1. Binge drinking and cardiovascular disease: a meta-analysis Vincenzo Bagnardi, Lorenza Scotti, Giovanni Corrao ( Department of Statistics, University of Milan- Bicocca, Milan, Italy) Carlo La Vecchia (Laboratory of Epidemiology, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy) Witold Zatonski (Department of Epidemiology and Cancer Prevention, Marie Sklodowska-Curie Memorial Cancer Centre, Warsaw)

2. Introduction There is convincing evidence that moderate alcohol consumption protects against the risk of coronary heart disease (CHD). On the other hand, it has been consistently shown that heavy alcohol consumption and problem drinking are associated with increased risk of CHD and other cardiovascular diseases. The combination of protective and harmful effects results in a U- or J-shaped dose-response relationship between alcohol and CHD.

3. Introduction Alcohol and coronary heart disease: a meta-analysis [Corrao et al., 2000]. RR

4. Introduction Evidence from Eastern Europe of a positive association between alcohol and cardiovascular diseases has challenged the prevailing view that drinking is cardioprotective. Decreasing cardiovascular mortality rates have been observed in Russia after the 1985 anti-alcohol campaign and in Poland in time of alcohol rationing, during the martial law in 1981-82. This differential effect could be related to the particular conseguences of binge drinking, which is common in Eastern Europe.

5. Introduction Different patterns of alcohol intake could interact with the dose-related effect. Alcohol and coronary heart disease: a meta-analysis [Corrao et al., 2000]. RR

6. With the main aim to evaluate whether drinking pattern modifies the effect of alcohol intake on the risk of CVD, we have summarized the available data on this topic using a meta-analytic approach. Binge drinking and cardiovascular disease: a meta-analysis Investigate the role of drinking pattern in modifying the effect of the amount of alcohol consumed is not straightforward. Only sparse data are still available on this topic.

7. Outcome investigated Outcome investigated: Cardiovascular Disease Cerebrovascular Disease Hemorrhagic stroke Ischemic stroke Coronary Heart Disease (CHD)

8. Exposure definition Due to the lack of a standard definition of pattern of alcohol drinking, the search focused on several terms: drinking pattern, irregular drinking, binge drinking, problem drinking, alcoholic intoxication, heavy episodic drinking, and hangover

9. case–control or cohort studies published as an original article. findings expressed as relative risk, considering different combinations of quantity and frequency of alcohol intake OR directly considering the drinking pattern (e.g. binging or irregular heavy drinking). precision of RR for each exposure category reported. considered abstainers as reference category. Inclusion criteria

10. Number of occasions in the past week =N Usual number of drinks they consumed per occasion =D g/day = 12.5 x [(N x D) / 7] g/day RR 1.0 Dose-response analysis (usual analysis)

11. No attempt to separate the effect of different patterns of drinking (i.e. Regular vs Irregular) Number of occasions in the past week =N Usual number of drinks they consumed per occasion =D g/day = 12.5 x [(N x D) / 7] g/day RR 1.0

12. Number of occasions in the past week =N Usual number of drinks they consumed per occasion =D g/week = 12.5 x (N x D) if N>=3:Regular drinkers if N<3:Irregular drinkers Different patterns Irregular Regular g/week RR 1.0 Hypothesis: Pattern as an effect modifier.

13. Number of occasions in the past week =N Usual number of drinks they consumed per occasion =D g/week = 12.5 x (N x D) if N>=3:Regular drinkers if N<3:Irregular drinkers Different patterns Irregular Regular g/week RR 1.0 Hypothesis: Pattern as an effect modifier. Few studies report this stratification

14. To estimate the dose-response relationship between cumulative weekly alcohol intake in regular and irregular drinkers, and to test the possible interaction between pattern and the relationship, several meta-regression non linear models (fractional polynomial models) were fitted. Analysis A g/week RR 1.0 Irregular Regular

15. Irregular Heavy Drinkers Regular Heavy Drinkers g/week RR 1.0 Irregular Regular Assumption: Irregular Heavy Drinkers could be considered as binge drinkers. Analysis B No transformation of data was performed: we simply used, in the calculation of pooled estimate, the RRs of the categories defined by the authors as Regular Heavy Drinkers, Irregular Heavy Drinkers or Binge Drinkers. + Binge drinkers (reported directly)

16. Assumption: Irregular Heavy Drinkers could be considered as binge drinkers. Analysis B Irregular Heavy Drinkers Regular Heavy Drinkers g/week RR 1.0 + Binge drinkers (reported directly) RR 1.0 vs. abstainers vs. abstainers No transformation of data was performed: we simply used, in the calculation of pooled estimate, the RRs of the categories defined by the authors as Regular Heavy Drinkers, Irregular Heavy Drinkers or Binge Drinkers.

17. Main characteristics of the 11 included studies.

18. Meta-regression dose-response relation between weekly alcohol intake and relative risk of stroke in regular and irregular drinkers. Results (Analysis A) p-value interaction parameters pattern*dose: n.s.

19. Results (Analysis B) Forest plots of drinking pattern and stroke. Regular Heavy Drinkers vs Abstainers Pooled RR: 1.2 (0.9 - 1.7) Irregular Heavy Drinkers and Binge vs Abstainers Pooled RR: 0.9 (0.7 -1.2) RR

20. Results (Analysis B) Forest plots of drinking pattern and stroke. Regular Heavy Drinkers vs Abstainers Pooled RR: 1.2 (0.9 - 1.7) Irregular Heavy Drinkers and Binge vs Abstainers Pooled RR: 0.9 (0.7 -1.2) RR = p-value homogeneity test: n.s.

21. Meta-regression dose-response relation between weekly alcohol intake and relative risk of CHD in regular and irregular drinkers. Results (Analysis A) p-value interaction parameters pattern*dose: <0.05

22. Results (Analysis B) Forest plots of drinking pattern and CHD. Regular Heavy Drinkers vs Abstainers Pooled RR: 0.7 (0.6 - 0.9) Irregular Heavy Drinkers and Binge vs Abstainers Pooled RR: 1.1 (1.0 -1.2)

23. Results (Analysis B) Forest plots of drinking pattern and CHD. Regular Heavy Drinkers vs Abstainers Pooled RR: 0.7 (0.6 - 0.9) Irregular Heavy Drinkers and Binge vs Abstainers Pooled RR: 1.1 (1.0 -1.2)  p-value homogeneity test: <0.05

24. Results (Analysis B) Forest plots of drinking pattern and CHD. Regular Heavy Drinkers vs Abstainers Pooled RR: 0.7 (0.6 - 0.9) Irregular Heavy Drinkers and Binge vs Abstainers Pooled RR: 1.1 (1.0 -1.2) = Pooled RR Irregular Heavy drinkers and Binge vs Regular Heavy drinkers : 1.5 (1.3 – 1.8) [1.5 in Men / 1.4 in Women]

25. Not included studies Other studies reporting estimates for proxy of binge drinking ( due to the heterogeneity of the exposure definition and reference category, no pooled estimates were computed ).

26. Conclusion  Drinking pattern modifies the action of alcohol intake on the CHD risk.  The well established protective effect of alcohol on the CHD risk was confirmed for regular drinkers.  Compared with abstainers, binge and heavy irregular drinkers are at increased risk of CHD.

27. Limits  Few epidemiological studies included information to test the hypothesis that drinking pattern could modify the protective effect of alcohol on the risk of CVD.  Publication bias.  Residual confounding due to socio-economic status.  Heterogeneity in the exposure definition.