Discussion
Our analysis showed that when the comparison group was lifetime abstainers in population studies, there was no indication for a protective association from chronic heavy drinking, contrary to our analysis using current abstainers as the reference and results from another meta-analysis, which reported a universal protective association between alcohol consumption and IHD.4 However, when current abstainers were the reference group, results indicated a ‘protective’ association, comparable in magnitude to that found in studies of moderate overall alcohol intake.2 ,4 Ronksley et al,4 similar to Roerecke et al,10 reported that former drinkers had an elevated IHD risk compared to lifetime abstainers. Thus, the difference in IHD risk found in the current meta-analysis is consistent with the fact that the inclusion of former drinkers in the reference group is responsible for the systematic bias in effect estimates when current abstainers are the reference group and leads to erroneous conclusions. Unfortunately, at this point, the majority of studies used current abstainers as the reference group, partly because large studies have limited space for each risk factor and assessing former drinking status requires more questionnaire space and interview time than assessing current abstention. It should be good epidemiological practice to include items that are able to differentiate between former and current drinking status in any epidemiological study on IHD risk.
The difference regarding the reference group was also evident within primary studies,34 where the risk was below RR=1 when current abstainers were the reference group, and above 1 when lifetime abstainers were the reference group. As most of the studies reported on mortality and only few studies examined IHD morbidity in comparison to lifetime abstainers, we were unable to draw firm conclusions about the relationship between chronic heavy alcohol consumption and IHD morbidity. More systematic research is needed in this area.
With regard to population studies, adjustment for confounders was not optimal in many studies; however subgroup analyses of studies with good adjustment did not change our conclusions (no beneficial association between chronic heavy alcohol consumption and IHD risk). In contrast to chronic heavy drinkers from population samples, clinical samples of patients with AUD showed a clear detrimental association with a 62% higher risk of heart disease mortality compared to the general population among men, and a twofold higher risk among women. However, there was an apparent lack of adjustment other than age and sex, and lack of recent studies investigating IHD among patients with AUD with only two studies with a baseline assessment after 1990. In particular, the complete lack of adjustment for smoking in clinical samples shows that better quality evidence is needed to confirm the role of alcohol consumption on IHD risk in patients with AUD. As the control group was the general population for clinical samples, the risk for IHD should be expected to be somewhat higher compared to population sample results (when the reference was lifetime abstainers) if one assumes a protective effect of moderate alcohol consumption. A recent meta-analysis on average alcohol consumption2 has shown strong evidence from observational studies that the risk of IHD among moderate drinkers is reduced in comparison to lifetime abstainers.
Among those reporting the strongest elevated risk for IHD are studies from Russia.36 ,37 However, because there are very few abstainers, the reference group is typically not abstainers, but people with low average alcohol intake. A relatively frequent consumption pattern in Russia is episodic heavy to very heavy consumption with sometimes prolonged binges (‘zapoi’, an episode of continuous drunkenness lasting two or more days in combination with withdrawal from normal social life). This drinking pattern is so extreme that it is heavy with regard to both average and episodic consumption.38 ,39 Nevertheless, the risk among heavy alcohol drinkers in comparison to low level drinkers36 ,37 was substantial, which points to no beneficial effects from heavy alcohol intake and is in support of our findings.
Limitations
The analysis was limited to English-language, German-language and Spanish-language studies, leaving the possibility of unidentified studies. Furthermore, as is the case for all meta-analyses, our analysis was subject to bias and uncontrolled confounding as they were inherent in the primary studies. I2 values were moderate to high in most analyses. Although adjustment for major IHD risk factors was investigated in population studies and did not result in a change of conclusions, adjustment for risk factors other than age and smoking was not optimal in most studies, and uncontrolled confounding may have contributed to any observed between-study heterogeneity. Uncontrolled confounding might have been most problematic in the clinical samples used in our study, which did not control for smoking or any other IHD risk factor other than sex and age. The choice of random-effect models (although giving more weight to smaller studies) was justified by the amount of heterogeneity detected and because epidemiological studies generally cannot control unobserved confounding in the same way a randomisation process can. However, conclusions were not affected by this choice. Nevertheless, all studies were observational and thus causality cannot be established. Ill-definition of cardiovascular deaths and substantial variation across countries in terms of the quality of classifications of IHD deaths may pose an additional problem.40 In a Swedish sample included in our analysis, Denison41 examined information from death certificates and independent evaluations from hospital and clinical autopsy reports, police reports, forensic autopsy reports and toxicology reports. They found only a slightly higher mortality risk for cardiovascular diseases compared to death certificate information. As we focused on high-quality epidemiological studies, we excluded self-reported IHD morbidity and other forms of heart disease not defined by ICD-10: I20–I25, and thus cannot generalise beyond the populations and outcomes in our study.
Study quality was substantially lower in clinical samples because of lack of adjustment for potential confounding. Only one study15 reported risk estimates adjusted for more than just age, one other study also adjusted for length of follow-up.41 Thus, confounding or effect modification from factors other than age and sex could not be examined. It seems likely that, given the close correlation of smoking with alcohol consumption in general and at high levels of alcohol consumption in particular, smoking had some undetected influence on IHD mortality in clinical samples because of a clearly established monotonous detrimental relationship of smoking with heart disease. However, there is surprisingly little research on this topic and it remains to be seen whether smoking explains the elevated risk for IHD seen in patients with AUD. Few studies have examined IHD risk stratified by alcohol and smoking in population studies,34 ,42 ,43 but no clear picture emerged. In particular, there are no studies investigating potential joint effects from smoking and chronic heavy alcohol consumption on IHD risk with lifetime abstainers as the reference group. If alcohol consumption in patients with AUD is the determining factor for an increased risk of IHD, evidence from AUD treatment outcome studies could provide further pieces of evidence for a potential causal effect. Many studies among patients with AUD showed that a reduction from chronic heavy drinking to moderate or low levels, including but not limited to abstention, can substantially reduce all-cause mortality.44 However, there seems to be no investigations regarding whether or not IHD as a cause of death played a substantial role in this reduction of all-cause mortality.
Experimental evidence for chronic heavy drinking and heart disease risk
What is the underlying experimental evidence base? Long-term randomised studies on IHD mortality or morbidity are unavailable. Although regular low to moderate alcohol intake has been found to have beneficial, dose-dependent effects on biomarkers for IHD in short-term experimental studies, mainly by increasing high-density lipoprotein (HDL) levels, inhibiting platelet activation, reducing fibrinogen levels and producing anti-inflammatory effects,6 chronic heavy drinking has been found to be related to detrimental effects on the heart, with adverse effects mainly on blood pressure, fibrinolytic factors and ventricular arrhythmia after cessation of heavy drinking, as well as in participants with existing ischaemic disease through silent myocardial ischaemia and angina.45 Chronic alcohol intake in particular is associated with physiological changes of the heart, including prolonged QT intervals and electrolyte abnormalities.46 There are some short-term experimental studies specifically on regular heavy drinking. During heavy alcohol intake, trygliceride levels were elevated in most studies,47–50 with transient positive effects on trygliceride in one study51 and HDL cholesterol was elevated in all studies.47–52 In fact, the highest HDL levels are observed in people with AUD.53 It seems that despite a beneficial effect on HDL cholesterol even in chronic heavy alcohol consumers, other effects of chronic heavy alcohol consumption on heart disease risk might negate those beneficial effects,54 ,55 resulting in an overall neutral or detrimental association found in our analysis. Further work on distinct biochemical pathways and differentiation of heart disease outcomes should be a priority in alcohol-heart research.
Conclusions
As the evidence base is scarce in women, we restrict our conclusions to men only. Our findings, in combination with previous investigations,2 ,20 lead to three main conclusions: First, there is no systematic evidence of a protective association between IHD and chronic heavy drinking. Second, the findings show that the reference category is crucial in determining IHD risk from any type of alcohol consumption. Public perception of a universal cardioprotective association, however, might overshadow these important parts of the alcohol-heart relationship, as it can be used as an excuse for heavier drinking. Third, a detrimental association of alcohol consumption on IHD is evident only for patients with AUD, the highest end of the spectrum of alcohol consumption. It should be stressed that there is a clear detrimental effect of any heavy drinking episodes on injuries and through overall intake on many cancers.56 ,57 Thus heavy drinking in all forms should be discouraged.
