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.

Conclusion: 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.

Figure 1

Relative risk of death from causes other than fungal infection in those who survived the fungal infection. Provided the two groups are still comparable after subtraction of fungal deaths from those randomised, the proportion of those who died from another cause than fungal infection would be expected to be the same in the two groups (fig. 1a). If, however, there was a bias in classification of cause of death in favour of the treated group, fewer deaths would be ascribed to fungal infection and more deaths to other causes in this group. This would result in a larger relative risk of death for those who did not die from fungal infection (fig. 1b). This risk is an estimate of bias overall: RR = (d_exp/(N_exp-F_exp))/(d_ctr/(N_ctr-F_ctr)), where exp: experimental group; ctr: control group; N_exp, N_ctr: numbers of randomised patients; F_exp, F_ctr: numbers of deaths from fungal infection; d_exp, d_ctr: numbers of deaths from causes other than fungal infection.