Excess Deaths in Tretinoin Trial Don"t Appear to be Caused by Drug

NEW YORK JAN 19, 2009(Reuters Health) - Although the Veterans Affairs Topical Tretinoin Chemoprevention (VATTC) Trial was stopped 6 months short of its 6-year end date because of an increased number of deaths associated with tretinoin, the investigators believe that the higher mortality rate was a chance finding and not a real biologic effect.

"The biological implausibility, lack of specificity of causes of death, inconsistency with previous experience, weakness of other supportive evidence in our data, and weak statistical signal cast doubt on a potential causal association of topical tretinoin with death in the VATTC trial," lead author Dr. Martin A. Weinstock and colleagues conclude in the January Archives of Dermatology.

The VATTC trial was a randomized, placebo-controlled trial designed to test the theory that topical tretinoin (0.1%) would prevent the development of basal cell and squamous cell carcinomas of the skin.

The 1131 trial participants had at least two keratinocyte carcinomas during the 5 years prior to the study, but were free of skin cancer at the time of randomization between 1998 and 2002. Patients with a very high risk of death within 3 years were excluded. Mean age at baseline was 71 years; 97% were men.

Study protocol called for study cream (tretinoin or vehicle control) to be applied to the face and ears up to twice daily as tolerated. Subjects were examined by a dermatologist every 6 months.

In the March 2004 database update, there were significantly more deaths in the intervention group (82 vs 53, p = 0.01), and the trial was stopped in May. Further review of the VA master death file identified more deaths. By the end of follow-up in November of that year, 122 deaths (22%) were documented in the tretinoin group and 90 (16%) in the control group (p = 0.02).

Dr. Weinstock, from Brown University and the VA Medical Center in Providence, Rhode Island, and his group note that topical tretinoin has been used "for decades, with no suggestion of an associated mortality risk."

"We do not conclude that this trial provides appropriate grounds for hesitating to use topical tretinoin in clinical practice in the absence of additional evidence," they conclude.

In an editorial published in the same issue of the journal, Drs. Lisa M. Schilling and Robert P. Dellavalle recommend that prescribing physicians discuss the VATTC trial results with elderly men - and perhaps all patients - using topical tretinoin.

Noting that systemic retinoid treatment has been associated with increased mortality among smokers, the editorialists suggest that "these discussions provide an opportunity for all health care providers prescribing tretinoin to emphasize tobacco prevention and cessation with their patients."

SOURCE:

• Arch Dermatol 2009;145:18-24,76.



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