Oral anticoagulation for prolonging survival in patients with cancer.

BACKGROUND: A number of basic research and clinical studies have led to the hypothesis that oral anticoagulants may improve the survival of patients with cancer through an antitumour effect in addition to their antithrombotic effect. OBJECTIVES: To evaluate the effectiveness and safety of oral anticoagulation (including vitamin K antagonists and ximelagatran) as an intervention to improve survival of patients with cancer. SEARCH STRATEGY: A comprehensive search for studies of anticoagulation in cancer patients including (1) a January 2007 electronic search of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, ISI the Web of Science; (2) hand search of the American Society of Clinical Oncology (starting with its first volume, 1982) and of the American Society of Hematology (starting with its 2003 issue); (3) checking of references of included studies; and (4) use of "related article" feature in PubMed. SELECTION CRITERIA: Randomized clinical trials (RCTs) comparing vitamin K antagonist or ximelagatran to no intervention or placebo in cancer patients without clinical evidence of venous thromboembolism. DATA COLLECTION AND ANALYSIS: Using a standardized data form we extracted data on methodological quality, participants, interventions and outcome of interest that included all cause mortality, symptomatic deep venous thrombosis, symptomatic pulmonary embolism, major bleeding and minor bleeding. MAIN RESULTS: Of 3986 identified citations five RCTs fulfilled the inclusion criteria. Warfarin was the oral anticoagulant in all of these RCTs and it was compared to either placebo or no intervention. The overall methodological quality of these RCTs was acceptable. The effect of warfarin on reduction in mortality was not statistically significant at six months (Relative risk (RR) = 0.96; 95% CI 0.80 to 1.16), at one year (RR = 0.95; 95% CI 0.86 to 1.05) at 2 years (RR = 0.97; 95% CI 0.87 to 1.08) or at five years (RR 0.91; 95% CI 0.83 to 1.01). In the subgroup of patients with small cell lung cancer (SCLC), warfarin reduced mortality at six months (RR = 0.69; 95% CI 0.50 to 0.96) but not at one year (RR = 0.88; 95% CI 0.77 to 1.01). This six month mortality benefit was statistically significant in the subgroup of extensive SCLC (RR = 0.65; 95% CI 0.45 to 0.93) but not in the subgroup of limited SCLC (RR = 0.68; 95% CI 0.36 to 1.28). One study assessed the effect of warfarin on venous thromboembolism and showed a RR reduction of 85% (p = 0.031). Warfarin increased both major bleeding (RR = 4.24; 95% CI 1.85 to 9.68) and minor bleeding (RR = 3.34; 95% CI 1.66 to 6.74). Warfarin increased the risk of major bleeding (RR 5.46; 95% CI 3.04 to 9.81) and minor bleeding (RR 4.01; 95% CI 1.30 to 12.42) also in patients with SCLC. There was no evidence for a significant reduction in mortality in any other cancer subtype. AUTHORS' CONCLUSIONS: Existing evidence does not suggest a mortality benefit from oral anticoagulation in patients with cancer. In patients with SCLC, the evidence suggests a survival benefit at six months from warfarin particularly when the disease is extensive. The decision for a patient with extensive SCLC to start warfarin for survival benefit should balance that benefit with the downsides of increased bleeding risk in light of patient values for these outcomes.

Anticoagulation for thrombosis prophylaxis in cancer patients with central venous catheters.

BACKGROUND: Central venous catheter (CVC) placement increases the risk of thrombosis in cancer patients. Thrombosis often necessitates the removal of the CVC, resulting in treatment delays and thrombosis related morbidity and mortality. OBJECTIVES: To evaluate the efficacy and safety of anticoagulation in reducing venous thromboembolic (VTE) events in cancer patients with CVC. SEARCH STRATEGY: A comprehensive search for studies of anticoagulation in cancer patients up to January 2006 was conducted in the following databases: The Cochrane Central Register of Controlled Trials ( CENTRAL), MEDLINE, EMBASE and ISI the Web of Science. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing unfractionated heparin (UFH), low molecular weight heparin (LMWH), vitamin K antagonists (VKA), fondaparinux or ximelagatran to no intervention or placebo in cancer patients with a CVC or comparing two different anticoagulants. DATA COLLECTION AND ANALYSIS: Data was extracted on methodological quality, patients, interventions and outcomes including all cause mortality (primary outcome), premature CVC removal, catheter-related infections, CVC site and non CVC site deep venous thrombosis (DVT), pulmonary embolism (PE), major and minor bleeding and thrombocytopenia. MAIN RESULTS: Of 3986 identified citations nine RCTs were included in the meta-analysis including one published as an abstract and one focusing on paediatric patients not included in the meta-analysis. None of these RCTs tested fondaparinux or ximelagatran. The use of heparin in cancer patients with CVC was associated with a trend towards a reduction in symptomatic DVT (Relative Risk (RR) = 0.43; 95% Confidence Interval (CI): 0.18 to 1.06), but the data did not show any statistically significant effect on mortality (RR = 0.74; 95% CI: 0.40 to 1.36), infection (RR = 0.91; 95% CI: 0.36 to 2.28), major bleeding (RR = 0.68; 95% CI: 0.10 to 4.78) or thrombocytopenia (RR = 0.85; 95% CI: 0.49 to 1.46). The effect warfarin on symptomatic DVT was not statistically significant (RR = 0.62; 95% CI: 0.30 to 1.27). When studies assessing different types of anticoagulants were pooled, symptomatic DVT rates were significantly reduced (RR = 0.56; 95% CI: 0.34 to 0.92). AUTHORS' CONCLUSIONS: Cancer patients with CVC considering anticoagulation, should consider the possible benefit of reduced incidence of thromboembolic complications with the burden and harms of anticoagulation. Future studies should be adequately powered and evaluate the effects of newer anticoagulants such as fondaparinux and ximelagatran in cancer patients with CVC.

Parenteral anticoagulation for prolonging survival in patients with cancer who have no other indication for anticoagulation.

BACKGROUND: Basic research and clinical studies have generated the hypothesis that anticoagulation may improve survival in patients with cancer through an antitumour effect in addition to the antithrombotic effect. OBJECTIVES: To evaluate the efficacy and safety of heparin (including unfractionated heparin (UFH) and low molecular weight heparin (LMWH)) and fondaparinux to improve survival of patients with cancer. SEARCH STRATEGY: A comprehensive search for studies of anticoagulation in cancer patients including (1) A January 2007 electronic search of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and ISI the Web of Science; (2) Hand search of the American Society of Clinical Oncology and of the American Society of Hematology; (3) Checking of references of included studies; and (4) Use of "related article" feature in PubMed. SELECTION CRITERIA: We included randomized controlled trials (RCTs) in cancer patients without clinical evidence of venous thromboembolism comparing UFH, LMWH or fondaparinux to no intervention or placebo and RCTs comparing two of the three agents of interest. DATA COLLECTION AND ANALYSIS: Using a standardized form we extracted in duplicate data on methodological quality, participants, interventions and outcomes of interest including all cause mortality, venous thrombosis, symptomatic pulmonary embolism, major bleeding and minor bleeding. MAIN RESULTS: Of 3986 identified citations five RCTs fulfilled the inclusion criteria. In all included RCTs the intervention consisted of heparin ( either UFH or LMWH). The overall methodological quality of the included studies was acceptable. Overall, heparin therapy was associated with a statistically and clinically significant survival benefit (hazard ratio (HR) = 0.77; 95% CI: 0.65 to 0.91). In subgroup analyses, patients with limited small cell lung cancer experienced a clear survival benefit (HR = 0.56; 95% CI: 0.38 to 0.83). The survival benefit was not statistically significant for either patients with extensive small cell lung cancer (HR = 0.80; 95% CI: 0.60 to 1.06) or patients with advanced cancer (HR = 0.84; 95%: 0.68 to 1.03). The increased risk of bleeding with heparin was not statistically significant (RR = 1.78; 95% CI: 0.73 to 4.38). AUTHORS' CONCLUSIONS: Heparin has a survival benefit in cancer patients in general, and in patients with limited small cell lung cancer in particular. Heparin might be particularly beneficial in cancer patients with limited cancer or a longer life expectancy. Future research should investigate the survival benefit of different types of anticoagulants (in different dosing, schedules and duration of therapy) in patients with different types and stages of cancers.

Oral anticoagulation may prolong survival of a subgroup of patients with cancer: a cochrane systematic review.

To evaluate the effectiveness and safety of oral anticoagulants in improving survival of cancer patients. We conducted in January 2007 a comprehensive search for relevant randomized clinical trials (RCTs). We extracted data on methodological quality, participants, interventions and outcomes using a standardized form. Five RCTs fulfilled the inclusion criteria and all compared warfarin to either placebo or no intervention. Their overall methodological quality was acceptable. The effect of warfarin on mortality was not statistically significant at 6 months (RR = 0.96; 95% CI 0.80-1.16), at 1 year (RR = 0.95; 95% CI 0.86-1.05), at 2 years (RR = 0.97; 95% CI 0.87-1.08) or at 5 years (RR 0.91; 95% CI 0.83-1.01). In the subgroup of patients with small cell lung cancer (SCLC), warfarin reduced mortality at 6 months (RR = 0.69; 95% CI 0.50-0.96) but not at 1 year (RR = 0.88; 95% CI 0.77-1.01). This 6 months mortality benefit was statistically significant in the subgroup of extensive SCLC (RR = 0.65; 95% CI 0.45-0.93) but not in the subgroup of limited SCLC (RR = 0.68; 95% CI 0.36-1.28). Warfarin increased both major bleeding (RR = 4.24; 95% CI 1.85-9.68) and minor bleeding (RR = 3.34; 95% CI 1.66-6.74). The evidence suggests a survival benefit from warfarin in patients with extensive SCLC, but not in other patient groups. This survival benefit should be weighed against the increased risk for hemorrhage.