title: Anticoagulation for the long-term treatment of venous thromboembolism in patients with cancer.
abstract: BACKGROUND
  Cancer increases the risk of thromboembolic events in patients including those receiving anticoagulation treatments.
  
  
  OBJECTIVE
  To compare the efficacy and safety of low molecular weight heparin (LMWH) and oral anticoagulants for the long-term treatment of venous thromboembolism (VTE) in patients with cancer.
  
  
  METHODS
  We conducted a comprehensive search for studies of anticoagulation in cancer patients including 1. a February 2013 electronic search of: the Cochrane Central Register of Controlled Trials (CENTRAL Issue 12, 2012), MEDLINE, and EMBASE; 2. a handsearch of conference proceedings; 3. checking of references of included studies; 4. use of the 'related citation' feature in PubMed; and 5. a search of clinicaltrials.gov for ongoing studies.
  
  
  METHODS
  We included randomized controlled trials (RCTs) comparing long-term treatment with LMWH versus oral anticoagulants (vitamin K antagonist (VKA) or ximelagatran) in patients with cancer and symptomatic objectively confirmed VTE.
  
  
  METHODS
  Using a standardized data form, we extracted data on methodological quality, participants, interventions and outcomes of interest: survival, recurrent VTE, major bleeding, minor bleeding, thrombocytopenia, and postphlebitic syndrome. We assessed the quality of evidence at the outcome level following the GRADE approach.
  
  
  RESULTS
  Of 9559 identified citations, 10 RCTs (11 reports) were eligible and reported data for 1981 patients with cancer. We excluded 14 studies in which patients with cancer constituted study subgroups, but did not report outcome data for them. Meta-analysis of seven RCTs comparing LMWH with VKA found no statistically significant survival benefit (hazard ratio (HR) 0.96; 95% confidence interval (CI) 0.81 to 1.14) but a statistically significant reduction in VTE (HR 0.47; 95% CI 0.32 to 0.71). The remaining findings did not exclude a beneficial or harmful effect of LMWH compared with VKA for the outcomes of major bleeding (RR 1.07; 95% CI 0.52 to 2.19), minor bleeding (RR 0.89; 95% CI 0.51 to 1.55), or thrombocytopenia (RR 0.98; 95% CI 0.57 to 1.66). We judged the quality of evidence as low for mortality, major bleeding, and minor bleeding, and as moderate for recurrent VTE.One RCT comparing dabigatran with VKA did not exclude beneficial or harmful effects of one agent over the other. One RCT comparing six months' extension of anticoagulation with 18 months of ximelagatran 24 mg twice daily versus no extended ximelagatran did not exclude beneficial or harmful effects for the outcomes of reduction in VTE, mortality, and minor bleeding. One RCT comparing once-weekly subcutaneous injection of idraparinux for three or six months versus standard treatment (parenteral anticoagulation followed by warfarin or acenocoumarol) suggested a reduction in recurrent VTE (HR 0.39; 95% CI 0.14 to 1.11) at six months, but did not exclude beneficial or harmful effects for the outcomes of mortality (HR 0.99; 95% CI 0.66 to 1.48) and major bleeding (RR 1.04; 95% CI 0.39 to 2.83).
  
  
  CONCLUSIONS
  For the long-term treatment of VTE in patients with cancer, LMWH compared with VKA reduces venous thromboembolic events but not mortality. The decision for a patient with cancer and VTE to start long-term LMWH versus oral anticoagulation should balance the benefits and harms and integrate the patient's values and preferences for the important outcomes and alternative management strategies.
authors.affiliation: Department of Internal Medicine, American University of Beirut, Riad El Solh St, Beirut, Lebanon.
authors.forename: Elie A
authors.initials: EA
authors.lastname: Akl
authors.forename: Lara
authors.initials: L
authors.lastname: Kahale
authors.forename: Maddalena
authors.initials: M
authors.lastname: Barba
authors.forename: Ignacio
authors.initials: I
authors.lastname: Neumann
authors.forename: Nawman
authors.initials: N
authors.lastname: Labedi
authors.forename: Irene
authors.initials: I
authors.lastname: Terrenato
authors.forename: Francesca
authors.initials: F
authors.lastname: Sperati
authors.forename: Paola
authors.initials: P
authors.lastname: Muti
authors.forename: Holger
authors.initials: H
authors.lastname: Schünemann
mesh_terms: D000284:Administration, Oral; D000925:Anticoagulants / Q000627:therapeutic use*; D001384:Azetidines / Q000627:therapeutic use; D001562:Benzimidazoles / Q000627:therapeutic use; D001596:Benzylamines / Q000627:therapeutic use; D000069604:Dabigatran; D006495:Heparin, Low-Molecular-Weight / Q000627:therapeutic use; D006801:Humans; D009369:Neoplasms / Q000150:complications*; D009844:Oligosaccharides / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D054556:Venous Thromboembolism / Q000188:drug therapy* / Q000209:etiology; D014812:Vitamin K / Q000037:antagonists & inhibitors; D015091:beta-Alanine / Q000031:analogs & derivatives / Q000627:therapeutic use
chemical_list: D000925:Anticoagulants; D001384:Azetidines; D001562:Benzimidazoles; D001596:Benzylamines; D006495:Heparin, Low-Molecular-Weight; D009844:Oligosaccharides; D015091:beta-Alanine; D014812:Vitamin K; C426686:ximelagatran; C479958:idraparinux; D000069604:Dabigatran