Pattern of Lifetime Alcohol Use and Cause of Death
Pattern of Lifetime Alcohol Use and Cause of Death
Among men, 98% had used alcohol at some point during their lifetime (N = 110 162) and of those the majority (96%) were alcohol users at the time of enrolment (Table 1). Most of these men (80%) were always light users (3%), always below the recommended limit (39%) or light to moderate users (38%). About one-fifth of alcohol users reported heavy alcohol use at some point in their lifetime. Of the non-users at enrolment (N = 6718), 73% were former alcohol users. Men who were lifetime light, below the recommended limit, or light to moderate alcohol users were more highly educated than lifetime or former heavy users. Lifetime heavy users were more likely to be younger, a long-term smoker, to have a higher meat intake and to have more abdominal obesity than lifetime light, below the recommended limit, or light to moderate alcohol users. Comparably, former heavy users were more likely to be heavy smokers and to report a prevalent disease.
In women, 15% were non-users of alcohol at enrolment, most of whom (68%) were never users (Table 2). Among lifetime alcohol users (N = 227 705), the vast majority (88%) were light (15%), below the recommended limit (44%), or light to moderate alcohol users (29%). Women with heavy alcohol consumption were on average younger, more likely to be highly educated, to be a smoker and to have a low intake of fruits and vegetables, and were less likely to report a prevalent disease than all other types of alcohol users. Among women who had used alcohol at some point during their lifetime (N = 240 767), 12% had used it heavily at least at one of these points. Similarly to men, a higher proportion of women who were former heavy alcohol users reported a prevalent disease or long-term smoking.
Compared with men who had used alcohol lightly throughout their lifetime up to enrolment, men who were former heavy users had higher relative risks of death for the largest number of causes, and this was most pronounced for alcohol-related cancers (5-fold increased risk), other causes (3.1-fold), diseases of the digestive (2.7-fold) or respiratory system (2.4-fold), but also for other neoplasms (1.8-fold), CHD and other CVD (1.7- and 1.6-fold, respectively) (Table 3). Former light to moderate users also had a higher risk of death from alcohol-related and other cancers and other causes (1.4–2.4-fold). Among lifetime alcohol users, men who were heavy or occasional heavy users had a higher risk of death from alcohol-related and other cancers, digestive diseases and external and other causes.
In contrast, men whose lifetime alcohol consumption remained below the recommended limit or light to moderate had a 28% and 24% lower risk of death from CVD, respectively. No association was seen among always or occasionally heavy users.
Similarly to men, women who were heavy alcohol users throughout their lifetime had higher risks of death from alcohol-related cancer (about 2-fold) respiratory (3.5-fold), digestive (about 10-fold) or other causes (about 3-fold) compared with lifetime light users. Also similarly to men, lower relative risks of death from cardiovascular events were observed in women who used alcohol always below the recommended limit, never-heavy or occasionally heavy (34%, 38% and 46%, respectively) compared with lifetime light users. It should be noted that the lower relative risk of death among occasionally heavy users was stronger and statistically significant only after multiple adjustments. The numbers of deaths among former heavy users was small for all causes; however, former heavy users had a higher risk of death from respiratory diseases and external causes (about 4–5-fold increased risk), digestive diseases (about 15-fold) and other causes (about 3-fold), compared with always light alcohol users (Table 4).
When analyses for broad causes of death (CVD, cancer and other causes) were stratified by disease status at enrolment, the lower risks of death from CVD in men and women were only evident amongst those who had not developed diseases before enrolment (Supplementary Tables 1 and 2, available as Supplementary data at IJE online). In women, but not in men, the shape of the relationship differed according to disease status (P for interaction = 0.013), although the risk estimates were similar between men and women, with a 50% lower risk of death from CVD among alcohol users without a chronic disease at enrolment and a 33% higher risk among never alcohol users who had developed a chronic disease at enrolment, compared with lifetime light alcohol users.
Further sensitivity analyses showed that excluding deaths that occurred within the first 3 years of follow-up, or participants who were aged ≤50 years at the time of enrolment, did not alter the results. However, some of the associations were more evident either in northern or in southern countries such as: death from CVD (excluding CHD) among men, where a lower risk of death among those who used alcohol within the recommended limit existed only in northern countries (P for interaction = 0.043); and death from other neoplasms in women, where the higher risks among never and former alcohol users were only seen in southern countries (P for interaction = 0.0049).
The risk relationship between alcohol consumption during midlife and cause of death was non-linear in men for CVD, respiratory, digestive, external and other causes, and for CHD, other neoplasms, respiratory and other causes in women (Figures 3 and 4). Although the gradients and the nadirs of the relative risk curves differed considerably, most of the associations between alcohol use and cause of death were statistically significant. In men, two patterns of curves were observed for alcohol consumption at the time of enrolment. One was associated with a higher relative risk of death from alcohol-related cancers, digestive and external causes, other neoplasms and other causes, only for consumption higher than 24g/day (Figure 3). However, this pattern was not observed for death from CHD, other CVD or respiratory diseases where the risk curve did not increase with higher alcohol consumption. In women, the risk relationships for death from almost all causes were similar to those seen in men except for external causes, alcohol-related cancers, and diseases of the digestive system, where with increasing alcohol consumption the relative risk curves of death from digestive causes increased more steeply and those from external causes and alcohol-related cancers attenuated apparently (Figure 4).
(Enlarge Image)
Figure 3.
Spline regression of the association of g/day alcohol use at enrolment and causes of death among men participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, whose alcohol use was >0 at that time, stratifying by centre and age, and adjusting for body mass index, height, waist circumference, intake of fruits, vegetables, red meat and meat products, dietary fibre, physical activity, education, smoking and prevalent disease (self-reported cancer, myocardial infarction, stroke, diabetes mellitus or hypertension).
P–values for linearity and for general effect respectively were for CHD = 0.151 and 0.004, CVD = 0.001 and 0.001, alcohol-related cancers = 0.059 and <0.001, other neoplasms = 0.172 and <0.001, respiratory causes = <0.001 and <0.001, digestive causes = <0.001 and <0.001, external causes = 0.044 and <0.001 and other causes = <0.001 and <0.001.
CHD, coronary heart disease; CVD, cardiovascular disease other than CHD; AC, alcohol-related cancer; ON, other neoplasms; R, respiratory system; D, digestive system; E, external causes; OC, other causes
(Enlarge Image)
Figure 4.
Spline regression of the association of g/d alcohol use at enrolment and causes of death among women participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, whose alcohol use was >0 at that time; stratifying by centre and age and adjusting for body mass index, height, waist circumference, intake of fruits, vegetables, red meat and meat products, dietary fibre, physical activity, education, smoking, menopausal hormone use, number of live births, menopausal status and prevalent disease (self-reported cancer, myocardial infarction, stroke, diabetes mellitus or hypertension).
P-values for linearity and for general effect respectively were for CHD = 0.028 and <0.001, CVD = 0.089 and 0.061, alcohol-related cancers = 0.076 and 0.028, other neoplasms = 0.013 and 0.033, respiratory causes = 0.001 and 0.003, digestive causes = 0.950 and 0.002, external causes = 0.399 and 0.602 and other causes = 0.001 and <0.001.
CHD, coronary heart disease; CVD, cardiovascular disease other than CHD; AC, alcohol-related cancer; ON, other neoplasms; R, respiratory system; D, digestive system; E, external causes; OC, other causes
Sensitivity analyses investigated the shapes of the curves following exclusion of participants with a self-reported prevalent disease and following adjustment for prevalent disease. The shapes of the risk relationship for alcohol consumption and death changed slightly in men and obviously in women for diseases of the digestive system, and slightly for alcohol-related cancer and other causes in women (Supplementary Figures 3 and 4, available as Supplementary data at IJE online). Excluding women with prevalent diseases (instead controlling for disease status at enrolment) attenuated the relative risk of death from alcohol-related cancers and increased the relative risk of death from a disease of the digestive system even further at a level of alcohol use higher than 12 g/day.
Compared with participants who used alcohol within recommended limits throughout their lifetime, those who had used it more heavily in the past (but not at enrolment) had higher risks of death from CVD [women: HR 1.21; 95% confidence interval (CI) 1.02, 1.43], alcohol-related cancer (men: HR 1.32; 95% CI 1.10, 1.60), disease of the respiratory system (men: HR 1.28; 95% CI 1.01, 1.62), external cause (men: HR 1.51; 95% CI 1.18, 1.93) or other causes (men: HR 1.49; 95% CI 1.24, 1.79; women: HR 1.27; 95% CI 1.03, 1.58). Compared with men who had a lifetime alcohol use below the recommended limit, there was a higher risk of death from alcohol-related cancer in men who used more than the recommended amount at enrolment, regardless of their past consumption habits (HR 1.36; 95% CI 1.05, 1.76 if their whole past consumption was below the limit or HR 1.57; 95% CI 1.33, 1.87 if their past consumption was always or occasionally above the limit). Higher risks were also seen with a lifetime alcohol use above the recommended limit for death from digestive (HR 1.42; 95% CI 1.02, 1.96), external (HR 1.57; 95% CI 1.24, 1.99) and other causes (HR 1.54; 95% CI 1.29, 1.84). In women however, compared with those who used alcohol below the recommended limit throughout their lifetime, a lower relative risk of death from CHD was seen among those who used alcohol heavily at enrolment although having using alcohol in the past below the recommended limit (HR 0.57; 95% CI 0.41, 0,78).
A total of 266 participants died from a cause directly related to alcohol use (e.g. alcohol-induced intoxication, dependence, certain external causes), of whom 197 were men. Compared with men who consistently used alcohol below the recommended limit (i.e. at enrolment and in the past), men who had previously used it above the limit (but whose consumption was lower at enrolment) had a risk of death from alcohol-related causes of 7.12 (95% CI 3.79, 13.37); those who had used more than the recommended limit, but not in the past, had a corresponding risk of 5.08 (95% CI 2.48, 10.52); men who used more than the recommended limit over their lifetime (i.e. in the past and at enrolment) had a risk of death from a cause directly related to alcohol of 9.22 (95% CI 5.11, 16.63). The number of women who died from a cause directly related to alcohol was too small for reasonable analysis.
The statistical tests for both models of lifetime alcohol use and alcohol consumption at enrolment showed different relationships for many causes in men and in women (Supplementary Tables 3 and 4, available as Supplementary data at IJE online). Distinct relationships were observed for death from alcohol-related cancer as compared with CHD or CVD in men and in women (all P-values for difference were statistically significant). Further contrasts between risk associations of lifetime pattern or alcohol use at enrolment emerged for external and other causes in men and for diseases of the digestive system in women when compared with all other groups of causes.
Compared with men and women who used alcohol lightly throughout their lifetime, those who used it in restricted amounts (i.e. below the recommended limits throughout their lifetime) had the lowest relative risk of overall death, whereas those who used alcohol heavily, either at enrolment or in the past, had the highest relative risk of death (Table 5). Women who were never alcohol users also had a greater risk of death than lifetime light users. Expressing the relative risks as advancement periods, compared with lifetime light alcohol users of the same age at enrolment, former light to moderate users had died, on average, 1.5–years earlier; former heavy users died, on average, 5.2 years earlier. The corresponding figures for women were 1.5 and 3.7 years, respectively. Lifetime heavy alcohol users died on average 3.2 (men) and 2.0 (women) years earlier than lifetime light users. Men who never used alcohol died 5.1 years earlier than lifetime light users when a prevalent disease was present at enrolment, whereas those without a disease had a death rate similar to that of lifetime light alcohol users. Further, former heavy alcohol users with a prevalent disease died about 17.4-years earlier than lifetime light users with a prevalent disease; among those without prevalent disease, former heavy users died only 3.4 years earlier than lifetime light users.
Results
Description of Alcohol Users
Among men, 98% had used alcohol at some point during their lifetime (N = 110 162) and of those the majority (96%) were alcohol users at the time of enrolment (Table 1). Most of these men (80%) were always light users (3%), always below the recommended limit (39%) or light to moderate users (38%). About one-fifth of alcohol users reported heavy alcohol use at some point in their lifetime. Of the non-users at enrolment (N = 6718), 73% were former alcohol users. Men who were lifetime light, below the recommended limit, or light to moderate alcohol users were more highly educated than lifetime or former heavy users. Lifetime heavy users were more likely to be younger, a long-term smoker, to have a higher meat intake and to have more abdominal obesity than lifetime light, below the recommended limit, or light to moderate alcohol users. Comparably, former heavy users were more likely to be heavy smokers and to report a prevalent disease.
In women, 15% were non-users of alcohol at enrolment, most of whom (68%) were never users (Table 2). Among lifetime alcohol users (N = 227 705), the vast majority (88%) were light (15%), below the recommended limit (44%), or light to moderate alcohol users (29%). Women with heavy alcohol consumption were on average younger, more likely to be highly educated, to be a smoker and to have a low intake of fruits and vegetables, and were less likely to report a prevalent disease than all other types of alcohol users. Among women who had used alcohol at some point during their lifetime (N = 240 767), 12% had used it heavily at least at one of these points. Similarly to men, a higher proportion of women who were former heavy alcohol users reported a prevalent disease or long-term smoking.
Cause-specific Mortality According to Lifetime Alcohol use
Compared with men who had used alcohol lightly throughout their lifetime up to enrolment, men who were former heavy users had higher relative risks of death for the largest number of causes, and this was most pronounced for alcohol-related cancers (5-fold increased risk), other causes (3.1-fold), diseases of the digestive (2.7-fold) or respiratory system (2.4-fold), but also for other neoplasms (1.8-fold), CHD and other CVD (1.7- and 1.6-fold, respectively) (Table 3). Former light to moderate users also had a higher risk of death from alcohol-related and other cancers and other causes (1.4–2.4-fold). Among lifetime alcohol users, men who were heavy or occasional heavy users had a higher risk of death from alcohol-related and other cancers, digestive diseases and external and other causes.
In contrast, men whose lifetime alcohol consumption remained below the recommended limit or light to moderate had a 28% and 24% lower risk of death from CVD, respectively. No association was seen among always or occasionally heavy users.
Similarly to men, women who were heavy alcohol users throughout their lifetime had higher risks of death from alcohol-related cancer (about 2-fold) respiratory (3.5-fold), digestive (about 10-fold) or other causes (about 3-fold) compared with lifetime light users. Also similarly to men, lower relative risks of death from cardiovascular events were observed in women who used alcohol always below the recommended limit, never-heavy or occasionally heavy (34%, 38% and 46%, respectively) compared with lifetime light users. It should be noted that the lower relative risk of death among occasionally heavy users was stronger and statistically significant only after multiple adjustments. The numbers of deaths among former heavy users was small for all causes; however, former heavy users had a higher risk of death from respiratory diseases and external causes (about 4–5-fold increased risk), digestive diseases (about 15-fold) and other causes (about 3-fold), compared with always light alcohol users (Table 4).
When analyses for broad causes of death (CVD, cancer and other causes) were stratified by disease status at enrolment, the lower risks of death from CVD in men and women were only evident amongst those who had not developed diseases before enrolment (Supplementary Tables 1 and 2, available as Supplementary data at IJE online). In women, but not in men, the shape of the relationship differed according to disease status (P for interaction = 0.013), although the risk estimates were similar between men and women, with a 50% lower risk of death from CVD among alcohol users without a chronic disease at enrolment and a 33% higher risk among never alcohol users who had developed a chronic disease at enrolment, compared with lifetime light alcohol users.
Further sensitivity analyses showed that excluding deaths that occurred within the first 3 years of follow-up, or participants who were aged ≤50 years at the time of enrolment, did not alter the results. However, some of the associations were more evident either in northern or in southern countries such as: death from CVD (excluding CHD) among men, where a lower risk of death among those who used alcohol within the recommended limit existed only in northern countries (P for interaction = 0.043); and death from other neoplasms in women, where the higher risks among never and former alcohol users were only seen in southern countries (P for interaction = 0.0049).
Relative Risk Curves for Alcohol Consumption at Enrolment
The risk relationship between alcohol consumption during midlife and cause of death was non-linear in men for CVD, respiratory, digestive, external and other causes, and for CHD, other neoplasms, respiratory and other causes in women (Figures 3 and 4). Although the gradients and the nadirs of the relative risk curves differed considerably, most of the associations between alcohol use and cause of death were statistically significant. In men, two patterns of curves were observed for alcohol consumption at the time of enrolment. One was associated with a higher relative risk of death from alcohol-related cancers, digestive and external causes, other neoplasms and other causes, only for consumption higher than 24g/day (Figure 3). However, this pattern was not observed for death from CHD, other CVD or respiratory diseases where the risk curve did not increase with higher alcohol consumption. In women, the risk relationships for death from almost all causes were similar to those seen in men except for external causes, alcohol-related cancers, and diseases of the digestive system, where with increasing alcohol consumption the relative risk curves of death from digestive causes increased more steeply and those from external causes and alcohol-related cancers attenuated apparently (Figure 4).
(Enlarge Image)
Figure 3.
Spline regression of the association of g/day alcohol use at enrolment and causes of death among men participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, whose alcohol use was >0 at that time, stratifying by centre and age, and adjusting for body mass index, height, waist circumference, intake of fruits, vegetables, red meat and meat products, dietary fibre, physical activity, education, smoking and prevalent disease (self-reported cancer, myocardial infarction, stroke, diabetes mellitus or hypertension).
P–values for linearity and for general effect respectively were for CHD = 0.151 and 0.004, CVD = 0.001 and 0.001, alcohol-related cancers = 0.059 and <0.001, other neoplasms = 0.172 and <0.001, respiratory causes = <0.001 and <0.001, digestive causes = <0.001 and <0.001, external causes = 0.044 and <0.001 and other causes = <0.001 and <0.001.
CHD, coronary heart disease; CVD, cardiovascular disease other than CHD; AC, alcohol-related cancer; ON, other neoplasms; R, respiratory system; D, digestive system; E, external causes; OC, other causes
(Enlarge Image)
Figure 4.
Spline regression of the association of g/d alcohol use at enrolment and causes of death among women participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, whose alcohol use was >0 at that time; stratifying by centre and age and adjusting for body mass index, height, waist circumference, intake of fruits, vegetables, red meat and meat products, dietary fibre, physical activity, education, smoking, menopausal hormone use, number of live births, menopausal status and prevalent disease (self-reported cancer, myocardial infarction, stroke, diabetes mellitus or hypertension).
P-values for linearity and for general effect respectively were for CHD = 0.028 and <0.001, CVD = 0.089 and 0.061, alcohol-related cancers = 0.076 and 0.028, other neoplasms = 0.013 and 0.033, respiratory causes = 0.001 and 0.003, digestive causes = 0.950 and 0.002, external causes = 0.399 and 0.602 and other causes = 0.001 and <0.001.
CHD, coronary heart disease; CVD, cardiovascular disease other than CHD; AC, alcohol-related cancer; ON, other neoplasms; R, respiratory system; D, digestive system; E, external causes; OC, other causes
Sensitivity analyses investigated the shapes of the curves following exclusion of participants with a self-reported prevalent disease and following adjustment for prevalent disease. The shapes of the risk relationship for alcohol consumption and death changed slightly in men and obviously in women for diseases of the digestive system, and slightly for alcohol-related cancer and other causes in women (Supplementary Figures 3 and 4, available as Supplementary data at IJE online). Excluding women with prevalent diseases (instead controlling for disease status at enrolment) attenuated the relative risk of death from alcohol-related cancers and increased the relative risk of death from a disease of the digestive system even further at a level of alcohol use higher than 12 g/day.
Alcohol Consumption at Enrolment and Cause of Death Taking Past Use Into Account
Compared with participants who used alcohol within recommended limits throughout their lifetime, those who had used it more heavily in the past (but not at enrolment) had higher risks of death from CVD [women: HR 1.21; 95% confidence interval (CI) 1.02, 1.43], alcohol-related cancer (men: HR 1.32; 95% CI 1.10, 1.60), disease of the respiratory system (men: HR 1.28; 95% CI 1.01, 1.62), external cause (men: HR 1.51; 95% CI 1.18, 1.93) or other causes (men: HR 1.49; 95% CI 1.24, 1.79; women: HR 1.27; 95% CI 1.03, 1.58). Compared with men who had a lifetime alcohol use below the recommended limit, there was a higher risk of death from alcohol-related cancer in men who used more than the recommended amount at enrolment, regardless of their past consumption habits (HR 1.36; 95% CI 1.05, 1.76 if their whole past consumption was below the limit or HR 1.57; 95% CI 1.33, 1.87 if their past consumption was always or occasionally above the limit). Higher risks were also seen with a lifetime alcohol use above the recommended limit for death from digestive (HR 1.42; 95% CI 1.02, 1.96), external (HR 1.57; 95% CI 1.24, 1.99) and other causes (HR 1.54; 95% CI 1.29, 1.84). In women however, compared with those who used alcohol below the recommended limit throughout their lifetime, a lower relative risk of death from CHD was seen among those who used alcohol heavily at enrolment although having using alcohol in the past below the recommended limit (HR 0.57; 95% CI 0.41, 0,78).
A total of 266 participants died from a cause directly related to alcohol use (e.g. alcohol-induced intoxication, dependence, certain external causes), of whom 197 were men. Compared with men who consistently used alcohol below the recommended limit (i.e. at enrolment and in the past), men who had previously used it above the limit (but whose consumption was lower at enrolment) had a risk of death from alcohol-related causes of 7.12 (95% CI 3.79, 13.37); those who had used more than the recommended limit, but not in the past, had a corresponding risk of 5.08 (95% CI 2.48, 10.52); men who used more than the recommended limit over their lifetime (i.e. in the past and at enrolment) had a risk of death from a cause directly related to alcohol of 9.22 (95% CI 5.11, 16.63). The number of women who died from a cause directly related to alcohol was too small for reasonable analysis.
Competing Risks Across Causes
The statistical tests for both models of lifetime alcohol use and alcohol consumption at enrolment showed different relationships for many causes in men and in women (Supplementary Tables 3 and 4, available as Supplementary data at IJE online). Distinct relationships were observed for death from alcohol-related cancer as compared with CHD or CVD in men and in women (all P-values for difference were statistically significant). Further contrasts between risk associations of lifetime pattern or alcohol use at enrolment emerged for external and other causes in men and for diseases of the digestive system in women when compared with all other groups of causes.
All-cause Mortality and Rate Advancement Period
Compared with men and women who used alcohol lightly throughout their lifetime, those who used it in restricted amounts (i.e. below the recommended limits throughout their lifetime) had the lowest relative risk of overall death, whereas those who used alcohol heavily, either at enrolment or in the past, had the highest relative risk of death (Table 5). Women who were never alcohol users also had a greater risk of death than lifetime light users. Expressing the relative risks as advancement periods, compared with lifetime light alcohol users of the same age at enrolment, former light to moderate users had died, on average, 1.5–years earlier; former heavy users died, on average, 5.2 years earlier. The corresponding figures for women were 1.5 and 3.7 years, respectively. Lifetime heavy alcohol users died on average 3.2 (men) and 2.0 (women) years earlier than lifetime light users. Men who never used alcohol died 5.1 years earlier than lifetime light users when a prevalent disease was present at enrolment, whereas those without a disease had a death rate similar to that of lifetime light alcohol users. Further, former heavy alcohol users with a prevalent disease died about 17.4-years earlier than lifetime light users with a prevalent disease; among those without prevalent disease, former heavy users died only 3.4 years earlier than lifetime light users.
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