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    • Following a thorough quality appraisal results

    2018-10-23

    Following a thorough quality appraisal, results from three studies were judged to be insufficiently credible for meta-analysis due to a lack of information presented about key components of their protocols (Bell and Orjasaeter, 1983; Fitzgerald et al., 1971; Kessel and Grossman, 1961). The quality of the included studies varied substantially. Frequently-encountered limitations included the lack of a reported definition for AD and results presented without confidence intervals or without adjustment for confounders. Summaries of the credibility domain of the quality appraisals are presented in Supplementary Table 3 for all studies included in the SLR. Thirty-nine studies included in the SLR were ultimately eligible for meta-analysis (Table 1). The majority of the studies included in the meta-analyses (28/39) involved patients selected from AD treatment facilities (Berglund and Tunving, 1985; Campos et al., 2011; de Lint and Levinson, 1975; Denison et al., 1997; Feuerlein et al., 1994; Finney and Moos, 1991; Gerdner and Berglund, 1997; Gillis, 1969; Gual et al., 2009; Haver et al., 2009; Hiroeh et al., 2008; Johnson, 2001; Mackenzie et al., 1986; Marshall et al., 1994; Martin et al., 1985b; Moos et al., 1994; Noda et al., 2001; Rankin et al., 1970; Saieva et al., 2012; Schmidt and de Lint, 1969; Smith et al., 1983; Storbjörk and Ullman, 2012; Tashiro and Lipscomb, 1963; Thorarinsson, 1979; Vaillant et al., 1983; Wells and Walker, 1990; Yoshino et al., 1997; De Silva and Ellawala, 1994). Two studies involved patients from hospital populations (Poser et al., 1992; Wallerstedt et al., 1995), although they were not necessarily being treated for AD. Eight studies identified alcohol-dependent subjects from general THZ1 manufacturer surveys (Mattisson et al., 2011; John et al., 2013; Markkula et al., 2012; Min et al., 2008; Murphy et al., 2008; Neumark et al., 2000; Perälä et al., 2010; Vaillant, 2003), and a single study was based on a survey of company employees (Pell and D\'Alonzo, 1973). Only four studies included in the meta-analyses reported mean daily or weekly alcohol consumption among alcohol-dependent subjects (Finney and Moos, 1991; Haver et al., 2009; Johnson, 2001; Perälä et al., 2010). The most commonly reported comparison was alcohol-dependent subjects vs the general population, which was reported in 27/39 of the studies eligible for meta-analysis, with a total of 13,523 deaths in the alcohol-dependent populations (Fig. 2a). The majority of studies in this category determined the expected death rate of the alcohol-dependent sample based on age- and sex-matched data from demographic records from the city or country of the study. The pooled RR calculated from these studies was 3.45 (95% CI [2.96, 4.02]; p<0.0001). Heterogeneity between studies was high (I2=97.9%; p<0.0001). Other all-cause mortality comparisons investigated in the meta-analyses included: alcohol-dependent subjects vs subjects without AUDs (six studies; RR=1.87; 95% CI [1.46, 2.40]; p<0.0001) (Fig. 2b); alcohol-dependent subjects vs subjects qualifying for a diagnosis of alcohol abuse (four studies; RR=1.25; 95% CI [1.05, 1.48]; p=0.012) (Fig. 2c); alcohol-dependent subjects who continued to drink heavily vs alcohol-dependent subjects who reduced their alcohol intake, excluding abstainers (five studies; RR=1.60; 95% CI [1.00, 2.55]; p=0.049) (Fig. 3a); alcohol-dependent subjects who continued to drink heavily vs alcohol-dependent subjects who reduced their alcohol intake, including abstainers (nine studies; RR=1.71; 95% CI [1.23, 2.39]; p=0.002) (Fig. 3b); and alcohol-dependent subjects who continued to drink heavily vs abstinent alcohol-dependent subjects (three studies; RR=3.03; 95% CI [1.63, 5.65]; p<0.0001) (Fig. 3c). Subgroup analyses within studies that compared alcohol-dependent subjects with the general population (Supplementary Fig. 1) indicated evidence of heterogeneity by level of adjustment and length of follow-up (p-value from meta-regression on each covariate; p=0.02 and p=0.03, respectively); a lower level of adjustment or a shorter follow-up corresponded to a higher RR. Furthermore, there was a noticeable difference in mortality between alcohol-dependent subjects selected from general population surveys (RR=1.76; 95% CI [1.48, 2.09]) and alcohol-dependent subjects selected from treatment centres (RR=3.65; 95% CI [3.10, 4.30]) or hospitals (RR=3.49; 95% CI [2.37, 5.12]). The definition of AD used in a study (DSM or ICD AD vs other definition vs no reported definition) did not have a significant effect on the RR (p=0.86).