Critique 035: A review of the association of alcohol consumption with cardiovascular disease outcomes – – – 5 March 2011

Ronksley PE, Brien SE, Turner BJ, Mukamal KJ, Ghali WA.  Association of alcohol consumption with selected cardiovascular disease outcomes: a systematic review and meta-analysis.  BMJ 2011;342:d671; doi:10.1136/bmj.d671

Authors’ Abstract

Objective To conduct a comprehensive systematic review and meta-analysis of studies assessing the effect of alcohol consumption on multiple cardiovascular outcomes.

Design Systematic review and meta-analysis.

Data sources A search of Medline (1950 through September 2009) and Embase (1980 through September 2009) supplemented by manual searches of bibliographies and conference proceedings.

Inclusion criteria Prospective cohort studies on the association between alcohol consumption and overall mortality from cardiovascular disease, incidence of and mortality from coronary heart disease, and incidence of and mortality from stroke.

Studies reviewed Of 4235 studies reviewed for eligibility, quality, and data extraction, 84 were included in the final analysis.

Results The pooled adjusted relative risks for alcohol drinkers relative to non-drinkers in random effects models for the outcomes of interest were 0.75 (95% confidence interval 0.70 to 0.80) for cardiovascular disease mortality (21 studies), 0.71 (0.66 to 0.77) for incident coronary heart disease (29 studies), 0.75 (0.68 to 0.81) for coronary heart disease mortality (31 studies), 0.98 (0.91 to 1.06) for incident stroke (17 studies), and 1.06 (0.91 to 1.23) for stroke mortality (10 studies). Dose-response analysis revealed that the lowest risk of coronary heart disease mortality occurred with 1–2 drinks a day, but for stroke mortality it occurred with ≤1 drink per day. Secondary analysis of mortality from all causes showed lower risk for drinkers compared with non-drinkers (relative risk 0.87 (0.83 to 0.92)).

Conclusions Light to moderate alcohol consumption is associated with a reduced risk of multiple cardiovascular outcomes.

Forum Comments

This paper is a companion piece to the recent paper in BMJ reviewed as Critique 0341.  As stated in that critique, it is unlikely that there will ever be adequate clinical trials to judge the effects of alcohol consumption on major cardiovascular outcomes such as myocardial infarction or cardiac death in humans.  Hence, for these lifestyle habits, we must use our best judgment based on carefully done observational studies, research into potential mechanisms of effect, and studies of intermediate outcomes that are in the pathways and processes in the development of disease.  The present paper synthesizes results from longitudinal cohort studies comparing alcohol drinkers with non-drinkers for the outcomes of overall mortality from cardiovascular disease (CVD), incident coronary heart disease (CHD), mortality from CHD, incident stroke, and mortality from stroke.

Comments on the paper:  This is another very well-done analysis and presentation of data, including a meta-analysis of effects for certain cardiovascular outcomes.  It includes sensitivity analyses based on using only lifetime abstainers as the referent group, varying lengths of follow up, variations in the amount of alcohol consumed, differences by sex, and effects associated with weak or strong adjustment for confounding.

Previous meta-analysis by Maclure in 19932 and by Corrao et al in 20003 are cited.  (It looks as if a comprehensive meta-analysis is coming out every decade.)  The results of this 2011 meta-analysis are in line with what we know from the previous meta-analyses and the many individual studies: risk reductions for alcohol drinkers relative to non-drinkers of 25% for cardiovascular disease mortality, 29% for incident coronary heart disease, 25% for CHD mortality and 13 % for all cause mortality.  For CHD, the effect seems to be “L-shaped,” without an increase in risk for heavier drinking, which is similar to that reported by Maclure.2 That the lowest risk of CHD mortality occurred with 1-2 drinks (15-30 grams of alcohol) per day is also in line with previous knowledge.

The lack of an overall association with stroke is likely related, at least in part, to the divergent effects of alcohol on ischemic and hemorrhagic stroke.  Further, one Forum reviewer added: “It is not surprising, that aspirin, an acetylated polyphenol, shows a similar dissociation in primary prevention trials.  Namely aspirin is quite effective (at a degree that is similar to that of alcohol reported here) against cardio-vascular events but less so against cerebro-vascular outcomes.  The fact that alcohol is not equally effective against heart and brain ischemic disease is a strong argument in favor of a causal relationship between alcohol and cardiac events.”

One Forum member stated: “The most important result of the meta-analysis concerns the mortality from all causes: a lower risk of all-cause mortality for drinkers compared with non-drinkers (relative risk 0.87 (0.83-0.92), with very little heterogeneity.  These days we have seen arguments from health authorities (for example, in France and Denmark) that no alcohol is the better option due to the risk of cancer, where a safe lower limit of consumption has been difficult to prove.  The health authorities focus on the alcohol-cancer epidemiology and never quote the data for total mortality.

Forum members agreed with the authors’ statement that the results of studies of alcohol and CHD over the past decade are remarkably consistent, and that “additional observational studies will have limited value except to elucidate more precisely the association of alcohol and stroke.”

There are two rather striking omissions from the paper: (1) a thorough discussion of the importance of the pattern of drinking on risk, and (2) a discussion of potential differences between the consumption of wine and of beer and spirits.  The study quoted by the authors in this paper to indicate no differences by beverage type4 refers to no differences for HDL-cholesterol, which is the usual finding in most studies.  However, the majority of quality epidemiologic studies have shown that wine drinkers have better outcomes, which are often (as in this paper) attributed to associated healthy lifestyle habits.  However, even in studies where potential confounders are adequately adjusted for, or in some instances in studies limited to subjects with very similar characteristics (e.g., business executives), wine drinkers tend to have better outcomes, particularly in studies from Europe.

Interest in the so-called “French Paradox” has stimulated extensive research into potential differences by type of beverage.  Evans et al5, for example, found strikingly different effects of drinking on CHD risk between France and Northern Ireland, even though the mean per capita alcohol consumption in the two countries was essentially identical.  Factors thought to contribute to the more beneficial effects of drinking in France than in Northern Ireland included differences in pattern of drinking (regular and moderate in France; mainly week-end drinking, frequently with binge-drinking, in Northern Ireland) and differences in the predominant beverages consumed (wine versus beer and spirits).  There are a large amount of data showing differences in outcome between regular moderate intake and episodic binge drinking, even when the total mean intake may be the same.6

Messages to the public:  Forum member Erik Skovenborg stated: “The public health messages should (and in many countries do) acknowledge the reduced risk of incidence and mortality of coronary heart disease associated with moderate drinking.  However, we should not expect official recommendations of light drinking on a par with exercise, vegetables, and not smoking.  The caveats would be too many, and official recommendations should be based on prospective, randomized studies (which, alas is not the case at all regarding weight, diet, exercise and tobacco smoking!).  The role of alcohol drinking is best discussed in a scenario of a patient taking medical advice from his personal physician.”

Professor Arthur Klatsky also had pertinent comments on this topic: “In the final section of the paper the authors are struggling with the matter of advice. They are trying to come up with a new angle. We should keep in mind that many practitioners have been interacting with their patients about the benefits of light-moderate drinking for years.  An overwhelming majority of persons (at least in our Northern California area) have heard of the benefits of light drinking, with many believing that this is specific for red wine.  Some do not believe it as, no doubt, do some practitioners.  The emotional baggage many have about alcohol will not go away.  For these reasons, my enthusiasm is limited for the authors’ suggested approach of ‘evaluating the receptivity of both physicians and patients’ to recommendations to drink moderately.’

“In the case of moderate drinking, we will probably be limited indefinitely to observational evidence.  In this paper, Ronksley et al do a nice job of demonstrating how the Hill criteria support causality.  As we know, those who demand randomized trials for proof of benefit for coronary disease have looser criteria for acceptance of harmful effects of lighter drinking.  Having practiced cardiology for 50 years, it is clear to me that all advice — even upon matters with good evidence — needs individualization.  With respect to light-moderate drinking, I’ll quote the final sentences of my JACC Editorial from 2010: ‘The risks of moderate drinking differ by sex, age, personal history, and family history.  As is often the case in medical practice, advice about lifestyle must be based on something less than certainty.  There is no substitute for balanced judgment by a knowledgeable, objective health professional.  What is required is a synthesis of common sense and the best available scientific facts.7’”

Future research:  The section on “Implications” in the paper is particularly thought provoking.  The authors state that current scientific data are so convincing that rather than carrying out further observational studies for most outcomes, “debate should center now on how to integrate this evidence into clinical practice and public health messages.  In the realm of clinical practice, the evidence could form a foundation for proposing counseling for selected patients to incorporate moderate amounts of alcohol into their diets to improve their coronary heart disease risk.”

The authors state further that future trials should focus on “evaluating the receptivity of both physicians and patients to the recommended consumption of alcohol for therapeutic purposes and the extent to which it can be successfully and safely implemented.”  There are challenges when such a message is translated into public health communications.  Advice regarding alcohol use will need to be focused on specific subsets of the population, as certain adverse effects of alcohol (such as injury and violence) are more common among the young, while cardiovascular disease occurs primarily in older adults.  Nevertheless, most Forum members agree that we must examine the multiple health and societal outcomes associated with alcohol consumption to learn how to maximize the benefits without increasing adverse effects, with the messages differing during different periods of life.  Still, as a Forum member stated, “We must not lose sight of the fact that moderate drinking is associated with decreases in total mortality risk.  The meta-analysis by Di Castelnuovo et al8 in 2006 indicated that studies have consistently shown a net overall benefit on this very hard endpoint to be associated with moderate alcohol consumption.”

A further comment from Professor De Gaetano: “Alcoholic beverages are not drugs and should not be used as such.  They belong to lifestyle and dietary habits whose modifications cannot be achieved by a pharmacology-like approach.  No one has performed, to my knowledge, a controlled clinical trial obliging people to smoke to see whether smoking was good or bad for their health.  Why should we do that for alcohol?  And even when a well performed drug-like trial on alcohol would give positive results, who would insist that abstainers start drinking?”

References in Forum review

1.  Brien SE, Ronksley PE,Turner BJ, Mukamal KJ, Ghali WA.  Effect of alcohol consumption on biological markers associated with risk of coronary heart disease: systematic review and meta-analysis of interventional studies.  BMJ 2011;342:d636; doi:10.1136/bmj.d636

2.  Maclure M.  Demonstration of deductive meta-analysis: ethanol intake and risk of myocardial infarction. Epidemiol Rev 1993;15:328-351.

3. Corrao G, Rubbiati L, Bagnardi V, Zambon A, Poikolainen K.  Alcohol and coronary heart disease: a meta-analysis.  Addiction 2000;95:1505-1523.

4.  Rimm EB, Williams P, Fosher K, Criqui M, Stampfer MJ.  Moderate alcohol intake and lower risk of coronary heart disease: meta-analysis of effects on lipids and haemostatic factors. BMJ 1999;319:1523-1528.

5.  Evans A, Marques-Vidal P, Ducimetiere P et al. Patterns of alcohol consumption and cardiovascular risk in Northern Ireland and France. Annals of Epidemiology 2007;17:S75-S80.

6.  Mukamal KJ, Maclure M, Muller JE, Mittleman MA.  Binge drinking and mortality after acute myocardial infarction.  Circulation 2005 ;112:3839-3845

7.  Klatsky AL.  Alcohol and cardiovascular mortality: common sense and scientific truth. J Am Coll Cardiol 2010;30;55:1336-1338.

8.  Di Castelnuovo A, Costanzo S, Bagnardi V, Donati MD, Iacoviello L, de Gaetano G.  Alcohol dosing and total mortality in men and women. An updated meta-analysis of 34 prospective studies.  Arch Intern Med 2006;166:2437-2445.

Summary of Forum review:  In an excellent summary, the authors of this paper have synthesized results from longitudinal cohort studies comparing alcohol drinkers with non-drinkers for the outcomes of overall mortality and mortality from cardiovascular disease (CVD), incident coronary heart disease (CHD), mortality from CHD, incident stroke, and mortality from stroke.  They conclude that light to moderate alcohol consumption is associated with a reduced risk of multiple cardiovascular outcomes.  Further, they suggest that current scientific data satisfy Hill criteria indicating causality, that alcohol intake is the cause of the lower risk of cardiovascular disease among moderate drinkers.

Forum members thought that this was a very well-done, comprehensive summary of a large number of studies on alcohol and cardiovascular disease.  Some believed that two topics were not adequately discussed: (1) greater benefits from wine than from other beverages, a result seen in many studies, and (2) the importance of the pattern of drinking on the health effects of alcohol.  However, Forum members welcomed the discussion in the paper as to causality and regarding future directions in research, with more emphasis into how physicians and individual patients might respond to encouragement to consume alcohol for its potentially beneficial effects on cardiovascular disease.  Most believe that there is no substitute for balanced judgment by a knowledgeable, objective health professional when discussing alcohol intake, and this requires is a synthesis of common sense and the best available scientific facts as they apply to the individual.

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Contributions to this critique by the International Scientific Forum on Alcohol Research were made by the following members:

Arthur Klatsky, MD, Dept. of Cardiology, Kaiser Permanente Medical Center, Oakland, CA, USA

Arne Svilaas, MD, PhD, general practice and lipidology, Oslo University Hospital, Oslo, Norway

R. Curtis Ellison, MD, Section of Preventive Medicine & Epidemiology, Boston University School of Medicine, Boston, MA, USA

Erik Skovenborg, MD, Scandinavian Medical Alcohol Board, Practitioner, Aarhus, Denmark

Harvey Finkel, MD, Hematology/Oncology, Boston University Medical Center, Boston,

Ulrich Keil, MD, PhD, Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany MA, USA

Gordon Troup, MSc, DSc, School of Physics, Monash University, Victoria, Australia

Fulvio Ursini, MD, Dept. of Biological Chemistry, University of Padova, Padova, Italy

Andrew L. Waterhouse, PhD, Department of Viticulture and Enology, University of California, Davis

Dominique Lanzmann-Petithory,MD, PhD, Nutrition/Cardiology, Praticien Hospitalier Hôpital Emile Roux, Paris, France

Giovanni de Gaetano, MD, PhD, Research Laboratories, Catholic University, Campobasso, Italy