The effect of beta-carotene on the mortality of male smokers is modified by smoking and by vitamins C and E : evidence against a uniform effect of nutrient

A previous analysis of the Alpha-Tocopherol Beta-Carotene (ATBC) Study on male smokers found that beta-carotene supplementation increased the risk of pneumonia 4-fold in those who started smoking at the age of >= 21 years and smoked >= 21 cigarettes/d (a subgroup of 7 % of the study population). The present study hypothesised that beta-carotene increases mortality in the same subgroup. The ATBC Study (1985-1993) recruited 29 133 Finnish male smokers (>= 5 cigarettes/d) aged 50-69 years. Cox regression models were constructed to estimate the effect of beta-carotene supplementation in subgroups. beta-Carotene increased mortality (risk ratio 1 center dot 56; 95 % CI 1 center dot 06, 2 center dot 3) in those who started to smoke at >= 21 years and smoked >= 21 cigarettes/d. Within this subgroup, there was strong evidence of further heterogeneity. The effect of beta-carotene supplementation was further modified by dietary vitamin C intake, fruit and vegetable intake (P = 0 center dot 0004), and by vitamin E supplementation (P = 0 center dot 011). Thus, harm from beta-carotene was not uniform within the study population. Interactions between beta-carotene and vitamins C and E were seen only within a subgroup of 7 % of the ATBC participants, and therefore should not be extrapolated to the general population. Heterogeneity of the beta-carotene effect on mortality challenges the validity of previous meta-analyses that have pooled many diverse antioxidants for one single estimate of effect using the assumption that a single estimate equally applies to all antioxidants and all people. Trial registration: ClinicalTrials.gov NCT00342992.Peer reviewe