Alcohol Consumption and Coronary Heart Disease Morbidity and Mortality

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1 American Journal of Epidemiology Copyright 1997 by The Johns Hopkins University School of Hygiene and Public Health All rights reserved Vol. 146, 6 Printed in U.S.A. Alcohol Consumption and Coronary Heart Disease Morbidity and Mortality Jurgen T. Rehm, 12 Susan J. Bondy, 12 Christopher T. Sempos, 3 and Cuong V. Vuong 4 Alcohol consumption is associated with a reduced risk of coronary heart disease (CHD) but an increased risk of other causes of morbidity and mortality. It remains unclear whether there is an upper limit to a protective effect of alcohol intake on CHD risk. Whether there is a U- or an L-shaped relation between alcohol consumption and CHD incidence (hospitalization and mortality due to ischemic heart disease: International Classification of Diseases codes ) is examined using the National Health and Nutrition Examination Survey I. Baseline data were collected in Follow-up data through 1987 (14.6 years mean follow-up) were analyzed for 6,788 European-American males and females (n = 3,828) aged years at baseline. Cox regression was used to assess the association between alcohol consumption and incidence of CHD. For females, an increased risk was found above 28 drinks per week relative to abstainers (relative risk = 2.6, 95 interval ), which was significant, but was based on small numbers. For males, no upturn in risk was found at higher intake. Mortality data supported these results. Sex differences should be explored further, since they are relevant to understanding causal mechanisms and public policy and prevention. Am J Epidemiol 1997; 146: alcohol drinking; coronary disease; incidence; morbidity; mortality; risk A protective effect of alcohol against coronary heart disease (CHD) is supported by extensive epidemiologic and biologic evidence (1,2). However, it is also clearly demonstrated that, at higher levels of alcohol intake, CHD protection is outweighed by other alcohol-related causes of death and overall mortality increases (3). An issue that has not been resolved satisfactorily is whether there is an upper limit to the average level of alcohol intake that is protective against coronary heart disease incidence or whether risk remains decreased in heavy drinkers. Maclure's meta-analysis of studies on alcohol and fatal myocardial infarction (the most prevalent subcategory of CHD mortality) found an L-shaped relation between alcohol intake and risk (4). A protective effect was found with consumption, which ranged from less than one drink a day to much higher levels, Received for publication January 3,1997, and in final form June 23, Abbreviations: CHD, coronary heart disease; NHANES I, National Health and Nutrition Examination Survey I; NHEFS, National Health Epidemiologic Follow-up Study; SE, standard error. 1 Addiction Research Foundation, Toronto, Ontario, Canada. 2 Department of Preventive Medicine and Biostatistics, University of Toronto, Toronto, Ontario, Canada. 3 Department of Internal Medicine and Division of Nutritional Sciences, University of Illinois, Urbana, IL 4 National Center for Health Statistics, Centers for Disease Control and Prevention, Hyattsville, MD. Reprint requests to Dr. Jurgen Rehm, Addiction Research Foundation, 33 Russell Street, Toronto, Ontario, Canada M5S 2S1. although the protective effect was no longer statistically significant above roughly 90 g of absolute alcohol per day (4). Because of the relative scarcity of data at higher levels of intake, Maclure concluded that a U-shaped relation could not yet be conclusively refuted. Most of the cardiovascular disease cohort studies do not have sufficient power to estimate relative risks at higher levels of alcohol intake because of limitations in study size and the low prevalence of high-volume consumption in the populations under study (3, 5-7). A minority of studies have found an increased risk of cardiovascular disease mortality, relative to abstainers, in the highest categories of intake, the lower bounds of which start as low as 30 g/day (6, 8-11). In studies in which the outcome examined is the broad category of cardiovascular disease, an excess risk for heavy drinkers may be partially explained by cardiomyopathy, hemorrhagic stroke, and sudden death (12). However, it is also possible that some noncardiovascular deaths are classified as cardiovascular deaths in heavy drinkers (2). Recent critical reviews, therefore, have emphasized the importance of disaggregating ischemic heart disease from other cardiovascular events, such as stroke, and incidence from mortality (2, 13). Accordingly, we used data from the National Health and Nutrition Examination Survey I (NHANES I) Epidemiologic Follow-up Study (NHEFS) to investigate the associations between al- 495

2 496 Rehm et al. cohol consumption and CHD incidence and mortality separately in a representative sample of US adults. MATERIALS AND METHODS Study design The baseline data for the NHEFS cohort were collected from 1971 to 1975 as part of NHANES I (14-18). NHANES I was designed as a representative sample of the US resident, noninstitutionalized population. The cohort consisted of 14,407 adults who were aged years at the time of NHANES I. Follow-up was conducted from 1982 to 1984, in 1986, and again in Subjects institutionalized after the baseline data collection were retained in NHEFS. At each follow-up, the subjects (or their proxies) were interviewed again, death certificates were obtained for subjects who had died, and hospital and nursing home records were obtained for overnight stays that had occurred since the most recent contact. Informed consent was obtained from the study subjects, and the protocols for NHANES I and NHEFS were reviewed and approved by the appropriate institutional review boards. Case definition Incident cases of CHD were identified by hospitalization or death. Cases were defined as diagnoses bearing International Classification of Diseases codes (ischemic heart disease) on the death certificate (indicating the underlying or an associated cause of death) and by the assignment of a diagnosis code at hospital discharge. Death certificates and hospital discharge diagnoses were coded according to the International Classification of Diseases, Ninth Revision. Only underlying causes of death were used in the analyses of cause-specific mortality. No attempt was made to identify cases that did not appear in hospital discharge data. In all, 1,560 cases of CHD were identified (710 females and 850 males). Deaths attributed to CHD totaled 552 (224 females and 328 males). Study variables Alcohol intake was measured with four questions (14). The first question asked whether at least one drink of beer, wine, or liquor had been consumed in the last year. People who responded negatively to this question were defined as abstainers. Three questions were used to quantify usual alcohol use: frequency of drinking occasions, average quantity of alcohol, and the kind of alcohol consumed. The first two questions were combined into an index of drinks per week, which served as the basis for the categories of drinking behavior used as the major independent variable in our analyses (19). The abstainer category was divided into lifetime versus previous year abstainers by integrating data from the first follow-up of NHANES I ( (15)), in which a question on lifetime abstinence had been included. Integrating this variable with baseline consumption data allowed us to make comparisons against lifetime abstainers as the reference category. Lifetime abstainers were chosen to rule out alternative explanations that the comparison group was confounded by persons abstaining for health reasons (20, 21). All covariates were measured at baseline and were defined as follows: age in years; smoking status with three levels (current smoker, ex-smoker, and never smoker); aspirin use during the 30 days before baseline interview (yes/no); body mass index calculated from measured height and weight (kg/m 2 ); and physical inactivity as indicated by little or no exercise in recreational activities and by no activities aside from recreation. The means, standard deviations, and standard errors of all variables are summarized in table 1. Study subjects Because of the small number of events in African Americans and others, the analyses were limited to TABLE 1. Description of baseline study variables by sex, United States National Health and Nutrition Examination Survey ( ), follow-up through 1987 of European- American men and women (n = 3,828) aged years at baseline Continuous variables Age Body mass index (kg/m*) Drinks per week Categorical variables Lifetime abstainer Last year abstainer Drinks per week >29 Current smokers Former smokers Aspirin user in last month Inactive (/? = 3,828) (Standard M@fln deviation) (1) (5.2) (5.3) Standard error (Standard Mean deviation) (10.3) (4.0) (15.1) Standard error

3 Alcohol Consumption and Coronary Heart Disease. 497 European Americans aged years at baseline (7,886 persons). Excluded were 126 (1.6 percent) subjects lost to follow-up and 63 (0.8 percent) subjects missing relevant data from the baseline examination. In addition, we excluded 909 (11.5 percent) subjects who reported a history of heart disease at baseline. Of the 909 subjects with a reported history of heart disease, 567 (7.2 percent of 7,886) had indicated a heart attack, 99 (1.3 percent of 7,886) a heart failure, and 243 (3.1 percent of 7,886) a weak heart. After all of the exclusions, there were 6,788 in the study sample, 3,828 females and 2,960 males. The number of CHD cases and deaths by sex and alcohol category are shown in table 2. Statistical analyses The Cox proportional hazards model (22) was used to examine the relation of alcohol consumption to the risk of an event in sex-specific multivariate models. We used t tests to examine the difference of /3 parameters from zero. As a first step, relative risks of different categories of alcohol consumption were adjusted only for smoking status and age. In a second step, the full multivariate model that included all other covariates listed above was estimated. The average follow-up was 14.6 years. Lifetime abstainers served as the reference group in all analyses. RESULTS Table 3 presents the results of the Cox regression models, showing relative risks for varying levels of alcohol consumption adjusted for age, smoking status, body mass index, physical activity, and aspirin use. When these results were compared with those adjusted for only age and smoking status (data not shown), identical conclusions were reached with respect to the influence of alcohol consumption on CHD incidence. Therefore, the model with the larger number of covariates was presented. A third model was estimated that included all variables from table 3 plus serum total cholesterol. This model yielded very consistent results (data not shown), although it was based on a smaller number of subjects because serum cholesterol values were missing for an additional 96 females and 49 males. Alcohol drinking in the range of two to seven drinks/week was associated with a significant reduction in the risk of CHD incidence for both males and females. For females, the risk reduction associated with drinking drinks/week was still pronounced but was no longer significantly different from the risk for lifetime abstainers. An increased risk for CHD incidence was observed for intake of more than 29 drinks a week, or four drinks a day on average (table 3). This relative risk was equal to 2.6 and was statistically significantly in comparison with lifetime abstainers, even though it is based on only seven cases (table 2). For males, no such upturn of the risk curve can be detected. Drinking up to 42 drinks/week, or an average of six drinks a day, was related to a significant risk reduction for CHD incidence. The largest consumption category (more than 42 drinks) had about the same risk for CHD incidence as the other drinking categories (relative risk = 0.62) but was no longer significantly different from one. who drink very sporadically (fewer than two drinks/week) seem to experience only a small reduction in risk relative to lifetime abstainers, while there is a more marked effect in males (table 3). Contrary to previous findings (20), and after control- TABLE 2. Cases of coronary heart disease incidence and mortality by alcohol consumption, United States National Health and Nutrition Examination Survey ( ), follow-up through 1987 of European-American men and women (n = 3,828) aged years at baseline Lifetime abstainers Abstainers last year Drinks/week > Incidence (n= 3,828) * Mortality Population risk 1, , Incidence * Mortality Population risk Total sample , ,960 ' Because of small numbers, the two highest consumption categories were combined for mortality.

4 498 Rehm et al. TABLE 3. risk of coronary heart disease incidence by alcohol consumption and other exposure variables, United States National Health and Nutrition Examination Survey ( ), follow-up through 1987 of European-American men and women (n = 3,828) aged years at baseline Exposure at baseline Lifetime abstainers! Current abstainers Drinks/week >42 Current smoker Former smoker Inactive Body mass index (kg/m 2 ) Aspirin use $ (n = 3,828) 95 interval * Derived from proportional hazards model, adjusted for age. t Reference category. t Because of small number of cases, estimates were combined for 29 or more drinks. 95 Interval ling for confounders, current abstainers were not at increased risk of CHD relative to lifetime abstainers. For females, the curve can be approximated as a U shape, as indicated by a significant linear term for consumption (/3 = per drink, standard error (SE) = 0.013, t = -2.51, p < 0.05) as well as for the square of consumption (/3 = , SE = , t = 3.52, p < 0.001). These values would indicate the lowest risk at 36 drinks per week, although the simple quadratic model may lead to severe overestimation of the point of optimal risk (23). For males, while the linear term reached significance (/3 = ; SE = , t , p < 0.05), the quadratic term was only marginally significant (/3 = , SE = , t = 1.76, p ~ 0.078). Thus, the results underline the U shape for females, which was already apparent from the categorical analyses, but are inconclusive with respect to males. Results for the other covariates were generally consistent with earlier literature. Smoking, higher body mass index, inactivity, and higher total cholesterol were each identified as risk factors for CHD, and each was significantly related to disease incidence. Aspirin use was positively associated with CHD risk, but this was not statistically significant. Table 4 gives an overview of the relation between TABLE 4. risk of coronary heart disease mortality by alcohol consumption, United States National Health and Nutrition Examination Survey ( ), follow-up through 1987 of European- American men and women (n = 3,828) aged years at baseline Alcohol consumption at baseline Lifetime abstainers! Current abstainers Drinks/week > (n = 3,828) 95 interval interval * Derived from proportional hazards model, adjusted for age and smoking status (current smoker, yes/no; former smoker, yes/no), t Reference category.

5 Alcohol Consumption and Coronary Heart Disease 499 alcohol consumption and CHD mortality. Again, the curve for females resembles a U. The upturn is quite high, with a relative risk of 4.6 (95 percent interval ), but since it is based only on three deaths, this result should not be overinterpreted. For males, the relative risk reached a low of 0.73 and then increased again. All interpretations of CHD mortality should be cautious because of the small number of deaths in most categories. Since the upturn was based on a small number of cases and subjects (seven incident cases in a population of 17), we systematically looked for possible alternative explanations. Table 5 gives an overview of all potential confounding variables by drinking categories to help detect potential residual confounding. When the group of female heavy drinkers (where the upturn occurs) was compared with other groups, their overall profile of risk factors was slightly more favorable than those for the other groups, with the exception of smoking. Although the rate of smoking in this group was 77 percent, smoking has been adjusted to the average smoking level of females in the Cox regression (24). However, on the basis of very few data, there is some indication that the average number of cigarettes smoked varied across drinking categories. Female smokers with an average consumption of 29 drinks or more per week averaged 30 cigarettes a day, compared with smoking female abstainers, for whom the average was 17 cigarettes per day (table 5). The other groups had intermediate values. Since the number of cigarettes is a variable with a substantial proportion of missing values, we could not control for it in the Cox regression analysis. However, the descriptive results indicate that smoking may contribute to the high relative risk found in heavy-drinking females. Future analysis with more information available should try to control for this effect with more sophisticated methods (25, 26). DISCUSSION With data from a large, representative US cohort, it has been possible to demonstrate an increase in the risk of CHD for European-American females with high levels of alcohol use, as well as when the influence of important confounders was excluded. This analysis confirmed previous research showing that abstainers are at greater risk for CHD than are most nonabstainers and that a significant protective effect may be demonstrated with small average amounts of alcohol, i.e., less than one drink a day. Some evidence of an upper limit to the protective effect was found for European-American females, with more than four drinks per day representing a significantly increased risk. For European-American I I UJ c o p 5 z o S 3 m co 7 "S «"8 3 CN a *. 2 n fi If o *o u c o «3. S" " i a cj ii o. c S II II l 8 O) j u o 2^5 5-2 d oi, d co" ^ sn» CVJ in c\i cq o> p co «- *- * co co in co r~ i-~ cq oi co" co co d T- CM CM CM CO co co CM co co *- r- CM CO CM O Q> CM O) *~ *-" CM" cq CVJ TT in <o d *" K cri T^ < > 00 CO in m to c\j (Q in T- to -*t o q ID ui Tt <o w cvl cj co o> «ui in to" oi cb o OJ y- Tt i>» do co <D cq q q in 8 S N cq in d oi oi in in in y- CM I 0 O N *- CM' ^ 1^; O> O h-; in in in co in IS co oi co 1 co ^ t ^~ T *' <t CM cq *- cq oi oi s ID oi CM cq r>- o» cq <O ^ O> 0> CO Tt Tf CO CO ^ cq cq O) cq cq CM cq CM c- cq T» cj CM oi in CM Tf CO CM CM *~I *~. cq o> cq *~ I s * CM co O> O> O) co TT in cq" in" cq"p" CM" Oi O> O O O) co r- q v oi co co m m in»- 00 CM O> O 83 S3S2 I il a 1 Zl O Q co

6 500 Rehm et al. males, the heaviest drinkers were not at a significantly increased risk relative to abstainers, although they were no longer significantly protected. Mortality findings presented generally confirm the results from incidence data; however, power for the study was not sufficient to allow precise estimation of the relative risk for alcohol use and CHD mortality. An upper limit to the protective effect of alcohol use was predicted by some earlier research. The antithrombotic effects of alcohol are not limited to lower levels of intake (27), and high levels of high density lipoprotein cholesterol and low levels of atherosclerosis are commonly observed in alcoholics (5). However, triglyceride levels are positively associated with alcohol (28, 29), and the net effect of lipid changes with heavy drinking remains unclear. Substantially depressed levels of high density lipoprotein cholesterol are also found in heavy drinkers when liver disease is present (30). Other mechanisms that would indicate a possible increased risk of infarction and death in heavy drinkers include hypertension, left ventricular hypertrophy, acute impairment of ventricular function, and underlying alcoholic cardiomyopathy (31, 32). In addition, binge drinking in high-volume drinkers also increases the risk of acute coronary events as a result of acutely raised blood pressure (33) and a reversal of the usually antithrombotic effects (34), both of which are seen with acute withdrawal from heavy drinking. The identification of an upturn in risk for females and not for males is consistent with some earlier findings. For example, English et al. (3) demonstrated that the average level of alcohol use associated with a significantly elevated risk of all-cause mortality, relative to abstainers, is lower in females (two drinks per day on average) than in males (four drinks per day). It is possible that an increased risk of CHD for heavy drinking is present for males, as was found for females, but this may occur at sufficiently high levels of alcohol consumption that this is difficult to demonstrate in existing cohort studies. The apparent sex difference in CHD risk may also explain contradictory findings regarding a monotonic or U-shaped effects across earlier published cohorts, which differ in terms of whether or not these cohorts included females. Until recently, there were too few cohorts studies of females to produce sex-specific estimates in metaanalyses (4, 35). This study contributes to this literature, although even this large cohort by itself is insufficient to provide a definitive answer. Even when studies have included both sexes, results are not always presented for each sex separately, nor are possible sex by exposure interaction effects explored. True interaction effects could exist through differences in the relations between alcohol and risk factors for males and females (29). However, at least one report (3) did not find evidence of an interaction between alcohol and sex for CHD mortality across existing studies. Sex-related differences may be metabolic or linked to unmeasured alcohol-related comorbidity. For example, females appear to be at increased risk for cirrhosis of the liver at relatively lower levels of alcohol exposure than do males (36). who consume alcohol at very high levels may also represent a greater level of severity of drinking problem than is seen in their male counterparts. Poorer nutritional status for heavy drinking females and sex-related diagnostic biases are also possible, but untested, explanations. The original question addressed here concerned a possible upturn of CHD risk for high levels of alcohol consumption. This could only be partially answered. For females, evidence of such an upturn was found both in the mortality data and in the incidence data. For males, we see the indication of an upturn for mortality, but not for incidence. As indicated above, it has to be acknowledged that existing samples, even those as large as the NHANES I, do not have enough statistical power to measure most health risks of heavy drinking. We therefore recommend the establishment of a cohort study designed for adequacy of sample size over a broader range of levels of exposure to alcohol. Sampling would be conducted disproportionately, with the probability of being sampled made directly proportional to average alcohol consumption. Such a cohort would require additional procedures for baseline screening and might effectively be combined with one or more major cross-sectional alcohol surveys, such as the United States National Surveys on Alcohol (37) or similar surveys in other countries. 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