The Meta-analysis: A noon conference presentation

1. The Meta-analysis: A noon conference presentation Kendall Moseley, MD Kevin Woods, MD With commentary by Hunter Young, MD MHS

2. Alcohol Dosing and Total Mortality in Men and Women An Updated Meta-analysis of 34 Prospective Studies Augusto Di Castelnuovo, ScD; Simona Costanzo, ScD; Vincenzo Bagnardi, ScD; Maria Benedetta Donati, MD, PhD; Licia Iacoviello, MD, PhD; Giovanni de Gaetano, MD, PhD

3. How much alcohol is healthy for you?

4. Background • Previous studies have shown that moderate amounts of alcohol have helped prevent coronary artery disease (CAD). • Alcohol abuse can be harmful. • Some studies indicate that alcohol may have different effects in men and women.

5. How is ETOH good for you? • Increased HDL cholesterol • Increased fibrinolysis • Decreased platelet aggregation and coagulation factors • Possible beneficial effects on endothelial function and inflammation

6. Clinical Questions • What is the relationship between alcohol dosing and all-cause mortality? • Is there a statistical difference between men and women?

7. Methods • Pubmed search • Limits: Human • Dates: (all studies – 12/2005) • Searched titles and abstracts containing: alcohol, beer, wine, spirits AND mortality or death

8. Exclusion Criteria • only 1 category of risk (n=4) • did not report mortality separately for the sexes (n=5) • considered mortality for specific causes (n=3) • comprised multiple reports (n=9) • reference category was not the one with the lowest alcohol intake (n=4) • relative risks or numbers of cases and person-years were not available (n=14)

9. Data Extraction ** 14 reported results separately for the sexes; 1 study reported data for 2 age groups; 1 study for wine and beer. (These studies contributed 2 dose-response curves each.) • Two studies contributed 4 curves (1 study reported results separately for 2 ethnic groups and sexes, and another for age groups and sexes.) Exclusion criteria applied

10. Define a Drink • The amount of a drink was taken as quantified by each author whenever possible; otherwise (7 studies) it was considered equivalent to 10 g of ethanol. • Considering a drink equivalent to either 12 or 14 g of ethanol did not change our results (data not shown).

11. A Standard Drink U.S.  DEPARTMENT OF HEALTH & HUMAN SERVICES, National Institutes of Health National Institute on Alcohol Abuse and Alcoholism, Helping Patients Who Drink Too Much : A CLINICIAN’S GUIDE 2005 Edition

12. Helpful Conversions U.S.  DEPARTMENT OF HEALTH & HUMAN SERVICES, National Institutes of Health National Institute on Alcohol Abuse and Alcoholism, Helping Patients Who Drink Too Much : A CLINICIAN’S GUIDE 2005 Edition

13. SUMMARY • Over 1 million Subjects • Studies representative of 5 countries • Follow up years ranged from 5.5 – 26 years • Level of Adjustment identified for over 20 factors.

14. Deriving the J-curve • The regression models were log (relative risk [RR])=1xp2xq ; exponents p and q were selected among the following set: {−2.0, −1.0, −0.5, 0.0, 0.5, 1.0, 2.0}. • When p=0, xp is replaced by log(x). • When p=q, the model becomes log(RR|x) =1xp2xq log(x).

15. Data Analysis • (1) the value x of alcohol intake (measured in grams per day) assigned as the midpoint of the reported ranges; x was defined as 1.2 times the lower boundary for the open-ended upper categories. • (2) frequency counts, adjusted relative risks, and 95% CIs for each x level • (3) covariates describing the characteristics of the study. Inverse variance–weighted methods, taking into account the correlation between estimates within each study, were used.

16. Subgroup Analysis • Level of Adjustment • Sex • Country • Sample size • Duration of follow up

17. Subgroup Analysis • Level of Adjustment • Sex • Country • Sample size • Duration of follow up _____________________ • Reversion point: the dose of alcohol at which the protection against total mortality is no longer statistically significant at the 99% confidence level.

18. 6 g/d 42 g/d Mortality benefit could be associated with up to 42 g/d of alcohol consumption (approx 4 drinks/ day) Lowest risk of to total mortality associated with 6g/d (approx 0.5 drinks/day)

19. Dose response curves are similar for both sexes when alcohol intake is light, but differs with heavier alcohol consumption Protection apparent up to 3 drinks/day in MEN Protection apparent up to 2 drinks/day in WOMEN

20. Obvious differences between women from different countries. (p >.54 for differences between countries)

21. However the differences between men from different countries were significant (p >.003) Maximum risk reduction for European Men (20 -28%) Maximum risk reduction for US Men (14-19%) ** no explanation was offered to explain this relationship

22. Why is there a difference between the Sexes?

23. Key Findings • Low levels of ETOH intake are significantly associated with reduced total mortality. • While both sexes benefit from moderate ETOH intake, the dose of ETOH at which this benefit is realized is different for men (3 drinks/day) and women (2 drinks/day) • The relationship of ETOH intake and decreased mortality is lower in US-based studies as opposed to European (men only)

24. Discussion

25. The Big Picture • Why a meta-analysis? (and by the way, what is a meta-analysis?) • How should this type of study be applied to your clinical decision-making?

26. Other Related Resourcs • National Institute on Alcohol Abuse and Alcoholism