title: Randomized Phase III Trial of Standard Therapy Plus Low Molecular Weight Heparin in Patients With Lung Cancer: FRAGMATIC Trial.
abstract: OBJECTIVE
  Venous thromboembolism (VTE) is common in cancer patients. Evidence has suggested that low molecular weight heparin (LMWH) might improve survival in patients with cancer by preventing both VTE and the progression of metastases. No trial in a single cancer type has been powered to demonstrate a clinically significant survival difference. The aim of this trial was to investigate this question in patients with lung cancer.
  
  
  METHODS
  We conducted a multicenter, open-label, randomized trial to evaluate the addition of a primary prophylactic dose of LMWH for 24 weeks to standard treatment in patients with newly diagnosed lung cancer of any stage and histology. The primary outcome was 1-year survival. Secondary outcomes included metastasis-free survival, VTE-free survival, toxicity, and quality of life.
  
  
  RESULTS
  For this trial, 2,202 patients were randomly assigned to the two treatment arms over 4 years. The trial did not reach its intended number of events for the primary analysis (2,047 deaths), and data were analyzed after 2,013 deaths after discussion with the independent data monitoring committee. There was no evidence of a difference in overall or metastasis-free survival between the two arms (hazard ratio [HR], 1.01; 95% CI, 0.93 to 1.10; P = .814; and HR, 0.99; 95% CI, 0.91 to 1.08; P = .864, respectively). There was a reduction in the risk of VTE from 9.7% to 5.5% (HR, 0.57; 95% CI, 0.42 to 0.79; P = .001) in the LMWH arm and no difference in major bleeding events but evidence of an increase in the composite of major and clinically relevant nonmajor bleeding in the LMWH arm.
  
  
  CONCLUSIONS
  LMWH did not improve overall survival in the patients with lung cancer in this trial. A significant reduction in VTE is associated with an increase in clinically relevant nonmajor bleeding. Strategies to target those at greatest risk of VTE are warranted.
authors.affiliation: Fergus Macbeth, Jessica Evans, Sheikh Ahmed, and Gareth Griffiths, Wales Cancer Trials Unit; Simon Noble and Kerenza Hood, Cardiff University; David Cohen and Mirella Longo, University of South Wales; Barbara Moore, National Institute for Social Care and Health Research Clinical Research Centre, Cardiff; Gareth Griffiths, University of Southampton, Southampton; Dana Knoyle, Prince Charles Hospital, Merthyr Tydfil; Penella J. Woll, Weston Park Hospital, Sheffield; Wiebke Appel, Royal Preston Hospital, Preston; Jeanette Dickson, Mount Vernon Cancer Center, Northwood; David Ferry, Royal Wolverhampton Hospitals National Health Service Trust, Wolverhampton; Caroline Brammer, Mid Staffordshire Hospital, Stafford, United Kingdom; and Seamus Linnane, Beaumont Hospital, Dublin, Ireland. fragmatic@cardiff.ac.uk.
authors.forename: Fergus
authors.initials: F
authors.lastname: Macbeth
authors.affiliation: Fergus Macbeth, Jessica Evans, Sheikh Ahmed, and Gareth Griffiths, Wales Cancer Trials Unit; Simon Noble and Kerenza Hood, Cardiff University; David Cohen and Mirella Longo, University of South Wales; Barbara Moore, National Institute for Social Care and Health Research Clinical Research Centre, Cardiff; Gareth Griffiths, University of Southampton, Southampton; Dana Knoyle, Prince Charles Hospital, Merthyr Tydfil; Penella J. Woll, Weston Park Hospital, Sheffield; Wiebke Appel, Royal Preston Hospital, Preston; Jeanette Dickson, Mount Vernon Cancer Center, Northwood; David Ferry, Royal Wolverhampton Hospitals National Health Service Trust, Wolverhampton; Caroline Brammer, Mid Staffordshire Hospital, Stafford, United Kingdom; and Seamus Linnane, Beaumont Hospital, Dublin, Ireland.
authors.forename: Simon
authors.initials: S
authors.lastname: Noble
authors.affiliation: Fergus Macbeth, Jessica Evans, Sheikh Ahmed, and Gareth Griffiths, Wales Cancer Trials Unit; Simon Noble and Kerenza Hood, Cardiff University; David Cohen and Mirella Longo, University of South Wales; Barbara Moore, National Institute for Social Care and Health Research Clinical Research Centre, Cardiff; Gareth Griffiths, University of Southampton, Southampton; Dana Knoyle, Prince Charles Hospital, Merthyr Tydfil; Penella J. Woll, Weston Park Hospital, Sheffield; Wiebke Appel, Royal Preston Hospital, Preston; Jeanette Dickson, Mount Vernon Cancer Center, Northwood; David Ferry, Royal Wolverhampton Hospitals National Health Service Trust, Wolverhampton; Caroline Brammer, Mid Staffordshire Hospital, Stafford, United Kingdom; and Seamus Linnane, Beaumont Hospital, Dublin, Ireland.
authors.forename: Jessica
authors.initials: J
authors.lastname: Evans
authors.affiliation: Fergus Macbeth, Jessica Evans, Sheikh Ahmed, and Gareth Griffiths, Wales Cancer Trials Unit; Simon Noble and Kerenza Hood, Cardiff University; David Cohen and Mirella Longo, University of South Wales; Barbara Moore, National Institute for Social Care and Health Research Clinical Research Centre, Cardiff; Gareth Griffiths, University of Southampton, Southampton; Dana Knoyle, Prince Charles Hospital, Merthyr Tydfil; Penella J. Woll, Weston Park Hospital, Sheffield; Wiebke Appel, Royal Preston Hospital, Preston; Jeanette Dickson, Mount Vernon Cancer Center, Northwood; David Ferry, Royal Wolverhampton Hospitals National Health Service Trust, Wolverhampton; Caroline Brammer, Mid Staffordshire Hospital, Stafford, United Kingdom; and Seamus Linnane, Beaumont Hospital, Dublin, Ireland.
authors.forename: Sheikh
authors.initials: S
authors.lastname: Ahmed
authors.affiliation: Fergus Macbeth, Jessica Evans, Sheikh Ahmed, and Gareth Griffiths, Wales Cancer Trials Unit; Simon Noble and Kerenza Hood, Cardiff University; David Cohen and Mirella Longo, University of South Wales; Barbara Moore, National Institute for Social Care and Health Research Clinical Research Centre, Cardiff; Gareth Griffiths, University of Southampton, Southampton; Dana Knoyle, Prince Charles Hospital, Merthyr Tydfil; Penella J. Woll, Weston Park Hospital, Sheffield; Wiebke Appel, Royal Preston Hospital, Preston; Jeanette Dickson, Mount Vernon Cancer Center, Northwood; David Ferry, Royal Wolverhampton Hospitals National Health Service Trust, Wolverhampton; Caroline Brammer, Mid Staffordshire Hospital, Stafford, United Kingdom; and Seamus Linnane, Beaumont Hospital, Dublin, Ireland.
authors.forename: David
authors.initials: D
authors.lastname: Cohen
authors.affiliation: Fergus Macbeth, Jessica Evans, Sheikh Ahmed, and Gareth Griffiths, Wales Cancer Trials Unit; Simon Noble and Kerenza Hood, Cardiff University; David Cohen and Mirella Longo, University of South Wales; Barbara Moore, National Institute for Social Care and Health Research Clinical Research Centre, Cardiff; Gareth Griffiths, University of Southampton, Southampton; Dana Knoyle, Prince Charles Hospital, Merthyr Tydfil; Penella J. Woll, Weston Park Hospital, Sheffield; Wiebke Appel, Royal Preston Hospital, Preston; Jeanette Dickson, Mount Vernon Cancer Center, Northwood; David Ferry, Royal Wolverhampton Hospitals National Health Service Trust, Wolverhampton; Caroline Brammer, Mid Staffordshire Hospital, Stafford, United Kingdom; and Seamus Linnane, Beaumont Hospital, Dublin, Ireland.
authors.forename: Kerenza
authors.initials: K
authors.lastname: Hood
authors.affiliation: Fergus Macbeth, Jessica Evans, Sheikh Ahmed, and Gareth Griffiths, Wales Cancer Trials Unit; Simon Noble and Kerenza Hood, Cardiff University; David Cohen and Mirella Longo, University of South Wales; Barbara Moore, National Institute for Social Care and Health Research Clinical Research Centre, Cardiff; Gareth Griffiths, University of Southampton, Southampton; Dana Knoyle, Prince Charles Hospital, Merthyr Tydfil; Penella J. Woll, Weston Park Hospital, Sheffield; Wiebke Appel, Royal Preston Hospital, Preston; Jeanette Dickson, Mount Vernon Cancer Center, Northwood; David Ferry, Royal Wolverhampton Hospitals National Health Service Trust, Wolverhampton; Caroline Brammer, Mid Staffordshire Hospital, Stafford, United Kingdom; and Seamus Linnane, Beaumont Hospital, Dublin, Ireland.
authors.forename: Dana
authors.initials: D
authors.lastname: Knoyle
authors.affiliation: Fergus Macbeth, Jessica Evans, Sheikh Ahmed, and Gareth Griffiths, Wales Cancer Trials Unit; Simon Noble and Kerenza Hood, Cardiff University; David Cohen and Mirella Longo, University of South Wales; Barbara Moore, National Institute for Social Care and Health Research Clinical Research Centre, Cardiff; Gareth Griffiths, University of Southampton, Southampton; Dana Knoyle, Prince Charles Hospital, Merthyr Tydfil; Penella J. Woll, Weston Park Hospital, Sheffield; Wiebke Appel, Royal Preston Hospital, Preston; Jeanette Dickson, Mount Vernon Cancer Center, Northwood; David Ferry, Royal Wolverhampton Hospitals National Health Service Trust, Wolverhampton; Caroline Brammer, Mid Staffordshire Hospital, Stafford, United Kingdom; and Seamus Linnane, Beaumont Hospital, Dublin, Ireland.
authors.forename: Seamus
authors.initials: S
authors.lastname: Linnane
authors.affiliation: Fergus Macbeth, Jessica Evans, Sheikh Ahmed, and Gareth Griffiths, Wales Cancer Trials Unit; Simon Noble and Kerenza Hood, Cardiff University; David Cohen and Mirella Longo, University of South Wales; Barbara Moore, National Institute for Social Care and Health Research Clinical Research Centre, Cardiff; Gareth Griffiths, University of Southampton, Southampton; Dana Knoyle, Prince Charles Hospital, Merthyr Tydfil; Penella J. Woll, Weston Park Hospital, Sheffield; Wiebke Appel, Royal Preston Hospital, Preston; Jeanette Dickson, Mount Vernon Cancer Center, Northwood; David Ferry, Royal Wolverhampton Hospitals National Health Service Trust, Wolverhampton; Caroline Brammer, Mid Staffordshire Hospital, Stafford, United Kingdom; and Seamus Linnane, Beaumont Hospital, Dublin, Ireland.
authors.forename: Mirella
authors.initials: M
authors.lastname: Longo
authors.affiliation: Fergus Macbeth, Jessica Evans, Sheikh Ahmed, and Gareth Griffiths, Wales Cancer Trials Unit; Simon Noble and Kerenza Hood, Cardiff University; David Cohen and Mirella Longo, University of South Wales; Barbara Moore, National Institute for Social Care and Health Research Clinical Research Centre, Cardiff; Gareth Griffiths, University of Southampton, Southampton; Dana Knoyle, Prince Charles Hospital, Merthyr Tydfil; Penella J. Woll, Weston Park Hospital, Sheffield; Wiebke Appel, Royal Preston Hospital, Preston; Jeanette Dickson, Mount Vernon Cancer Center, Northwood; David Ferry, Royal Wolverhampton Hospitals National Health Service Trust, Wolverhampton; Caroline Brammer, Mid Staffordshire Hospital, Stafford, United Kingdom; and Seamus Linnane, Beaumont Hospital, Dublin, Ireland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Moore
authors.affiliation: Fergus Macbeth, Jessica Evans, Sheikh Ahmed, and Gareth Griffiths, Wales Cancer Trials Unit; Simon Noble and Kerenza Hood, Cardiff University; David Cohen and Mirella Longo, University of South Wales; Barbara Moore, National Institute for Social Care and Health Research Clinical Research Centre, Cardiff; Gareth Griffiths, University of Southampton, Southampton; Dana Knoyle, Prince Charles Hospital, Merthyr Tydfil; Penella J. Woll, Weston Park Hospital, Sheffield; Wiebke Appel, Royal Preston Hospital, Preston; Jeanette Dickson, Mount Vernon Cancer Center, Northwood; David Ferry, Royal Wolverhampton Hospitals National Health Service Trust, Wolverhampton; Caroline Brammer, Mid Staffordshire Hospital, Stafford, United Kingdom; and Seamus Linnane, Beaumont Hospital, Dublin, Ireland.
authors.forename: Penella J
authors.initials: PJ
authors.lastname: Woll
authors.affiliation: Fergus Macbeth, Jessica Evans, Sheikh Ahmed, and Gareth Griffiths, Wales Cancer Trials Unit; Simon Noble and Kerenza Hood, Cardiff University; David Cohen and Mirella Longo, University of South Wales; Barbara Moore, National Institute for Social Care and Health Research Clinical Research Centre, Cardiff; Gareth Griffiths, University of Southampton, Southampton; Dana Knoyle, Prince Charles Hospital, Merthyr Tydfil; Penella J. Woll, Weston Park Hospital, Sheffield; Wiebke Appel, Royal Preston Hospital, Preston; Jeanette Dickson, Mount Vernon Cancer Center, Northwood; David Ferry, Royal Wolverhampton Hospitals National Health Service Trust, Wolverhampton; Caroline Brammer, Mid Staffordshire Hospital, Stafford, United Kingdom; and Seamus Linnane, Beaumont Hospital, Dublin, Ireland.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Appel
authors.affiliation: Fergus Macbeth, Jessica Evans, Sheikh Ahmed, and Gareth Griffiths, Wales Cancer Trials Unit; Simon Noble and Kerenza Hood, Cardiff University; David Cohen and Mirella Longo, University of South Wales; Barbara Moore, National Institute for Social Care and Health Research Clinical Research Centre, Cardiff; Gareth Griffiths, University of Southampton, Southampton; Dana Knoyle, Prince Charles Hospital, Merthyr Tydfil; Penella J. Woll, Weston Park Hospital, Sheffield; Wiebke Appel, Royal Preston Hospital, Preston; Jeanette Dickson, Mount Vernon Cancer Center, Northwood; David Ferry, Royal Wolverhampton Hospitals National Health Service Trust, Wolverhampton; Caroline Brammer, Mid Staffordshire Hospital, Stafford, United Kingdom; and Seamus Linnane, Beaumont Hospital, Dublin, Ireland.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Dickson
authors.affiliation: Fergus Macbeth, Jessica Evans, Sheikh Ahmed, and Gareth Griffiths, Wales Cancer Trials Unit; Simon Noble and Kerenza Hood, Cardiff University; David Cohen and Mirella Longo, University of South Wales; Barbara Moore, National Institute for Social Care and Health Research Clinical Research Centre, Cardiff; Gareth Griffiths, University of Southampton, Southampton; Dana Knoyle, Prince Charles Hospital, Merthyr Tydfil; Penella J. Woll, Weston Park Hospital, Sheffield; Wiebke Appel, Royal Preston Hospital, Preston; Jeanette Dickson, Mount Vernon Cancer Center, Northwood; David Ferry, Royal Wolverhampton Hospitals National Health Service Trust, Wolverhampton; Caroline Brammer, Mid Staffordshire Hospital, Stafford, United Kingdom; and Seamus Linnane, Beaumont Hospital, Dublin, Ireland.
authors.forename: David
authors.initials: D
authors.lastname: Ferry
authors.affiliation: Fergus Macbeth, Jessica Evans, Sheikh Ahmed, and Gareth Griffiths, Wales Cancer Trials Unit; Simon Noble and Kerenza Hood, Cardiff University; David Cohen and Mirella Longo, University of South Wales; Barbara Moore, National Institute for Social Care and Health Research Clinical Research Centre, Cardiff; Gareth Griffiths, University of Southampton, Southampton; Dana Knoyle, Prince Charles Hospital, Merthyr Tydfil; Penella J. Woll, Weston Park Hospital, Sheffield; Wiebke Appel, Royal Preston Hospital, Preston; Jeanette Dickson, Mount Vernon Cancer Center, Northwood; David Ferry, Royal Wolverhampton Hospitals National Health Service Trust, Wolverhampton; Caroline Brammer, Mid Staffordshire Hospital, Stafford, United Kingdom; and Seamus Linnane, Beaumont Hospital, Dublin, Ireland.
authors.forename: Caroline
authors.initials: C
authors.lastname: Brammer
authors.affiliation: Fergus Macbeth, Jessica Evans, Sheikh Ahmed, and Gareth Griffiths, Wales Cancer Trials Unit; Simon Noble and Kerenza Hood, Cardiff University; David Cohen and Mirella Longo, University of South Wales; Barbara Moore, National Institute for Social Care and Health Research Clinical Research Centre, Cardiff; Gareth Griffiths, University of Southampton, Southampton; Dana Knoyle, Prince Charles Hospital, Merthyr Tydfil; Penella J. Woll, Weston Park Hospital, Sheffield; Wiebke Appel, Royal Preston Hospital, Preston; Jeanette Dickson, Mount Vernon Cancer Center, Northwood; David Ferry, Royal Wolverhampton Hospitals National Health Service Trust, Wolverhampton; Caroline Brammer, Mid Staffordshire Hospital, Stafford, United Kingdom; and Seamus Linnane, Beaumont Hospital, Dublin, Ireland.
authors.forename: Gareth
authors.initials: G
authors.lastname: Griffiths
mesh_terms: D000368:Aged; D000925:Anticoagulants / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006495:Heparin, Low-Molecular-Weight / Q000627:therapeutic use*; D006801:Humans; D008175:Lung Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D059039:Standard of Care; D015996:Survival Rate; D054556:Venous Thromboembolism / Q000209:etiology / Q000401:mortality / Q000517:prevention & control*
chemical_list: D000925:Anticoagulants; D006495:Heparin, Low-Molecular-Weight