title: Fungal infection-related mortality versus total mortality as an outcome in trials of antifungal agents.
abstract: BACKGROUND
  Disease specific mortality is often used as outcome rather than total mortality in clinical trials. This approach assumes that the classification of cause of death is unbiased. We explored whether use of fungal infection-related mortality as outcome rather than total mortality leads to bias in trials of antifungal agents in cancer patients.
  
  
  METHODS
  As an estimate of bias we used relative risk of death in those patients the authors considered had not died from fungal infection. Our sample consisted of 69 trials included in four systematic reviews of prophylactic or empirical antifungal treatment in patients with cancer and neutropenia we have published previously.
  
  
  RESULTS
  Thirty trials met the inclusion criteria. The trials comprised 6130 patients and 869 deaths, 220 (25%) of which were ascribed to fungal infection. The relative risk of death was 0.85 (95% CI 0.75-0.96) for total mortality, 0.57 (95% CI 0.44-0.74) for fungal mortality, and 0.95 (95% CI 0.82-1.09) for mortality among those who did not die from fungal infection.
  
  
  CONCLUSIONS
  We could not support the hypothesis that use of disease specific mortality introduces bias in antifungal trials on cancer patients as our estimate of the relative risk for mortality in those who survived the fungal infection was not increased. We conclude that it seems to be reliable to use fungal mortality as the primary outcome in trials of antifungal agents. Data on total mortality should be reported as well, however, to guard against the possible introduction of harmful treatments.
authors.affiliation: Nordic Cochrane Centre, Rigshospitalet, Dept, 7112, Blegdamsvej 9, DK-2100 København Ø, Denmark. anne.k.due@sol.dk
authors.forename: Anne K
authors.initials: AK
authors.lastname: Due
authors.forename: Helle K
authors.initials: HK
authors.lastname: Johansen
authors.forename: Peter C
authors.initials: PC
authors.lastname: Gøtzsche
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015982:Bias; D002423:Cause of Death; D016638:Critical Illness / Q000401:mortality; D006801:Humans; D016867:Immunocompromised Host; D015994:Incidence; D009181:Mycoses / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D009369:Neoplasms / Q000150:complications / Q000276:immunology / Q000401:mortality*; D009503:Neutropenia / Q000150:complications / Q000276:immunology / Q000401:mortality*; D009894:Opportunistic Infections / Q000150:complications / Q000401:mortality*; D016032:Randomized Controlled Trials as Topic; D012306:Risk; D016896:Treatment Outcome
chemical_list: D000935:Antifungal Agents