title: Use of heparins in patients with cancer: individual participant data meta-analysis of randomised trials study protocol.
abstract: BACKGROUND
  Parenteral anticoagulants may improve outcomes in patients with cancer by reducing risk of venous thromboembolic disease and through a direct antitumour effect. Study-level systematic reviews indicate a reduction in venous thromboembolism and provide moderate confidence that a small survival benefit exists. It remains unclear if any patient subgroups experience potential benefits.
  
  
  METHODS
  First, we will perform a comprehensive systematic search of MEDLINE, EMBASE and The Cochrane Library, hand search scientific conference abstracts and check clinical trials registries for randomised control trials of participants with solid cancers who are administered parenteral anticoagulants. We anticipate identifying at least 15 trials, exceeding 9000 participants. Second, we will perform an individual participant data meta-analysis to explore the magnitude of survival benefit and address whether subgroups of patients are more likely to benefit from parenteral anticoagulants. All analyses will follow the intention-to-treat principle. For our primary outcome, mortality, we will use multivariable hierarchical models with patient-level variables as fixed effects and a categorical trial variable as a random effect. We will adjust analysis for important prognostic characteristics. To investigate whether intervention effects vary by predefined subgroups of patients, we will test interaction terms in the statistical model. Furthermore, we will develop a risk-prediction model for venous thromboembolism, with a focus on control patients of randomised trials.
  
  
  BACKGROUND
  Aside from maintaining participant anonymity, there are no major ethical concerns. This will be the first individual participant data meta-analysis addressing heparin use among patients with cancer and will directly influence recommendations in clinical practice guidelines. Major cancer guideline development organisations will use eventual results to inform their guideline recommendations. Several knowledge users will disseminate results through presentations at clinical rounds as well as national and international conferences. We will prepare an evidence brief and facilitate dialogue to engage policymakers and stakeholders in acting on findings.
  
  
  BACKGROUND
  PROSPERO CRD42013003526.
authors.affiliation: Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Holger J
authors.initials: HJ
authors.lastname: Schünemann
authors.affiliation: Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada Department of Community Health Studies, Brock University, St Catharines, Ontario, Canada.
authors.forename: Matthew
authors.initials: M
authors.lastname: Ventresca
authors.affiliation: St Joseph's Hospital, and Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Crowther
authors.affiliation: Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada Basel Institute for Clinical Epidemiology and Biostatistics, University Hospital Basel CH, Basel, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Briel
authors.affiliation: Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: University of Washington School of Medicine, Seattle, Washington, USA.
authors.forename: David
authors.initials: D
authors.lastname: Garcia
authors.affiliation: Hutchinson Institute for Cancer Outcomes Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Lyman
authors.affiliation: Marie Curie Palliative Care Research Centre, Cardiff University, Wales, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Noble
authors.affiliation: Wales Cancer Trials Unit, School of Medicine, Cardiff University, Wales, UK.
authors.forename: Fergus
authors.initials: F
authors.lastname: Macbeth
authors.affiliation: Wales Cancer Trials Unit, School of Medicine, Cardiff University, Wales, UK Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, UK.
authors.forename: Gareth
authors.initials: G
authors.lastname: Griffiths
authors.affiliation: Department of Medical, Oral and Biotechnological Sciences, University "G D'Annunzio" of Chieti-Pescara, Chieti, Italy Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Marcello
authors.initials: M
authors.lastname: DiNisio
authors.affiliation: Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada Division of Hematology, Department of Medicine, Hamilton, Ontario, Canada.
authors.forename: Alfonso
authors.identifier: http://orcid.org/0000-0002-3331-8766
authors.initials: A
authors.lastname: Iorio
authors.affiliation: Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Joseph
authors.initials: J
authors.lastname: Beyene
authors.affiliation: Biostatistics Unit, Father Sean O'Sullivan Research Centre, St Joseph's Healthcare, Hamilton, Ontario, Canada.
authors.forename: Lawrance
authors.initials: L
authors.lastname: Mbuagbaw
authors.affiliation: Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada Department of Internal Medicine, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Neumann
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Nick
authors.initials: N
authors.lastname: Van Es
authors.affiliation: Department of Oncology, Escarpment Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Melissa
authors.initials: M
authors.lastname: Brouwers
authors.affiliation: Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Jan
authors.initials: J
authors.lastname: Brozek
authors.affiliation: Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Gordon
authors.initials: G
authors.lastname: Guyatt
authors.affiliation: Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Levine
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Moll
authors.affiliation: Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Nancy
authors.initials: N
authors.lastname: Santesso
authors.affiliation: Department of Hematology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Streiff
authors.affiliation: Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Tejan
authors.initials: T
authors.lastname: Baldeh
authors.affiliation: Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada Department of Paediatrics, Universidad de Antioquia, Medellin, Colombia.
authors.forename: Ivan
authors.initials: I
authors.lastname: Florez
authors.affiliation: Department of Statistics, Mugla S tk Kocman Unv, Mugla, Turkey.
authors.forename: Ozlem
authors.initials: O
authors.lastname: Gurunlu Alma
authors.affiliation: Division of Hematology/Oncology, Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Ziad
authors.initials: Z
authors.lastname: Solh
authors.affiliation: Department of Clinical and Experimental Medicine, University of Insubria, Varese, Italy.
authors.forename: Walter
authors.initials: W
authors.lastname: Ageno
authors.affiliation: Department of Clinical Sciences and Community Health, University of Milan & Geriatrics, Fondazione-IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Maura
authors.initials: M
authors.lastname: Marcucci
authors.affiliation: Academic Department of Medical Oncology, Castle Hill Hospital, Cottingham, Hull and East Yorkshire Hospitals NHS Trust, UK.
authors.forename: George
authors.initials: G
authors.lastname: Bozas
authors.affiliation: Department of Readaptation and Palliative Medicine, Geneva University Hospitals, Switzerland.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Zulian
authors.affiliation: Division of Cancer-Hull York Medical School, University of Hull, Hull, UK.
authors.forename: Anthony
authors.initials: A
authors.lastname: Maraveyas
authors.affiliation: Service de Pneumologie, Hôpital Saint-Antoine, Assistance Publique-Hôpitaux de Paris, Université Pierre et Marie Curie, Paris, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Lebeau
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Harry
authors.initials: H
authors.lastname: Buller
authors.affiliation: Wales Cancer Trials Unit, School of Medicine, Cardiff University, Wales, UK.
authors.forename: Jessica
authors.initials: J
authors.lastname: Evans
authors.affiliation: Cardiology and Hematology Departments, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: McBane
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Bleker
authors.affiliation: Division of Hematology, Oncology and Tumor Immunology, Medical Department, Charité Comprehensive Cancer Center, Charité Medical University, Berlin, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Pelzer
authors.affiliation: Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada Department of Internal Medicine, American University of Beirut, Lebanon.
authors.forename: Elie A
authors.initials: EA
authors.lastname: Akl
mesh_terms: D006801:Humans; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects; D004334:Drug Administration Schedule; D006493:Heparin / Q000008:administration & dosage / Q000009:adverse effects; D015201:Meta-Analysis as Topic; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy / Q000401:mortality; D018579:Patient Selection; D017410:Practice Guidelines as Topic; D011379:Prognosis; D011788:Quality of Life; D016032:Randomized Controlled Trials as Topic; D016019:Survival Analysis; D054556:Venous Thromboembolism / Q000139:chemically induced / Q000401:mortality / Q000517:prevention & control
chemical_list: D000925:Anticoagulants; D006493:Heparin
keywords: cancer; deep vein thrombosis; individual participant data meta-analysis; low molecular weight heparin; mortality; protocol