1. www.alcoholandhealth.org1 Journal Club Alcohol and Health: Current Evidence July-August 2006

2. www.alcoholandhealth.org2 Featured Article Effect of oral acamprosate on abstinence in patients with alcohol dependence in a double-blind, placebo-controlled trial: the role of patient motivation Mason BJ, et al. J Psychiatr Res. 2006;40(5):382–392.

3. www.alcoholandhealth.org3 Study Objective To evaluate the… efficacy of acamprosate to maintain abstinence in U.S. patients with alcohol dependence

4. www.alcoholandhealth.org4 Study Design First randomized controlled trial of acamprosate in the United States Occurred in 21 alcohol treatment clinics Subjects, recruited primarily by newspaper ads, were assigned to receive daily… –2 g of acamprosate (n=258), –3 g of acamprosate (n=83), or –placebo (n=260) Also received self-help materials and 8 sessions of brief counseling

5. www.alcoholandhealth.org5 Are the Results of the Study Valid? Primary Guides: Was the assignment of patients to treatments randomized? Yes, and there were no statistically significant differences between groups at baseline. Were all patients who entered the trial properly accounted for and attributed at its conclusion? Yes. Was follow-up complete? 99% of subjects provided data for efficacy analyses; 13% were lost to follow-up, and 51% of subjects withdrew from the study. Were patients analyzed in the groups to which they were randomized? Yes, for the main analysis.

6. www.alcoholandhealth.org6 Are the Results of the Study Valid? (cont.) Secondary Guides: Were patients, health workers, and study personnel "blind" to treatment? Yes, patients and study personnel were blinded to treatment assignment. Were the groups similar at the start of the trial? Yes. Aside from the experimental intervention, were the groups treated equally? Yes.

7. www.alcoholandhealth.org7 What Were the Results? -How large was the treatment effect? -How precise was the estimate of the treatment effect? Group% Days Abstinent Overall Placebo54 2 g of acamprosate56 3 g of acamprosate61 The groups did not significantly differ in unadjusted analyses. The study sample size was calculated to detect an effect size of 0.30.

8. www.alcoholandhealth.org8 What Were the Results? (cont.) The researchers decided to perform post-hoc analyses adjusted for factors associated with treatment outcomes including… –baseline goal of total abstinence, –alcoholism severity, –stage of readiness to change, –psychological antecedents (e.g., psychiatric hospitalizations or suicide attempts), –addiction severity, –treatment exposure, and –study site.

9. www.alcoholandhealth.org9 What Were the Results? (cont). P=0.04 for 2g vs placebo P=0.01 for linear trend across the 3 groups The adjusted analysis was then repeated in subjects committed to total abstinence (n=115 for placebo; n=100 for 2 g; n=26 for 3 g). GroupAdjusted % Days Abstinent Placebo52 2 g of acamprosate58 3 g of acamprosate63

10. www.alcoholandhealth.org10 Guidelines for Interpreting Subgroup Analyses Is the effect suggested by comparisons within rather than between studies? Did the hypothesis precede rather than follow the analysis? Was the subgroup effect one of a small number of hypothesized effects tested? Is the magnitude of the effect large? Was the effect statistically significant? Is the interaction consistent across studies? Is there indirect evidence that supports the hypothesized interaction?

11. www.alcoholandhealth.org11 Is the effect suggested by comparisons within rather than between studies? The analysis compared randomized groups within a single study. It directly compared 3 groups of subjects committed to abstinence.

12. www.alcoholandhealth.org12 Did the hypothesis precede rather than follow the analysis? The hypothesis followed the analysis. –After finding that most patients did not have abstinence as a treatment goal, the researchers chose to examine results from the 241 patients with this goal.

13. www.alcoholandhealth.org13 Was the subgroup effect one of a small number of hypothesized effects tested?  The authors do not state explicitly the number of subgroup analyses performed.  However, they reported only 1 subgroup analysis.

14. www.alcoholandhealth.org14 Is the magnitude of the effect large? The magnitude of the effect was large. There was an absolute increase of 12% in percent days abstinent. Group% Days Abstinent Among Subjects With an Abstinence Goal Placebo58 2 g of acamprosate70 3 g of acamprosate73 Analyses were adjusted for baseline variables and treatment exposure

15. www.alcoholandhealth.org15 Was the effect statistically significant? Yes, the P value for the comparison of 2 g of acamprosate vs placebo was 0.02. Similarly, the P value for the linear trend in abstinence across the 3 groups was 0.02.

16. www.alcoholandhealth.org16 Is the interaction consistent across studies? A meta-analysis of international studies found that acamprosate improves odds of abstinence. –Patients in these studies were usually abstinent for 5 days and entered the studies directly from inpatient detoxification. –These studies are consistent with others that show acamprosate has efficacy in patients with more stable initiation of abstinence.

17. www.alcoholandhealth.org17 Is the interaction consistent across studies? (cont.) Another U.S. study (Anton et al, 2006) that did not require substantial abstinence as an eligibility criterion also found no efficacy for acamprosate. Two other studies involving patients who were actively drinking reported no efficacy for acamprosate.

18. www.alcoholandhealth.org18 Is there indirect evidence that supports the hypothesized interaction? The effect was consistent with previous studies of acamprosate. The effect was also present for other outcomes, such as GGT levels, abstinence >=90% of days, and abstinence <=10% of days.

19. www.alcoholandhealth.org19 Is there indirect evidence that supports the hypothesized interaction? (cont.) Brain hyperexcitability during alcohol withdrawal and protracted abstinence is hypothesized to be a particularly sensitive target for acamprosate’s therapeutic actions (al Qatari et al., 1998; Spanagel and Zieglgansberger, 1997). The drug appears to act primarily by restoring normal N- methyl-D-aspartate (NMDA) receptor tone in the glutamate system (Spanagel and Zieglgansberger, 1997). Acamprosate has been shown to have a specific dose- dependent effect on decreasing excessive alcohol intake in animal models of alcohol dependence.

20. www.alcoholandhealth.org20 Summary In a 3-group randomized controlled trial of acamprosate, the drug was not efficacious. Investigators noticed that… –their subjects had not been required to abstain before study entry (unlike in most previous studies), and –most did not have abstinence as a goal. Investigators performed adjusted subgroup analyses and found that acamprosate had efficacy in subjects committed to abstinence.

21. www.alcoholandhealth.org21 Summary (cont.) Although caution should be used when interpreting these post-hoc subgroup analyses… –the findings are biologically plausible, consistent with previous studies, and from a direct within study comparison, and –the magnitude of the effect is large and statistically significant (although whether other subgroup analyses were tested is unclear). Although confirmation would be useful, it is likely that acamprosate has efficacy in patients motivated to be abstinent.