In this prospective cohort of postmenopausal women, alcohol consumption among never smokers was inversely associated with CHD mortality. Among former smokers, alcohol consumption was inversely associated with CHD mortality but consuming at least 1 drink daily was positively associated with cancer incidence. Among current smokers, alcohol consumption was not associated with CHD mortality but was positively associated with cancer incidence among those consuming at least 1 drink daily. The differing associations of alcohol with CHD mortality by smoking history were statistically significant, and approached significance for cancer mortality and cancer incidence. Our finding of an inverse association of moderate alcohol consumption with CHD mortality among never and former smokers is consistent in direction61,62
and magnitude with previously published reports (HR, 0.5).63
Our findings contribute to the literature by simultaneously evaluating an interaction of alcohol consumption and cigarette smoking on CHD mortality and cancer incidence and mortality.
Numerous reports from cohort studies on the association of alcohol consumption with CHD morbidity and mortality have been published and adjustment for smoking history has generally not affected this association.35
However, relatively few studies have formally evaluated whether this association varies by smoking history (interaction). We identified 9 cohort analyses that explicitly evaluated and reported on whether there was an interaction among males,7,23,28,39
and a combined group17,40
(gender-specific results not reported). Among males, all 4 analyses found no evidence for an interaction. However, in 2 of these studies28,39
alcohol was not inversely associated with CHD overall. In Suhonen et al.,28
both smokers and nonsmokers who consumed alcohol had a higher relative risk of age-adjusted CHD death compared to nonsmoking abstainers. In Kivela et al.,39
no statistically significant relationship existed between low and moderate or heavy alcohol consumption and the odds of CHD death among smokers and nonsmokers after adjustment relative to abstainers, although higher levels of alcohol consumption were observed to have a modest inverse relationship among nonsmokers and a modest direct relationship among smokers for the odds of CHD death. Among combined cohorts who did not provide gender-specific results, a possible interaction was suggested in two independent cohorts of subjects undergoing health examinations at Kaiser (1964–1968, 1978–1985).17,40
In Klatsky et al.,17
the reduced risk of CHD mortality for consumers of 1–2 drinks/day compared to lifelong abstainers was greatest among ex-smokers (HR, 0.5; P
<.001) and nonsignificant for never smokers (HR, 1.0) and current smokers (HR, 0.6; P
=NS). These results are similar to our findings in former smokers but contrast with our finding of a significant inverse association between alcohol consumption and CHD mortality in never smokers. Finally, among females, all 3 analyses found an overall inverse association of alcohol with CHD, but no evidence for an interaction. However, 2 of these studies were likely underpowered to evaluate the interaction (approximately 200 events each).7,24
The third study was a follow-up of the National Health and Nutrition Examination Survey I (NHANES I) cohort10
in which the inverse association was seen in both nonsmokers and smokers, but it was not clear which group included former smokers.
Our observation that never smokers experience the greatest potential cardioprotection from alcohol may be related to the counteractive effects of alcohol and smoking on other risk factors for cardiovascular disease or events. Alcohol has been shown to raise high-density lipoprotein (HDL).64
However, multivariate analyses of epidemiologic data suggest that HDL changes can explain only 50% of the inverse association, suggesting a role for other hematologic or vascular effects. In a meta-analysis of 42 experimental studies, alcohol was shown to be associated with significantly higher concentrations of not only HDL but also apolipoprotein A-1 and plasminogen as well as lower concentrations of fibrinogen.65
Alcohol has also been suggested to be associated with increased fibrinolytic activity, decreased ADP-induced platelet aggregation,35
and improved insulin sensitivity.66
All of these effects could potentially decrease the risk for CHD events. However, these potentially cardioprotective effects may be negated by the adverse effects of smoking. Cigarette smoking has been associated with decreased concentrations of HDL67
and increased concentrations of both triglycerides and low-density lipoprotein (LDL),68
although more recent evidence suggests that the adverse effects of smoking operate independently of the lipid pathways.26
Smoking has also been associated with biologic markers of endothelial dysfunction,69
enhanced platelet aggregation,71
and impaired fibrinolysis.72
Smoking may also cause genomic destabilization, which may play an important role in the development of atherosclerosis.73
Because we did not obtain biological samples in our population, we could not evaluate these potential pathways.
Based upon evidence from human studies, alcohol is classified as a Group 1 carcinogen by the International Agency for Research on Cancer.49
Alcohol is considered to be causally associated with the development of cancer of the oral cavity, pharynx, larynx, esophagus, and liver, and data are suggestive for a positive association with rectal and breast cancer. No firm conclusions regarding alcohol's association with colon cancer have been made, and alcohol was considered unlikely for cancers of the lung, stomach, pancreatic cancer, urinary bladder, kidney, ovary, prostate, and lymphatic and hematopoietic systems. For all other sites, there were insufficient data regarding the role of alcohol. In our data, the differing effect of alcohol on cancer mortality varied by smoking history (test for interaction, P
=.05). This is consistent with previously published reports in women.40,74
We did not evaluate the association of alcohol with individual cancer sites, as this report was focused on cancer prevention more broadly defined. Furthermore, patients may be more concerned with preventing all types of cancer rather than site-specific cancers. Our results may inform general cancer risk reduction discussions that health professionals conduct with their patients.
This study has several strengths. First, this is a population-based study with 14 years of virtually complete follow-up for mortality. Second, we used a semiquantitative food frequency questionnaire for baseline data collection that has been shown to be reproducible for alcohol consumption in this population.56
Third, we excluded women with prior cardiovascular disease and cancer, decreasing the impact of including ex-drinkers with preexisting disease in the group of alcohol abstainers.30
Fourth, cancer incidence data were collected through SEER, requiring both clinical and histologic verification of cancer diagnoses. Finally, we analyzed the association of alcohol across the major causes of morbidity and mortality, which gives a broad perspective on the global impact of alcohol in this population.
There are several potential limitations to this study. First of all, we are using CHD mortality data and not incidence. Therefore, we may be unable to estimate the association of alcohol with coronary artery disease overall. However, our results may represent a potentially less biased estimate, especially compared to self-reported cardiac events, because the sensitivity of self-report for myocardial infarction among older patients is problematic.75
Another potential limitation relates to the fact that analyses were performed based upon alcohol consumption on the baseline questionnaire. This potentially results in misclassification of women whose alcohol pattern changed after completing the baseline survey. However, data from several U.S. prospective studies suggest that moderate drinkers and abstainers have more stable drinking patterns than heavy drinkers76
and our population consisted of mostly light drinkers. Another limitation of this study relates to the external validity of our findings. Ninety-eight percent of the women in the cohort consumed ≤40 g/day of alcohol, or less than 3 drinks daily. This may not be representative of women from other geographic regions who may have a higher rate or intensity of use.77
Further, we were unable to adequately assess the association of larger quantities of alcohol consumption (>3 drinks daily) on mortality and cancer incidence. Finally, while the inverse relationship between moderate alcohol consumption and CHD mortality has been demonstrated in multiple ethnic groups,63
we only examined predominantly white, Midwestern women, so these results may not be generalizable to other ethnic populations.
At present, many health professionals do not discourage their patients from consuming alcohol and some health professionals may recommend it with appropriate screening and precautions.78
If our observations are confirmed, our findings suggest that smoking history should be considered when clinicians engage patients in health behavior counseling relating to alcohol consumption and cardioprotection.