EUROPEAN JOURNAL OF PUBLIC HEALTH 2002; 12: A balance in 1983 and 1996 GIOVANNI CORRAO, LUCA RUBBIATI, ANTONELLA ZAMBON, SARINO ARICÒ *

Transcription

1 EUROPEAN JOURNAL OF PUBLIC HEALTH 2002; 12: S U B S T A N C E A B U S E Alcohol-attributable and alcohol-preventable mortality in Italy A balance in 1983 and 1996 GIOVANNI CORRAO, LUCA RUBBIATI, ANTONELLA ZAMBON, SARINO ARICÒ * Background: Since the mid-1970s, a striking reduction in alcohol consumption has been observed in Italy and other developed countries. Alcohol-related mortality in Italy has been estimated for 1983 and Methods: Alcoholattributable and alcohol-preventable deaths were estimated by: i) data on prevalence of drinkers from two Italian surveys; ii) the parameters of meta-regression models investigating the relationship between alcohol intake and the risk of several conditions positively and negatively related to alcohol; and iii) the number of deaths from 21 alcohol-related conditions. Results: About 68,000 and 42,000 deaths were attributed to alcohol consumption in 1983 and in 1996 respectively, mostly from hemorrhagic stroke, liver cirrhosis, cancer, and injuries. About 6,600 deaths from coronary heart disease were prevented by alcohol. Light intake (25 g/day or less) caused about 30% of deaths attributable to any consumption in women. In men, about one-half of the deaths were attributable to the highest category of intake (100 g/day or more), while a lower proportion of deaths was attributed to light intake (almost 7%). In 1996 the number of the deaths caused and those prevented by light intake was approximately the same (5,400 and 5,200 respectively) and did not significantly differ. Conclusion: The estimated number of deaths attributable to alcohol consumption in Italy still far exceeds the number prevented for both women and men. Despite the cardiac protective effect, alcohol consumption remains a major public health problem in Italy. Both population and high risk strategies in preventing alcohol-related problems should be implemented. Keywords: alcohol consumption, attributable fraction, attributable mortality 214 * G. Corrao 1, L. Rubbiati 1, A. Zambon 1, S. Aricò 2 1 Department of Statistics, Chair of Medical Statistics and Epidemiology, University of Milan-Bicocca, Milano, Italy 2 Gastroenterology Unit, Hospital Mauriziano Umberto I, Turin, Italy Correspondence: Prof. Giovanni Corrao, Dipartimento di Statistica, Università degli Studi di Milano-Bicocca, Via Bicocca degli Arcimboldi, 8, Edificio U7, Milano, Italy, tel , fax , giovanni.corrao@unimib.it In spite of the heavy impact of alcohol consumption on public health, social and cultural differences in the evaluation of alcohol drinking 1 have until recently hampered the quantification of this impact. While all the cases of some nosological entities such as alcoholic psychoses and alcoholic cirrhosis must wholly be attributed to alcohol, for many other diseases or traumatic events alcohol is only one of the potential etiologic factors, so that alcoholattributable proportions must be calculated. Until the latter half of the 1980s, alcohol-related deaths were seen only with reference to mortality attributable to alcoholism. 2 In the 1980s the first proposal for a method to evaluate alcohol-related mortality appeared in France. 3 On the basis of clinical experience, a proportion of deaths from various causes was empirically attributed to alcohol. 4 Ravenholt 5 and subsequently the American Centre for Disease Control (CDC) 6 provided more complete lists of alcohol-related causes of death and, for each condition included in this list, the corresponding population alcoholattributable fraction (AAF) was supplied. Although the derivation of these AAFs was not explained, by their use, alcohol-related mortality was estimated in the USA as a whole, 5,7 in California, 8 and, with some marginal modification, in Italy. 9 More recently, estimates of deaths attributable to alcohol consumption based on a thorough quantitative overview of the epidemiologic literature 10 have been reported for Australia, 11 New Zealand 12 and England and Wales. 13 The use of published AAFs to estimate alcohol-related mortality in a given country is questionable. It is well known that AAF is a positive function of two quantities: the prevalence of drinkers from each alcohol drinkers category and the relative risk function of each alcoholrelated condition. Differences in exposure prevalence in different countries are obviously expected. It has been suggested, moreover, that the drinking pattern might affect the slope of the alcohol-related risk. 14 Thus, both quantitative (how many light, moderate and heavy drinkers are there in the target population?) and qualitative characteristics (drinking habits such daily versus weekend consumption, prevalent use of some alcoholic beverages, etc.) of alcohol exposure prevent the generalizability of data derived from a single population. Several studies have consistently reported that moderate alcohol drinkers have a lower risk of the occurrence of

2 Alcohol-related mortality in Italy and mortality from coronary heart disease than abstainers. 15 Consequently, a balance between harmful and beneficial effects of alcohol should be considered to measure the impact of alcohol intake on the health of a given population. In the last 25 years in Italy and in other developed countries, an unexpected and important reduction in alcohol consumption has occurred. 16 By using data on the prevalence of drinkers deduced from two Italian surveys and the results of two recent meta-analyses including several conditions which are positively 17 or negatively 18 related to alcohol, the deaths attributable to and preventable by alcohol consumption in Italy in 1983 and in 1996 have been estimated. A balance between death occurrences caused by or avoided because of moderate alcohol consumption has also been provided. METHODS Sources of exposure prevalence data Exposure prevalences were obtained from the following two national surveys, conducted in 1983 (Health Status of the Italian population) and 1996 (Multipurpose Survey on the Italian Families) by the Italian National Institute of Statistics (ISTAT). 19,20 Both surveys were designed to obtain reliable estimates of several social and health characteristics and behaviours of the Italians and were consequently conducted by extracting a random sample from the entire population. In total, 75,397 and 67,400 subjects were interviewed in 1983 and 1996 respectively, with about 90% response rates stated by ISTAT for all the national surveys performed in the considered years. There were no differences between participants and the entire Italian populations in the two investigated years concerning age and gender distributions. Alcohol questions enquired about the usual quantity and frequency of consumption of standard glasses of wine, beer and spirits in the twelve months preceding the actual interview. Proportions of women and men aged 15 years or more reporting abstinence from alcohol or alcohol consumption of 25 g/day or less (up to two standard glasses), g/day (three or four standard glasses),, 201 g/day or more (more than sixteen standard glasses), were derived from these surveys. Choosing the alcohol-related conditions A list of 21 conditions classified into four categories was considered. The first category, referring to causes of death entirely attributable to alcohol, includes the following eight conditions: alcoholic psychoses [ICD-9 code: 291], alcohol dependence syndrome [303], nondependent abuse of alcohol [305.0], alcoholic polyneuropathy [357.5], alcoholic cardiomyopathy [425.5], alcoholic gastritis [353.3], excessive blood level of alcohol [790.3] and accidental poisoning by ethyl alcohol, not elsewhere specified [E860.0, E860.1]. With respect to other lists, alcoholic fatty liver, acute alcoholic hepatitis, alcoholic cirrhosis of the liver and unspecified alcoholic liver damage were excluded, since it has been reported that the etiologic diagnosis of chronic liver diseases has suspect validity, partly because of deficiencies in recording alcohol as the cause on death certificates. 21 These diagnoses were considered in the nosological sector of cirrhosis and other chronic diseases of the liver (without mention of alcoholic aetiology) that was included in the second category. The second and third categories include diseases only partially attributable to alcohol. With respect to other lists, these causes of death were divided into two categories on the basis of the solidity of the evidence of alcohol causality using causal verification criteria described by Susser 22 and the International Agency for Research on Cancer. 23 Thus, it was assumed that sufficient evidence of the causal association with alcohol exists for the following seven conditions (second category): malignant neoplasms of the lip, oral cavity and pharynx [ ], of the oesophagus [150], of the liver and intrahepatic bile ducts [155] and of the larynx [161], hemorrhagic stroke [ ], cirrhosis and other chronic diseases of the liver [571, 572.2, 572.3], and injures and adverse effects [ ]. Conversely, included in the third category were malignant neoplasms of the colon [153], of the rectum [154] and of the breast [174] due to the limited evidence of causality, and essential hypertension [401], and chronic pancreatitis [577.1] due to the insufficient number of epidemiological studies that have investigated the dose-response relationship with alcohol consumption. 17 Regarding conditions considered by other lists, excluded were: i) pulmonary and other respiratory tuberculosis, pneumonia and influenza and acute pancreatitis since, as far as is known, no epidemiological studies are available on the dose-response relationship between alcohol and the risk of these diseases; ii) gastric, pancreatic, lung, endometrial, ovarian, bladder and renal parenchymal cancers, since evidence of causal associations with alcohol are inconsistent and/or inconclusive; 24,25 iii) diabetes mellitus, since contradictory results have been reported in the literature; iv) ischemic stroke and gastric and duodenal ulcer, since most studies have not provided evidence of association. 17,31,32 In contrast with other lists, moreover, injures and adverse effects were grouped together, due to the difficulty in estimating the dose-response relationship for each cause. Finally, the fourth category includes causes of death for which consistent evidence of protective action of moderate alcohol consumption is available. According to a recent meta-analysis 18 showing that a J-shaped curve describes the relationship between alcohol intake and the risk of coronary heart disease [ ], this fourth category considered the portion of disease preventable by intakes lower than the last dose still showing evidence of protective action from the meta-analysis (39 and 99 g/day in women and men, respectively). The portion of disease caused by higher intakes was included in the second category, since sufficient evidence exists on the causal association between problem drinking and increased risk of coronary heart disease. 14,33 215

3 EUROPEAN JOURNAL OF PUBLIC HEALTH VOL NO. 3 Sources of mortality data The number of deaths which occurred in 1983 and in 1996 in women and men aged 15 years or more were obtained from the Italian National Institute of Statistics. Besides the 21 causes of death in the list, also ill-defined causes [ICD-9 code: ] were considered. For this purpose, the deaths from ill-defined causes (14,364 and 9,320 deaths corresponding to 2.7% and 1.7% of the total number of deaths occurring in 1983 and 1996, respectively) were distributed to each cause of death on the list (with the exception of injuries) on the basis of the genderand age-specific proportional mortality ratio and added the number of deaths so obtained to that observed for each cause of death on the list. Estimating the alcohol-attributable and alcohol-preventable fractions The following two quantities were used for the calculations. First, the prevalence of population drinking different amounts of alcohol was derived from the 1983 and 1996 Italian surveys described above. Second, the relative risk of a given condition for each level of alcohol consumption was obtained by the exponential transformation of the β coefficients of the meta-regression models described 17,18 elsewhere. Table 1 reports the β coefficients used in this paper and some characteristics of the studies included in the corresponding meta-analyses. The proportion of cases of each condition listed in the second and third categories attributable to alcohol consumption (AAF) and the proportion of coronary heart disease avoidable from intakes lower than 39 g/day and 99 g/day in women and men respectively (APF) were therefore computed by means of the classical methods for multiple levels of exposure. 34,35 Exploring consistency of the estimates Since from 1992 to 1998 six Italian case-control studies have been published reporting AAFs for neoplasms of oral cavity, 36 oesophagus, 37 liver, 38 larynx 39 and breast 40 and for liver cirrhosis, 41 the external consistency of our estimates was investigated by comparing our findings referred to the year 1996 with those reported in the literature. Estimating the alcohol-related mortality As far as the first category of the list is concerned, all deaths were considered as entirely alcohol-attributable. For each other condition on the list, the specific AAF (second and third category) or APF (fourth category) was multiplied by the total number of deaths aged over 15 years and the alcohol-related deaths were derived by means of the sum of the cause-specific attributable (or avoidable) deaths. Three estimates were computed. The first considered all the causes of death of the first, second and third categories (global estimate of alcohol-caused deaths). The second excluded from the list diseases with uncertain evidence of causality being attributed at the third category (conservative estimate of alcohol-caused deaths). Finally, the estimate of the number of deaths avoided by alcohol Table 1 Meta-regression models and corresponding studies included in meta-analysis for each alcohol-related condition Condition Model a Number and characteristics of the included studies lip, oral cavity and pharynx ln RR = alc ( ) alc 2 + ( ) alc (alc gender) 8 studies with good quality score and presenting gender s effects from which estimates referred to Mediterranean alcohol habits were derived oesophagus ln RR = alc ( ) alc 3 14 studies presenting estimates adjusted for the main risk factors from which estimates referred to Mediterranean alcohol habits were derived colon ln RR = alc 16 studies rectum ln RR = alc (alc gender) 3 studies with good quality score and presenting gender s effects liver ln RR = alc ( ) alc 2 10 studies with good quality score larynx ln RR = alc ( ) alc 3 20 studies from which estimates referred to Mediterranean alcohol habits were derived breast ln RR = alc 29 studies with good quality score from which estimates referred to Mediterranean alcohol habits were derived Essential hypertension ln RR = alc 2 studies with good quality score Coronary hearth disease ln RR = alc alc 1/ (alc gender) Hemorrhagic stroke ln RR = alc 9 studies Liver cirrhosis ln RR = alc ( ) alc (alc gender) 26 studies with good quality score and presenting gender s effects 8 studies with good quality score and presenting gender s effects from which estimates referred to Mediterranean alcohol habits were derived Chronic pancreatitis ln RR = alc 2 studies Injuries and adverse effects ln RR = alc 9 studies presenting estimates adjusted for age and gender from which estimates referred to studies considering death as outcome variable were derived 216 a: ln RR = natural logarithm of the relative risk alc: alcohol intake expressed as g/day; gender coded as 0 (men) or 1 (women)

4 Alcohol-related mortality in Italy 50 WOM EN 40 prevalence (%) <= >= 126 alcohol consumption (g/day) MEN prevalence (%) <= >= 201 alcohol consumption (g/day) Figure 1 Prevalence of non-drinkers and of drinkers of various amounts of alcohol according to two Italian surveys consumption was also computed (alcohol-prevented deaths). The corresponding estimates were calculated for any alcohol consumption and with reference to specific drinking categories ( 25, 26 50, and 101 g/day). Confidence intervals of the fractions and of the number of deaths caused or prevented by alcohol consumption were constructed using the delta method. 42 Details of the statistical methods are reported in the appendix. RESULTS Prevalence of drinkers Figure 1 shows the prevalence of drinkers at various levels of alcohol consumption according to 1983 and 1996 Italian surveys. Increasing prevalences of non-drinkers and of light drinkers (25 g/day of alcohol or less) and decreasing prevalences of drinkers of 26 g/day of alcohol or more were observed for both women and men. As a result, average per capita alcohol consumption decreased from 18 g/day to 7 g/day in women ( 61%) and from 49 to 28 g/day in men ( 43%). Alcohol-attributable and alcohol-preventable fractions Table 2 reports the estimated alcohol-attributable and alcohol-preventable fractions for each condition partially caused or avoided by alcohol consumption in Italy in the two considered years. Liver cirrhosis, neoplasms of the upper respiratory and digestive tracts, hemorrhagic stroke and injuries and adverse effects were the conditions with higher attributable fractions. Important reductions in attributable fractions were observed ranging from 10% (liver cirrhosis in men) to 65% (fraction of coronary heart disease caused by higher consumption in men). Conversely, increasing fractions of coronary heart disease avoided by alcohol were observed in both women and men. Consistency of the estimates The comparison between AAFs based on six Italian casecontrol studies and on our approach is shown in table 3. Fractions attributable to intakes higher than 50 g/day or 75 g/day were in some cases shown to allow comparison between estimates reported in the literature and ours. With the exception of laryngeal cancer in women, our estimates are about the same as those published. Alcohol-related mortality Table 4 shows the estimated number of deaths for each alcohol-related condition caused or avoided by alcohol consumption. Although the number of deaths from causes entirely attributable to alcohol weakly increased from 1983 to 1996, it constantly represented a small fraction of alcohol-related mortality. Important reductions in the number of deaths from conditions partially caused by alcohol were always observed. Hemorrhagic stroke, liver cirrhosis and injures and adverse effects contributed to alcohol-related mortality with the highest number of deaths (almost 66 74%). In the two considered years, moreover, an almost equal number of deaths from coronary heart disease avoided by alcohol intake was observed. The estimated number of deaths caused and prevented by any dose and by specific classes of alcohol consumption is reported in table 5. Our method attributes to any dose of alcohol consumption almost 68,000 deaths (corresponding to 12% of all deaths) in 1983 and 42,000 deaths (8%) in 1996, with a 38% decrease over the considered period (52% in women and 32% in men). Conservative estimates generated almost 6 9,000 deaths less than in global estimates, but the extent of the reductions did not vary appreciably. About 6,500 6,700 deaths ( %) were avoided by alcohol consumption, with weak variations over the considered period. In women, almost 30% of alcohol-attributable deaths was caused by drinking

5 EUROPEAN JOURNAL OF PUBLIC HEALTH VOL NO. 3 g/day of alcohol or less. Moreover, in 1996 the number of deaths caused and that prevented by light intakes did not significantly differ (3,023 and 2,439 respectively). In men, alcohol-attributable deaths were mainly explained by the highest category of drinkers (100 g/day or more) while a small proportion of deaths were attributed to light intakes (3% in 1983 to 7% in 1996). In 1996 the number of deaths prevented by light intake did not significantly differ from that of the corresponding caused deaths (2,775 and 2,337 respectively). DISCUSSION Since 1975 Italy has experienced an important reduction in average per capita alcohol consumption, much greater than other European countries 43,44 and exceeding the 25% reduction by the year 2000 recommended by the European Region of the World Health Organisation. 45 It is surprising to note that this reduction has occurred in spite of the fact that alcoholic beverages are an integrated and accepted part of daily life in Italy, where control measures reflect this acceptance. For example, the tax burden on alcoholic beverages is low in comparison with other countries, the value-added tax rates for alcoholic beverages have not increased since 1973, and no particular control measures have been introduced in the last twenty years. 46 However, it can be speculated that the reduction trend might be considered as a great natural experiment to verify the public health consequences of variation in alcohol intake in a given population. As expected, an important reduction in alcohol-related mortality was observed, although it is lower than the reduction in average per capita alcohol consumption. Table 2 Estimated fractions of conditions that are partially caused or avoided by alcohol consumption, and corresponding 95% confidence intervals (95% CI); Italy, 1983 and 1996 Women Men % AAF (95% CI) Difference % AAF (95% CI) Difference Condition [ICD-9 code] % % Diseases and conditions partially caused by alcohol with sufficient evidence of causality (alcohol-attributable fractions) oral cavity [ ] 53.0 ( ) 30.9 ( ) ( ) 68.3 ( ) 15.8 oesophagus [150] 33.2 ( ) 16.7 ( ) ( ) 52.2 ( ) 24.9 liver [155] 11.8 ( ) 5.3 ( ) ( ) 18.1 ( ) 35.1 larynx [161] 36.2 ( ) 19.0 ( ) ( ) 58.0 ( ) 23.0 Coronary hearth disease [ ] a 5.3 ( ) 2.6 ( ) ( ) 1.8 ( ) 65.0 Hemorrhagic stroke [ ] 27.2 ( ) 13.3 ( ) ( ) 44.8 ( ) 28.7 Liver cirrhosis [571] 67.7 ( ) 54.4 ( ) ( ) 83.3 ( ) 9.9 Injures and adverse effects [ ] 24.9 ( ) 12.0 ( ) ( ) 41.1 ( ) 30.1 Diseases partially caused by alcohol with limited evidence of causality (alcoholattributable fractions) colon [153] 23.4 ( ) 11.1 ( ) ( ) 38.6 ( ) 31.1 rectum [154] 63.7 ( ) 51.5 ( ) ( ) 12.1 ( ) 39.5 breast [174] 22.0 ( ) 10.4 ( ) 52.8 Essential hypertension [401] 25.7 ( ) 12.5 ( ) ( ) 42.5 ( ) 29.6 Chronic pancreatitis [577.1] 20.8 ( ) 9.7 ( ) ( ) 34.3 ( ) 32.6 Diseases partially avoided by alcohol (alcohol-avoidable fractions) Coronary hearth disease [ ] b 7.4 ( ) 8.3 ( ) ( ) 11.2 ( ) a: Fractions of coronary hearth disease caused by alcohol consumption higher than 39 and 99 g/day in women and men respectively b: Fractions of coronary hearth disease avoided by alcohol consumption lower than 39 and 99 g/day in women and men respectively AAF: alcohol-attributable fraction

6 Alcohol-related mortality in Italy Overall results give an estimate of 68,000 deaths in 1983 and of 42,000 in 1996 attributed to any alcohol consumption, mostly for hemorrhagic stroke, liver cirrhosis, cancer and accidents. On the other hand, almost 6,500 and 6,700 extra deaths from coronary heart disease would have occurred if Italian drinkers had shifted into the nondrinking category. In terms of crude balance, it is reasonable to subtract these figures from those relating to caused deaths, in analogy with the studies from Australia, New Zealand and England and Wales Table 3 Alcohol-attributable fractions based on six Italian case-control studies and on the approach used in the current paper for the year 1996 Women Disease Reference Alcohol dose Case-control estimate Our estimate Alcohol dose Case-control estimate Our estimate Oral cavity g/day g/day Oesophagus g/day g/day Liver g/day g/day 9 11 Larynx g/day g/day Breast 40 Any Liver cirrhosis 41 Any Any Men Table 4 Estimated number of deaths for each alcohol-related condition caused and avoided by alcohol consumption; Italy, 1983 and 1996 Women Men Condition [ICD-9 code] Causes of death entirely attributable to alcohol Alcoholic psychoses [291] Alcohol dependence syndrome [303] Nondependent abuse of alcohol [305.0] Alcoholic polyneuropathy [357.5] Alcoholic cardiomyopathy [425.5] Alcoholic gastritis [353.3] Excessive blood level of alcohol [790.3] Accidental poisoning by ethyl alcohol [E860.0, E860.1] Total Diseases and conditions partially caused by alcohol with solid evidence of causality oral cavity [ ] oesophagus [150] liver [155] larynx [161] Coronary hearth disease [ ] a Hemorrhagic stroke [ ] Liver cirrhosis [571] Injures and adverse effects [ ] Total Diseases partially caused by alcohol with limited evidence of causality colon [153] rectum [154] breast [174] Essential hypertension [401] Chronic pancreatitis [577.1] Total Diseases partially avoided by alcohol Coronary hearth disease [ ] b a: Number of deaths for coronary hearth disease caused by alcohol consumption higher than 39 and 99 g/day in women and men respectively b: Number of deaths for coronary hearth disease avoided by alcohol consumption lower than 39 and 99 g/day in women and men respectively 219

7 EUROPEAN JOURNAL OF PUBLIC HEALTH VOL NO. 3 Estimation of mortality attributable to any dose of alcohol has been criticized since it is not a goal of public health policy to eliminate drinking. 47 In this paper, estimations of mortality attributable to specific intakes have also been calculated. In women, the estimated number of deaths caused by an intake of 25 g/day or less represented about 30% of deaths attributable to any consumption. In men, about one-half of the deaths were still attributable to the highest drinkers category in 1996, while a lower proportion of deaths was attributed to light intakes (almost 7% in 1996). Owing to the shift of the distribution of drinkers from higher to lower consumption, particularly in men, both the caused and the prevented deaths attributable to light intakes increased during the period considered. In both women and men, moreover, weak and not significant differences between caused and prevented deaths in the category of light drinkers were observed. In agreement with a recent meta-analysis, 48,49 these results are inconsistent with the belief that daily consumption of a few glasses of wine has salutary effects and therefore do not support the promotion of drinking to promote health. The validity of these findings might be questioned on the basis of putative weakness of the main assumptions underlying the estimation methods. The most important assumption is that the observed associations between alcohol consumption and mortality are causal. Very strict criteria were used for inclusion of alcohol-related conditions according to the guidelines for causal verification. 22,23 Conservative estimates excluding causes of death with uncertain causal association were also obtained with slight differences with respect to global estimates (59,000 in 1983 and 36,000 in 1996). Another assumption is that the relative risks for each alcohol-related condition are unbiased. Biases might occur if relative risks are obtained from studies: i) considering populations unrepresentative of that from which the prevalence of drinkers was drawn; ii) with poor qualitative characteristics; and/or iii) reporting estimates unadjusted for the known risk factors of the specific disease (e.g. smoking for respiratory tract cancers, hepatotropic virus infections for cirrhosis, etc.). With the aim of avoiding, as far as possible, these sources of bias, the results of two recently published meta-analyses 17,18 were used that allowed the use of relative risks pooled from studies: i) performed in Mediterranean countries; ii) with good qualitative characteristics; and/or iii) reporting relative risks adjusted for the main risk factors. Other sources of bias cannot however be excluded. For example, our estimates Table 5 Estimated number of deaths caused and prevented by any dose and by specific classes of alcohol consumption; Italy, 1983 and 1996 Women Men Deaths (95% CI) Difference Deaths (95% CI) Difference Alcohol intake (g/day) % % Global estimates of the number of deaths caused by alcohol consumption ( ) 3023 ( ) ( ) 2337 ( ) ( ) 2920 ( ) ( ) 3981 ( ) ( ) 2355 ( ) ( ) 9395 ( ) ( ) 1778 ( ) ( ) 16148( ) 34.6 Total number of caused deaths 21009( ) ( ) ( ) 31861( ) 32.1 Percentage of total deaths Conservative estimates of the number of deaths caused by alcohol consumption ( ) 2090 ( ) ( ) 2062 ( ) ( ) 2116 ( ) ( ) 3359 ( ) ( ) 1842 ( ) ( ) 8309 ( ) ( ) 1460 ( ) ( ) 14809( ) 36.0 Total number of caused deaths 15946( ) 7508 ( ) ( ) 28539( ) 33.9 Percentage of total deaths Estimates of the number of deaths prevented by alcohol consumption ( ) 2439 ( ) ( ) 2775 ( ) (68 241) 12 (5 19) ( ) 1139 ( ) ( ) 370 ( ) 40.4 Total number of avoided deaths 2391 ( ) 2451 ( ) ( ) 4284 ( ) +5.1 Percentage of total deaths

8 Alcohol-related mortality in Italy for injuries and adverse effects were imperfect since all the different causes of death within this condition (e.g. road injuries, occupational accidents, suicides, drowning, etc.) were grouped together in the meta-analysis. This reflects a substantial lack of epidemiological literature on this issue and the choice not to consider investigations in which alcohol data were obtained by alcohol blood level measurement (since these studies do not allow reliable estimations of relative risk). Moreover, our estimates for injuries and adverse effects are mainly derived from studies performed in northern Europe where, under the same weekly alcohol consumption, a higher slope of the relationship between alcohol intake and risk of injuries is expected owing to a higher occurrence of binge drinking. Thus, it is suspected that an overestimation of accidental deaths is generated by our approach. The third assumption is that alcohol-attributable fractions for each alcohol-related condition are unbiased. Our estimates are based on questionable prevalence data. In spite of high response rates obtained from the two surveys no attempt to verify the reliability of the alcohol questions has been made. However, average per capita alcohol consumption obtained from the two surveys is consistent with that obtained from the method of availability 16 (33 and 18 g/day according to ISTAT surveys and 32 and 21 g/day according to alcohol availability, in 1983 and 1996 respectively). Obviously, this does not guarantee that systematic underreporting of alcohol consumption in responders 50 and high prevalence of alcohol abusers and addictions in non-responders 51 might lead to underestimating the impact of alcohol on mortality. However, in spite of differences in the study design, measuring alcohol consumption and data analysis strategy, attributable fractions found in the current paper were generally consistent with those reported by several Italian case-control studies, with the exception of laryngeal cancer in women, likely because of problems in the statistical power of the compared study. 39 Finally, the fourth assumption is that the classification of causes of death is not affected by systematic errors. Of course, this is a critical point of our approach since a substantial inexactness of death certificates is expected, particularly among older people. Furthermore, owing to the difficulty in considering contributory causes of death, an underestimation of the impact of alcohol on mortality is expected by our approach. An alternative approach might be to use relative risk functions obtained by pooling studies investigating alcohol and all-causes mortality. Even if this offers the possibility to leave out reliability of causes of death, there are good reasons for taking the disease-specific approach. First of all, the etiologic fraction for each condition is of interest to epidemiologists, clinicians and public health operators thus orienting etiologic research, clinical choices and public health policies according to realistic estimates of the relative role of alcohol, with respect to other risk factors, at the onset of alcohol-related conditions. Secondly, there are relatively few studies in which all-cause mortality has been examined and almost all are cohort studies performed in countries outside the Mediterranean area. Thus, differences in patterns of alcohol intake and in the distribution of causes of death limit the possibility of using the all-cause mortality approach in any social and cultural environment. Furthermore, the all-cause mortality approach offers lower potential to control for risk factors confounding the effect of alcohol on the risk of specific causes of death (e.g. viral hepatitis markers, nutritional factors and hormonal factors for chronic liver diseases, digestive neoplasms and breast cancer, respectively). Finally, a disease-specific approach is less likely to confuse harmful and beneficial effects. The impact on all-cause mortality involves simultaneous consideration of health benefits as well as adverse effects, and thus over-summarizes the data. 11 Reliability of our estimates depends on availability of data on relative risks reported by epidemiological literature. Thus, since almost all the studies included in the metaanalyses considered adult subjects, our estimates are limited to individuals aged more than 15 years. In these conditions, we are not able to estimate alcohol-related deaths occurring in younger subjects, including those caused by accidents. The age structure of the Italian population slightly changed over the considered period. However, since reliable data on age-specific relative risks for all the investigated conditions are not actually available, it was preferred not to consider the age effect rather than assuming the same relative risk for all ages. This limitation precludes the possibility of comparing the impact of alcohol consumption according to age and standardizing the reported figures for age. Another limitation of our study is that latency periods between alcohol exposure and death have not been taken into account. Latency periods are likely heterogeneous for the considered conditions, but the literature is dramatically poor on this topic. Thus, rather than arbitrarily assuming unknown latencies, it was preferred to apply the alcoholrelated fractions, estimated according to the consumption of a given year, to the deaths occurring in that year. Since alcohol consumption decreased noticeably in the last 25 years, we should accept that our results cautiously underestimate the impact of alcohol on mortality. A distinction is usually made between high risk and population strategies for the prevention of a given condition. Rose 52 showed that the population strategy has a greater potential for preventing a broad range of health problems. The so-called prevention paradox is explained by the fact that the risk group, comprising individuals with a risk exposure that is considered hazardous, is so small that it accounts for only a small fraction of the total damage load. Risk exposure is certainly smaller in the remaining population, but simply because this group is more numerous, it generates the major part of cases. Empirical and model-based evidence supported the hypothesis that the preventive paradox might find application in the context of alcohol damage, but no data on southern and central European countries are available at the moment. 56 As recently suggested by the European Region of the World Health Organisation, 57 our results suggest that both high risk and population strategies 221

9 EUROPEAN JOURNAL OF PUBLIC HEALTH VOL NO should be implemented for the prevention of alcoholrelated problems. The observation that an important proportion of the alcohol-attributable mortality in women is caused by intakes corresponding to two glasses of wine every day suggests the need for population strategies. On the other hand, the observation that the greater body of alcohol-related mortality in men is caused by high intakes suggests the promotion of high risk strategies. Of course, empirical studies aimed at assessing the validity of these conclusions should be performed. In summary, although a striking reduction in alcoholrelated mortality has been observed in Italy between 1983 and 1996, the estimated number of deaths attributable to alcohol consumption in Italy still far exceeds the number prevented for both women and men. Despite the cardiac protective effect, alcohol consumption remains a major public health problem. Both high risk and population strategies preventing alcohol-related problems should be implemented in Italy, the former to target men who are frequently exposed to high alcohol intakes, and the latter to target women whose greater proportion of alcoholattributable deaths is explained by moderate alcohol intake. The adoption of both strategies at the same time could give an answer to the prevention paradox. Support for this study came from the Italian Ministry of Health and from the Italian Ministry of the University and Scientific and Technologic Research. The authors are grateful to Drs Rina Camporese and Linda Laura Sabbadini of the National Institute of Statistics who supplied unpublished data about the 1996 Multipurpose Survey on Italian Families and to Dr Riccardo Scipione of the Superior Institute of Health who supplied mortality data. Contributions to this study came from the consultant commission of the Epidemiological Group of Italian Society of Alcohology (GESIA): Dr Giovanni Addolorato (Istituto di Medicina Interna, Università Cattolica del Sacro Cuore, Roma), Dr Claudia Braga and Professor Carlo La Vecchia (Istituto di Ricerche Farmacologiche Mario Negri, Milano), Dr Fabio Caputo (Istituto di Clinica Medica; Università di Bologna), Professor Gino Farchi and Dr Franco Taggi (Laboratorio di Epidemiologia e Biostatistica, Istituto Superiore di Sanità, Roma), Dr Natalia Magliocchetti (Dipartimento della Prevenzione e dei Farmaci, Ministero della Sanità, Roma), Dr Andrea Noventa (Servizio Tossicodipendenze, Bergamo), Dr Mario Salvagnini (Divisione di Medicina; Ospedale Civile; Vicenza), and Dr Giuseppe Francesco Stefanini (Divisione di Medicina; Ospedale Civile; Faenza). The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the opinions of these colleagues or the official views of GESIA. REFERENCES 1 Skog OJ. The collectivity of drinking cultures: a theory of the distribution of alcohol consumption. Br J Addict 1985;80: McDonnell R, Maynard A. Estimation of life years lost from alcohol-related premature death. Alcohol Alcoholism 1985;20: Comité National de Defense Contre l Alcolisme. Paris: Statistiques, Pignon JP, Hill C. Nombre de décès attribuables à l alcool en France, en Gastroenterol Clin Biol 1991;15: Ravenholt RT. Addiction mortality in the United States, 1980: tobacco, alcohol, and other substances. Pop Dev Rev 1984;10: Schultz J, Rice D, Parker D. Alcohol-related mortality and years of potential life lost. Morb Mort Weekly Rep 1990;39: Stinson FS, DeBakey SF. Alcohol-related mortality in the United States, Br J Addict 1992;87: Sutocky JW, Shultz JM, Kizer KW. Alcohol-related mortality in California, 1980 to Am J Public Health 1993;83: Cipriani F, Balzi D, Sorso B, Buiatti E. Alcohol-related mortality in Italy. Public Health 1998;112: Holman CD, English DR, Milne E, Winter MG. Meta-analysis of alcohol and all-cause mortality: a validation of NHMRC recommendations. Med J Aust 1996;164: English DR, Holman CDJ, Milne E, Winter MG, Hulse GK, Codde JP, et al. The quantification of drug caused morbidity and mortality in Australia, 1995 edition. Canberra: Commonwealth Department of Human Services and Health, Scragg R. A quantification of alcohol-related mortality in New Zealand. Aust NZ J Med 1995;25: Britton A, McPherson K. Mortality in England and Wales attributable to current alcohol consumption. J Epidemiol Community Health 2001;55: Poikolainen K. It can be bad for the heart too - drinking patterns and coronary heart disease. Addiction 1998;93: Rimm EB, Klatsky A, Grobbee D, Stampfer MJ. Review of moderate alcohol consumption and reduced risk of coronary heart disease: is the effect due to beer, wine, or spirits? Br Med J 1996;312: Produktschap Voor Gedistilleerde Dranken. World drink trends. International Beverage Alcohol Consumption and Production Trends. Oxford: NCT Publications Ltd, Corrao G, Bagnardi V, Zambon A, Aricò S. Exploring the dose-response relationship between alcohol consumption and the risk of several alcohol-related conditions: a meta-analysis. Addiction 1999;94: Corrao G, Rubbiati L, Bagnardi V, Zambon A, Poikolainen K. Alcohol and coronary heart disease: a meta-analysis. Addiction 2000:95: Istituto Centrale di Statistica. Indagine statistica sulle condizioni di salute della popolazione e sul ricorso ai servizi sanitari. Novembre Roma: ISTAT Note e Relazioni, Istituto Nazionale di Statistica. Stili di vita e condizioni di salute. Indagini multiscopo sulle famiglie. Anni Roma: ISTAT, Dufour MC. Chronic liver disease and cirrhosis. Congress on Alcohol and Health. U.S. Department of Health and Human Services. In: Everhart J, editor. Digestive diseases in the United States: epidemiology and impact. Washington DC: Superintendent of Documents, Government Printing Office, Susser M. Falsification, verification and causal inference in epidemiology: reconsiderations in the light of Sir Karl Popper s philosophy. In: Rothman KJ, editor. Causal inference. Chesnut Hill: Epidemiology Resources Inc., 1988: International Agency on Research on Cancer. Solar and ultraviolet radiation. IARC Monographs on the evaluation of carcinogenic risks to humans. Vol. 55. Lyon: IARC, International Agency on Research on Cancer. Alcohol drinking. IARC Monographs on the evaluation of carcinogenic risks to humans. Vol. 44. Lyon: IARC, Doll R, Forman D, La Vecchia C, Woutersen R. Alcoholic beverages and cancers of the digestive tract and larynx. In: Verschuren PM, editor. Health issues related to alcohol consumption, Washington DC: ILSI Press, 1993: Stampfer MJ, Colditz GA, Willett WC, Manson JE, Arky RA, Hennekens CH, Speizer FE. A prospective study of moderate alcohol drinking and risk of diabetes in women. Am J Epidemiol 1988;128: Holbrook TL, Barrett-Connor E, Wingard DL. A prospective population-based study of alcohol use and non-insulin-dependent diabetes mellitus. Am J Epidemiol 1990;132: Hodge AM, Dowse GK, Collins VR, Zimmet PZ. Abnormal glucose tolerance and alcohol consumption in three populations at high risk of non-insulin-dependent diabetes mellitus. Am J Epidemiol 1993;137: Gurwitz JH, Field TS, Glynn RJ, Manson JE, Avorn J, Taylor JO, Hennekens CH. Risk factors for non-insulin-dependent diabetes mellitus requiring treatment in the elderly. J Am Geriatr Soc 1994;42: Rimm EB, Chan J, Stampfer MJ, Colditz GA, Willett WC. Prospective study of cigarette smoking, alcohol use, and the risk of diabetes in men. Br Med J 1995;310: Van Gijn J, Stampfer MJ, Wolfe C, Algra A. The association between alcohol and stroke. In: Verschuren PM, editor. Health

10 Alcohol-related mortality in Italy issues related to alcohol consumption. Washington DC: ILSI Press, 1993: Schubert TT, Bologna SD, Nensey Y, Schubert AB, Mascha EJ, Ma CK. Ulcer risk factors: interactions between Helicobacter Pylori infection, nonsteroidal use, and age. Am J Med 1993;94: Preedy VR, Richardson PJ. Ethanol induced cardiovascular disease. Br Med Bull 1994;50: Coughlin SS, Benichou J, Weed DL. Attributable risk in case-control studies. Epidemiol Rev 1994;16: Miettinen O. Proportion of disease caused and prevented by a given exposure, trait or intervention. Am J Epidemiol 1974;99: Negri E, La Vecchia C, Franceschi S, Tavani A. Attributable risk for oral cancer in Northern Italy. Cancer Epidemiol Biomarkers Prev 1993;2: Negri E, La Vecchia C, Franceschi S, Decarli A, Bruzzi P. Attributable risks for oesophageal cancer in northern Italy. Eur J Cancer 1992;28: Braga C, La Vecchia C, Negri E, Franceschi S. Attributable risks for hepatocellular carcinoma in Northern Italy. Eur J Cancer 1997;33: Tavani A, Negri E, Franceschi S, Barbone F, La Vecchia C. Attributable risk for laryngeal cancer in Northern Italy. Cancer Epidemiol Biomarkers Prev 1994;3: Mezzetti M, La Vecchia C, Decarli A, Boyle P, Talamini R, Franceschi S. Population attributable risk for breast cancer: diet, nutrition, and physical exercise. J Natl Cancer Inst 1998;90: Corrao G, Zambon A, Torchio PF, Aricò S, La Vecchia C, Di Orio F. Attributable risk for symptomatic liver cirrhosis in Italy. J Hepatol 1998;25: Bender R. Calculating confidence intervals for summary measures of individual curves via nonlinear regression models. Int J Biomed Comput 1996;41: Corrao G, Ferrari P, Zambon A, Torchio P, Aricò S, Decarli A. Trends of liver cirrhosis mortality in Europe, : age-period-cohort analysis and changing alcohol consumption. Int J Epidemiol 1997;26: Corrao G, Ferrari P, Zambon A, Torchio P. Are the recent trends in liver cirrhosis mortality affected by the changes of alcohol consumption? Analysis of latency period in European countries. J Study Alcohol 1997;58: World Health Organization. Regional targets in support of the regional strategy for health for all. Geneva: World Heath Organization, European Region, Brewers Association of Canada. Alcoholic beverage taxation and control policies. Ottawa: Brewers Association of Canada, Holman CDJ, English DR. An improved aetiologic fraction of alcohol caused mortality. Aust J Public Health 1995;19: Leino EV, Romelsjo A, Shoemaker C, et al. Alcohol consumption and mortality. II: studies of male populations. Addiction 1998;93: Fillmore KM, Golding JM, Graves KL, et al. Alcohol consumption and mortality. III: studies of female populations. Addiction 1998;93: Midanik LT. Validity of self-reported alcohol use. Br J Addict 1988;83: Hill A, Roberts J, Ewings P, Gunnell D. Non-response bias in a lifestyle survey. J Public Health Med 1997;19: Rose G. The strategy of preventive medicine. Oxford: Oxford University Press, Norstrom T. Prevention strategies and alcohol policy. Addiction 1995;90: Moore MH, Gerstein DR. Alcohol and public policy: beyond the shadow of prohibition. Washington DC: National Academy Press, Kreitmann N. Alcohol consumption and the preventive paradox. Br J Addict 1986;81: Edwards G, Anderson P, Babor TF, et al. Alcohol policy and the public good: a good public debate. Addiction 1996;91: World Health Organization. Health 21. An introduction to the health for all policy framework for the WHO European region. European Health for All Series No. 5. Copenhagen: Received 12 January 2001, accepted 19 October 2001 Appendix Let pi be the prevalence of drinkers of the ith dose of alcohol and RRi the corresponding relative risk with respect to the baseline level (i = 0). Then the population alcohol-attributable fraction for the ith exposure level (AAFi) is estimated by: 33 p i ( RR i 1 ) AAF i = 1 + p i ( RR i 1 ) i and the fraction of cases attributable to any dose is estimate by: AAF = A AF i i Analogously, the population alcohol-preventable fraction for the ith exposure level (APFi) is: 34 p i ( 1 RR i ) APF i = 1 + p i ( 1 RR i ) i (2) and the fraction of cases avoidable by any dose showing protective action is computed as: APF = A PF i i (1) The standard errors of these quantities, as measures of the corresponding precision, have been estimated by means of the delta method. 41 Assuming that pi is not affected by random error, by taking the derivative of equations (1) and (2) with respect to RRi, the estimates of the standard error (SE) of AAFi: p i ( 1 + p j ( RR j 1 ) ) j i SE ( AAF i ) = SE ( ln RR i ) (3) ( 1 + p j ( RR j 1 ) ) 2 j and of APFi: p i ( 1 + p j ( 1 RR j ) ) j i SE ( APF i ) = SE ( ln RR i ) (4) ( 1 + p j ( 1 RR j ) ) 2 j have been obtained. In equations (3) and (4), the SE of the natural logarithm of RR has been derived from the variance/covariance matrix of the meta-regression β coefficients. The corresponding 95% confidence intervals (95% CI), as measures of the random uncertainty in both AAF and APF, are: AAF ± 1.96 SE ( AAF ) and APF ± 1.96 SE ( APF ) where SE(AAF) and SE(APF) have been obtained by summing the corresponding dose-specific standard errors. The 95% CIs of the number of deaths caused or prevented by alcohol consumption have been directly derived from the corresponding AAF and APF 95% CIs. The normal approximation has been used to compare the number of deaths attributable to or avoided by categories of intakes. 223