Design Population based cohort study.

Setting Denmark, 1993-2002.

Participants 28 448 women and 25 052 men aged 50-65 years, who were free of cardiovascular disease at entry to the study.

Main outcome measures Incidence of coronary heart disease occurring during a median follow-up period of 5.7 years.

Results 749 and 1283 coronary heart disease events occurred among women and men. Women who drank alcohol on at least one day a week had a lower risk of coronary heart disease than women who drank alcohol on less than one day a week. Little difference was found, however, between drinking frequency: one day a week (hazard ratio 0.64, 95% confidence interval 0.51 to 0.81), 2-4 days a week (0.63, 0.52 to 0.77), five or six days a week (0.79, 0.61 to 1.03), and seven days a week (0.65, 0.51 to 0.84). For men an inverse association was found between drinking frequency and risk of coronary heart disease across the entire range of drinking frequencies. The lowest risk was observed among men who drank daily (0.59, 0.48 to 0.71) compared with men who drank alcohol on less than one day a week.

In the food frequency questionnaire alcohol intake was reported as the average amount over the preceding year. Total intake was calculated and converted into number of standard drinks, defined as containing 12 g of ethanol. Drinking frequency was reported in the background questionnaire in predefined categories (never, less than once a month, 1-3 times monthly, once a week, 2-4 times weekly, 5 or 6 times weekly, and daily). We defined abstainers as those who reported no alcohol intake (amount) and no drinking occasions (frequency). To increase homogeneity among abstainers we excluded 786 people who reported no amount but a frequency greater than zero (or vice versa). We also excluded people with missing information (n = 303) or with conflicting answers on amount and frequency of alcohol intake (n = 97). In all, 53 500 people were eligible for this study.

Infrequent drinkers (less than one day a week) and daily drinkers (daily) were more likely to be smokers, to have a lower intake of fruit and vegetables, and to be less educated than participants in the in between drinking frequencies (table 1). Body mass index was inversely associated with drinking frequency and frequent drinkers had the lowest body mass index. These trends were the same for both sexes. Generally, fewer women than men were current and heavy smokers (> 25 g of tobacco daily) and women had more hours of physical activity a week and consumed more fruit and vegetables.

During follow-up (median 5.7 years, range 0.01-8.10) 749 women and 1283 men developed coronary heart disease. Information on 1933 of these cases came from the Danish Hospital Discharge Register. Based on incidence rates from the general population the expected number of cases from this register was 716 women (737 observed) and 1217 men (1196 observed). The observed number did not differ significantly from the expected (P > 0.10).

Amount of alcohol intake was inversely associated with coronary heart disease among women and men (figure).

Among women, drinking on at least one day a week was associated with a lower risk of coronary heart disease than drinking more rarely than one day a week (table 2). Hazard ratios were similar for drinking on one day a week (0.64, 95% confidence interval 0.51 to 0.81), 2-4 days a week (0.63, 0.52 to 0.77), five or six days a week (0.79, 0.61 to 1.03), and seven days a week (0.65, 0.51 to 0.84). A test for trend not including women that were drinking more rarely than one day a week was statistically insignificant (P = 0.49).

Among men, drinking frequency was inversely associated with risk of coronary heart disease over the whole range of drinking frequencies (table 2). Hazard ratios were 0.93 (0.75 to 1.16) for drinking on one day a week, 0.78 (0.66 to 0.94) for 2-4 days a week, 0.71 (0.57 to 0.87) for five or six days a week, and 0.59 (0.48 to 0.71) for seven days a week (P for trend < 0.0001). The test for linear trend remained statistically significant after excluding men drinking more rarely than on one day a week (P < 0.0001).

A statistically significant interaction was found between sex and drinking frequency on the risk of coronary heart disease (P = 0.02).

Table 3 lists the hazard ratios of coronary heart disease for different combinations of alcohol amount and drinking frequency. Within similar categories of drinking frequency, women drinking the largest amounts generally had the lowest risk. For example, among women drinking on 2-4 days a week the hazard ratio was 0.78 (0.63 to 0.97) for 1-6 drinks a week, 0.74 (0.57 to 0.96) for 7-13 drinks a week, and 0.27 (0.13 to 0.58) for 14 or more drinks a week (P for trend < 0.0001). For men, hazard ratios were generally lowest for the most frequent intake within similar categories of amount (table 3). For example, among men drinking on average 7-13 drinks a week, hazard ratios of coronary heart disease were 0.89 (0.62 to 1.29) for drinking alcohol on one or less days a week, 0.81 (0.67 to 0.98) for 2-4 days a week, and 0.66 (0.52 to 0.83) for 5-7 days a week (P for trend = 0.0001). Within categories of drinking frequency, hazard ratios tended to be similar.

A limitation of our study is that only 35% of the invited people participated and hence caution should be taken when generalising our findings. People who choose to participate may have a different risk profile and be in better health than those who decline. However, the observed incidence of coronary heart disease did not differ from that of the general population.

We found that the association between drinking frequency and coronary heart disease was different for men and women. The number of cases was substantially lower among women than among men, however, and hence results for women are less certain and warrant further study.

We cannot exclude the possibility that participants with early symptoms of coronary heart disease at baseline had reduced their drinking frequency, explaining the inverse association. However, this association persisted when we analysed early cases separately, indicating that the observed association is unlikely to be explained by this possible bias.

Some unhealthy traits (smoking and a low intake of fruit and vegetables) were common at both extremes of drinking frequency. Everyday drinking may be associated with borderline addictive behaviour, and a strong association between smoking and drinking has been observed in many studies.¹⁵ For the most rare drinkers, the unhealthy lifestyle may be explained by the fact that they were the poorest educated, which probably correlates with low social status. Also this category may include former alcoholics. Together, results for the extremes of drinking frequency are more likely to be residually confounded than results for the in between drinking frequencies and should be interpreted with caution. However, at least among men, we found an inverse association between drinking frequency and coronary heart disease over the entire range of drinking frequencies.

Drinking patterns in our study were constructed by combining information on average intake with drinking frequency, as done in another study.⁶ We have avoided the term “binge drinking,” which is mostly defined as drinking a minimum number of drinks per occasion and we cannot comment on this with the present data.

Several explanations may account for a possible interaction between sex and drinking frequency. One explanation is sex specific drinking habits, such as drinking with meals. We cannot exclude that men who drink frequently are more likely to drink with meals, which may contribute to a greater risk reduction compared with men with a less frequent alcohol intake. The beneficial effect of meal related alcohol intake is, however, controversial.⁶ It is unlikely that wine drinking, which may be more beneficial than drinking beer or spirits,¹⁶ is responsible for our results because it has been shown that wine drinkers in this cohort drink less often than beer drinkers.¹⁷ Differences in alcohol pharmacokinetics between sexes may be another explanation.⁷

The association between alcohol and coronary heart disease among women may be modified by menopausal status. Oestrogens have beneficial effects on the cardiovascular system, protecting women until menopause, when the incidence rapidly approaches that among men.¹⁸ Moderate alcohol drinking is thought to increase oestrogen levels.⁸ Few women in this study (17%) were premenopausal and our findings may be limited to postmenopausal women.

The inverse association between alcohol and coronary heart disease can be explained by several biologically plausible mechanisms, including dose dependent effects on high density lipoprotein levels, lower plasma fibrinogen levels, and reduced platelet aggregation.¹⁹ These potential beneficial effects of alcohol must be considered along with potential adverse effects of a high intake, such as high blood pressure and increased triglyceride levels.²⁰ The question is if the balance between beneficial and harmful effects is affected by drinking pattern. Heavy weekend drinkers have been found to have a higher daily blood pressure²¹ and to have greater between day variability in blood pressure than heavy daily drinkers.^22,23 Results are conflicting as to whether drinking pattern modifies lipid levels. Some studies found that only regular drinking can raise high density lipoprotein levels,^24,25 whereas others found this among weekend drinkers.²⁶ The presumed lowering effect of alcohol on fibrinogen levels has been found to be independent of drinking pattern (daily versus weekend drinking).²⁷ It has not been investigated if drinking pattern affects the presumed association between alcohol and increased oestrogen levels among women.

Heavy alcohol drinking is positively associated with many problems such as liver diseases, cancers, and road crashes, and overall mortality is higher among individuals with a high alcohol intake compared with light consumers, reflecting that the beneficial effects of alcohol on coronary heart disease is by far exceeded by the detrimental effects of alcohol at these levels. Also, the beneficial effect of alcohol is probably confined to middle aged or older people.²⁸ Therefore the inverse association between alcohol intake and coronary heart disease should be viewed in this context when giving public health advice. In conclusion, we found that drinking frequency seemed to be the main determinant of the inverse association between alcohol intake and coronary heart disease among men, which confirms results from another study.⁶ For women, amount of alcohol may be more important than frequency.