burden of anticoagulants.

Low molecular weight heparin versus unfractionated heparin for perioperative thromboprophylaxis in patients with cancer.

BACKGROUND: The choice of the appropriate perioperative thromboprophylaxis in patients with cancer depends on the relative benefits and harms of low molecular weight heparin (LMWH) and unfractionated heparin (UFH). OBJECTIVES: To update a systematic review of the evidence for the relative efficacy and safety of LMWH and UFH for perioperative thromboprophylaxis in patients with cancer. SEARCH METHODS: We performed a comprehensive search for trials of anticoagulation in patients with cancer including a February 2013 electronic search of: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE. We also handsearched conference proceedings, reviewed reference list of included studies, used the 'related citations' feature in PubMed, and searched clinicaltrials.gov for ongoing studies. SELECTION CRITERIA: Randomized controlled trials (RCTs) that enrolled patients with cancer undergoing a surgical intervention and compared the effects of LMWH to UFH on mortality, deep venous thrombosis (DVT), pulmonary embolism (PE), bleeding outcomes, or thrombocytopenia. DATA COLLECTION AND ANALYSIS: Two review authors independently used a standardized form to extract in duplicate data on participants, interventions, outcomes of interest, and risk of bias. Where possible, we conducted meta-analyses using the random-effects model. MAIN RESULTS: Of 9559 identified unique citations, we included 16 RCTs with 12,890 patients with cancer, all using preoperative prophylactic anticoagulation. We identified no new study with this update. The overall quality of evidence was moderate. The meta-analyses did not conclusively rule out either a beneficial or harmful effect of LMWH compared with UFH for the following outcomes: mortality (risk ratio (RR) 0.89; 95% confidence interval (CI) 0.74 to 1.08), PE (RR 0.73; 95% CI 0.34 to 1.54), symptomatic DVT (RR 0.50; 95% CI 0.20 to 1.28), asymptomatic DVT (RR 0.81; 95% CI 0.66 to 1.01),major bleeding (RR 0.85; 95% CI 0.52 to 1.37), and minor bleeding (RR 0.92; 95% CI 0.47 to 1.79). LMWH was associated with lower incidence of wound hematoma (RR 0.68; 95% CI 0.52 to 0.88) but higher volume of intraoperative transfusion (mean difference (MD) 74 mL; 95% CI 47 to 102). The meta-analyses found no statistically significant differences for any of the following outcomes: reoperation for bleeding (RR 0.72; 95% CI 0.06 to 8.48) , intraoperative blood loss (MD= -6mL; 95% CI -87 to 74), postoperative transfusion (MD= 79mL; 95% CI -54 to 211), postoperative drain volume (MD= 27mL; 95% CI -44 to 98), and thrombocytopenia (RR 1.33; 95% CI 0.59 to 3.00). AUTHORS' CONCLUSIONS: We found no difference between perioperative thromboprophylaxis with LMWH versus UFH in their effects on mortality, thromboembolic outcomes, major bleeding, or minor bleeding in patients with cancer. Further trials are needed to evaluate the benefits and harms of different heparin thromboprophylaxis strategies in this population more thoroughly.

Parenteral anticoagulation in ambulatory patients with cancer.

BACKGROUND: Anticoagulation may improve survival in patients with cancer through an antitumor effect in addition to the perceived antithrombotic effect. OBJECTIVES: To evaluate the efficacy and safety of parenteral anticoagulants in ambulatory patients with cancer who, typically, are undergoing chemotherapy, hormonal therapy or radiotherapy, but otherwise have no standard therapeutic or prophylactic indication for anticoagulation. SEARCH METHODS: A comprehensive search included (1) an electronic search (February 2013) of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 1), MEDLINE (1966 to February 2013; accessed via OVID) and EMBASE(1980 to February 2013; accessed via OVID); (2) handsearching of conference proceedings; (3) checking of references of included studies; (4) use of the 'related citation' feature in PubMed and (5) a search for ongoing studies. SELECTION CRITERIA: Randomized controlled trials (RCTs) assessing the benefits and harms of parenteral anticoagulation in ambulatory patients with cancer. Typically, these patients are undergoing chemotherapy, hormonal therapy or radiotherapy, but otherwise have no standard therapeutic or prophylactic indication for anticoagulation. DATA COLLECTION AND ANALYSIS: Using a standardized form we extracted data in duplicate on methodological quality, participants, interventions and outcomes of interest including all-cause mortality, symptomatic venous thromboembolism (VTE), symptomatic deep vein thrombosis (DVT), symptomatic pulmonary embolism (PE), arterial thrombosis (e.g. stroke, myocardial infarction), major bleeding, minor bleeding and quality of life. MAIN RESULTS: Of 9559 identified citations, 15 RCTs fulfilled the eligibility criteria. These trials enrolled 7622 participants for whom follow-up data were available. In all included RCTs the intervention consisted of heparin (either unfractionated heparin or low molecular weight heparin). Overall, heparin may have a small effect on mortality at 12 months and 24 months (risk ratio (RR) 0.97; 95% confidence interval (CI) 0.92 to 1.01 and RR 0.95; 95% CI 0.90 to 1.00, respectively). Heparin therapy was associated with a statistically and clinically important reduction in venous thromboembolism (RR 0.56; 95% CI 0.42 to 0.74) and a clinically important increase in the risk of minor bleeding (RR 1.32; 95% 1.02 to 1.71). Results failed to show or to exclude a beneficial or detrimental effect of heparin on major bleeding (RR 1.14; 95% CI 0.70 to 1.85) or quality of life. Our confidence in the effect estimates (i.e. quality of evidence) was high for symptomatic venous thromboembolism, moderate for mortality, major bleeding and minor bleeding, and low for quality of life. AUTHORS' CONCLUSIONS: Heparin may have a small effect on mortality at 12 months and 24 months. It is associated with a reduction in venous thromboembolism and a likely increase in minor bleeding. Future research should further investigate the survival benefit of different types of anticoagulants in patients with different types and stages of cancer. The decision for a patient with cancer to start heparin therapy for survival benefit should balance the benefits and downsides, and should integrate the patient's values and preferences.

Oral anticoagulation in patients with cancer who have no therapeutic or prophylactic indication for anticoagulation.

BACKGROUND: Several basic research and clinical studies have led to the hypothesis that oral anticoagulants may improve the survival of patients with cancer through an antitumor effect in addition to their antithrombotic effect. OBJECTIVES: To evaluate the efficacy and safety of oral anticoagulants in patients with cancer with no therapeutic or prophylactic indication for anticoagulation. SEARCH METHODS: We performed a comprehensive search for studies of anticoagulation in patients with cancer including 1. a February 2013 electronic search of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE; 2. a handsearch of the American Society of Clinical Oncology (starting with its first volume, 1982) and of the American Society of Hematology (starting with the 2003 issue); 3. checking of references of included studies; 4. use of the 'related citation' feature in PubMed; and 5. searching clinical trials.gov for ongoing studies. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing vitamin K antagonist or other oral anticoagulants with no intervention or placebo in patients with cancer without clinical evidence of venous thromboembolism. DATA COLLECTION AND ANALYSIS: Using a standardized data form, we extracted data on risk of bias, participants, interventions and outcomes of interest that included all-cause mortality, venous thromboembolism, major bleeding, and minor bleeding. MAIN RESULTS: Of 9559 identified citations, seven RCTs (eight reports) fulfilled the inclusion criteria. The oral anticoagulant was warfarin in six of these RCTs and apixaban in the seventh RCT. The comparator was either placebo or no intervention. The use of warfarin had no effect on mortality at six months (risk ratio (RR) 0.98; 95% confidence interval (CI) 0.82 to 1.22), one year (RR 0.97; 95% CI 0.89 to 1.04), two years (RR 0.98; 95% CI 0.81 to 1.18), or five years (RR 0.92; 95% CI 0.83 to 1.01). One study assessed the effect of warfarin on venous thromboembolism and did not show or exclude a beneficial or detrimental of effect (RR 0.15; 95% CI 0.02 to 1.20). Warfarin increased both major bleeding (RR 4.24; 95% CI 1.86 to 9.65) and minor bleeding (RR 3.19; 95% CI 1.83 to 5.55). We judged the quality of evidence as moderate for all outcomes.The study assessing the effect of apixaban did not show or exclude a beneficial effect or detrimental of apixaban on mortality at six months (RR 0.16; 95% CI 0.01 to 1.66); major bleeding (RR 0.62; 95% CI 0.06 to 6.63); and minor bleeding (RR 2.87; 95% CI 0.16 to 51.82). We judged the quality of evidence as low for all outcomes. AUTHORS' CONCLUSIONS: Existing evidence does not suggest a mortality benefit from oral anticoagulation in patients with cancer while the risk for bleeding is increased.

Oral anticoagulation in patients with cancer who have no therapeutic or prophylactic indication for anticoagulation.

BACKGROUND: Several basic research and clinical studies have led to the hypothesis that oral anticoagulants may improve the survival of patients with cancer through an antitumor effect in addition to their antithrombotic effect. OBJECTIVES: To evaluate the efficacy and safety of oral anticoagulants in patients with cancer with no therapeutic or prophylactic indication for anticoagulation. SEARCH METHODS: We performed a comprehensive search for studies of anticoagulation in patients with cancer including 1. a February 2013 electronic search of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE; 2. a handsearch of the American Society of Clinical Oncology (starting with its first volume, 1982) and of the American Society of Hematology (starting with the 2003 issue); 3. checking of references of included studies; 4. use of the 'related citation' feature in PubMed; and 5. searching clinical trials.gov for ongoing studies. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing vitamin K antagonist or other oral anticoagulants with no intervention or placebo in patients with cancer without clinical evidence of venous thromboembolism. DATA COLLECTION AND ANALYSIS: Using a standardized data form, we extracted data on risk of bias, participants, interventions and outcomes of interest that included all-cause mortality, venous thromboembolism, major bleeding, and minor bleeding. MAIN RESULTS: Of 9559 identified citations, seven RCTs (eight reports) fulfilled the inclusion criteria. The oral anticoagulant was warfarin in six of these RCTs and apixaban in the seventh RCT. The comparator was either placebo or no intervention. The use of warfarin had no effect on mortality at six months (risk ratio (RR) 0.98; 95% confidence interval (CI) 0.82 to 1.22), one year (RR 0.97; 95% CI 0.89 to 1.04), two years (RR 0.98; 95% CI 0.81 to 1.18), or five years (RR 0.92; 95% CI 0.83 to 1.01). One study assessed the effect of warfarin on venous thromboembolism and did not show or exclude a beneficial or detrimental of effect (RR 0.15; 95% CI 0.02 to 1.20). Warfarin increased both major bleeding (RR 4.24; 95% CI 1.86 to 9.65) and minor bleeding (RR 3.19; 95% CI 1.83 to 5.55). We judged the quality of evidence as moderate for all outcomes.The study assessing the effect of apixaban did not show or exclude a beneficial effect or detrimental of apixaban on mortality at six months (RR 0.16; 95% CI 0.01 to 1.66); major bleeding (RR 0.62; 95% CI 0.06 to 6.63); and minor bleeding (RR 2.87; 95% CI 0.16 to 51.82). We judged the quality of evidence as low for all outcomes. AUTHORS' CONCLUSIONS: Existing evidence does not suggest a mortality benefit from oral anticoagulation in patients with cancer while the risk for bleeding is increased.