Objective: To evaluate the relation of topical tretinoin, a commonly used retinoid cream, with all-cause mortality in the Veterans Affairs Topical Tretinoin Chemoprevention Trial (VATTC). The planned outcome of this trial was risk of keratinocyte carcinoma, and systemic administration of certain retinoid compounds has been shown to reduce risk of this cancer but has also been associated with increased mortality risk among smokers. Design: The VATTC Trial was a blinded randomized chemoprevention trial, with 2- to 6-year follow-up. Oversight was provided by multiple independent committees. Setting: US Department of Veterans Affairs medical centers. Patients: A total of 1131 veterans were randomized. Their mean age was 71 years. Patients with a very high estimated short-term risk of death were excluded. Interventions: Application of tretinoin, 0.1%, or vehicle control cream twice daily to the face and ears. Main Outcome Measures: Death, which was not contemplated as an end point in the original study design. Results: The intervention was terminated 6 months early because of an excessive number of deaths in the tretinoin-treated group. Post hoc analysis of this difference revealed minor imbalances in age, comorbidity, and smoking status, all of which were important predictors of death. After adjusting for these imbalances, the difference in mortality between the randomized groups remained statistically significant. Conclusions: We observed an association of topical tretinoin therapy with death, but we do not infer a causal association that current evidence suggests is unlikely. Trial Registration: clinicaltrials.gov Identifier: NCT00007631.
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