Zhang C, Qin Y-Y,Chen Q, Jiang H, Chen X-Z, Xu C-L, Mao P-J, He J, Zhou Y-H. Alcohol intake and risk of stroke: A dose–response meta-analysis of prospective studies. Int J Cardiol 2014; pre-publication; http://dx.doi.org/10.1016/j.ijcard.2014.04.225.
Background: Alcohol intake is inconsistently associated with the risk of stroke morbidity and mortality. The purpose of this study was to summarize the evidence regarding this relationship by using a dose–response meta-analytic approach.
Methods: We performed electronic searches of PubMed, EMBASE, and the Cochrane Library to identify relevant prospective studies. Only prospective studies that reported effect estimates with 95% confidence intervals (CIs) of stroke morbidity and mortality for more than 2 categories of alcohol intake were included.
Results: We included 27 prospective studies reporting data on 1,425,513 individuals. Low alcohol intake was associated with a reduced risk of total stroke (risk ratio [RR], 0.85; 95% CI: 0.75–0.95; P= 0.005), ischemic stroke (RR, 0.81; 95% CI: 0.74–0.90; P = 0.001), and stroke mortality (RR, 0.67; 95% CI: 0.53–0.85; P= 0.001), but it had no significant effect on hemorrhagic stroke. Moderate alcohol intake had little or no effect on the risks of total stroke, hemorrhagic stroke, ischemic stroke, and stroke mortality. Heavy alcohol intake was associated with an increased risk of total stroke (RR, 1.20; 95% CI: 1.01–1.43; P = 0.034), but it had no significant effect on hemorrhagic stroke, ischemic stroke, and stroke mortality.
Conclusions: Low alcohol intake is associated with a reduced risk of stroke morbidity and mortality, whereas heavy alcohol intake is associated with an increased risk of total stroke. The association between alcohol intake and stroke morbidity and mortality is J-shaped.
Most epidemiologic studies have shown a reduction in the risk of ischemic stroke (and total stroke, as ischemic stroke is by far the most common type in western countries) to be associated with light to moderate alcohol consumption. The present study supports these findings, with a decrease for most strokes with light drinking and possibly an increase in strokes for heavy drinking.
Differences in effect of alcohol on ischemic stroke by pattern of drinking and type of alcohol: Forum member Stockley provided a good summary of our previous understanding of the relation of alcohol to ischemic stroke: “This meta-analysis confirms or adds to results of previous ones, such as those of Corrao et al (1999, 2004), Reynolds et al (2003), Patra et al (2010), and Ronksley et al (2011). The apparent inverse association of moderate alcohol consumption and risk of ischaemic stroke occurs at a lower amount of alcohol and with a lower magnitude of risk reduction than does the corresponding association with risk of coronary heart disease (Klatsky et al 2001, Reynolds et al 2003, Mukamal, Ascherio, et al 2005, Mukamal et al 2006, Ronksley et al 2011). Only a regular pattern of light consumption is consistently associated with a reduced risk of ischaemic stroke (Mukamal, Chung, et al 2005, Ikehara et al 2008, Ruidavets et al 2010). For example, in the Prospective Epidemiological Study of Myocardial Infarction (PRIME), binge drinking approximately doubled the risk of an ischaemic stroke compared with regular consumption (Ruidavets et al 2010).”
Reviewer Lanzmann-Petithory pointed out that a number of studies have shown that the reduction in stroke risk associated with light-to-moderate alcohol consumption is more apparent for consumers of wine than of other beverages. As stated by Mukamal, Ascherio, et al (2005), “Red wine consumption was inversely associated with risk in a graded manner (P = 0.02 for trend), but other beverages were not.” A similar difference by type of beverage was reported by Djoussé et al (2002), who stated: “In beverage-specific analysis, only wine consumption was related to a decreased risk of ischemic stroke.” In a large prospective study in Eastern France, Renaud et al (2004) demonstrated that wine consumers had lower hypertension-related mortality than beer and spirits drinkers.
Differences in effect of alcohol by type of stroke: Stockley also commented on differences between ischemic stroke and hemorrhagic stroke. “There is consensus among studies that heavy alcohol consumption is usually associated with a higher risk of both ischaemic and haemorrhagic strokes. The relationship between moderate alcohol consumption and haemorrhagic stroke is less certain. Some studies have observed a J-shaped relationship while others observed a linear and dose-dependent relationship between the amount of alcohol consumed and the risk of hemorrhagic stroke (Klatsky et al 2002, Ariesen et al 2003, Corrao et al 2004, Feigin et al 2005, Patra et al 2010). If J-shaped, the optimal amount of alcohol is even lower than that for ischaemic stroke. For example, while Corrao et al (2004) calculated a significantly increased risk for ischaemic stroke at 100 g alcohol/day, for haemorrhagic stroke this was calculated at 50 g/day. This difference in risk between stroke types may be associated with an alcohol-induced increase in blood pressure in heavier consumers (Klatsky et al 2002, Iso et al 2004) or may relate to effects of alcohol on blood clotting mechanisms (Renaud 2001, Ruf et al 1995).”
Forum member Lanzmann-Petithory also commented on differences in alcohol effect according to type of stroke: “Generally, ischemic stroke and hemorrhagic strokes (the latter make up about 10-15% of strokes) have different, even opposite, effects from nutritional factors, particularly in lipids, as explained by Renaud (2001). The physiopathology is not the same for ischemic stroke (thrombosis and atherosclerosis) as for hemorrhagic stroke (membrane frailty and bleeding). (For example, saturated fat, as in butter, may protect against hemorrhagic stroke.) High blood pressure is a risk factor for both. Concerning alcohol, quantity increases the risk of hemorrhagic stroke, and binge drinking increases particularly the risk for ischemic stroke by a platelet rebound effect of alcohol withdrawal, as shown in rats (Ruf et al 1995); such an effect is less pronounced for wine than for other alcoholic beverages.”
Comments of Form members on the present study: This seems to be a straight-forward analysis of prospective studies. The authors state that “no restrictions were placed on language or publication status (published, in press, in progress)”. A total of 27 prospective studies met criteria to be included in the meta-analysis. The authors used restricted cubic splines to generate their dose-response curve, with knots at 10%, 50%, and 90% of the distribution. They categorized a reported average alcohol intake of <15 g/day (up to about 1½ “typical drinks”) as light consumption and of 15-30 g/day (about 2 to 3 drinks) as moderate consumption. Overall, 24 of the studies included in the analysis were adjusted for smoking and most other potential risk factors. The authors point out differences (greater smoking, larger amounts of alcohol) among the Chinese subjects, which may explain some of the differences shown between alcohol’s effects in different countries. They also point out that they had no data on pattern of drinking. Forum reviewer Yuqing Zhang considered the statistical methods used in the meta-analysis to be sound and appropriate.
The key results of the study are a significant 15% reduction in total stroke for low alcohol intake, no effect for moderate, and a 20% increased risk for heavy alcohol consumption (RR 1.20, 95% CI 1.01, 1.43). For ischemic stroke and stroke mortality there were decreases for low alcohol intake, but no significant effects of either moderate or heavy intake. For hemorrhagic stroke, the RR for subjects reporting heavy alcohol intake was increased, but none of the differences between drinkers and non-drinkers was statistically significant.
Reviewer Skovenborg considered that “The present meta-analysis of alcohol intake and risk of stroke was well executed with proper use of state-of-the-art principles. Most of the results are not surprising and the confirmation of a J-shaped association between alcohol intake and risk of stroke was expected. The wide confidence intervals are surprising considering the large number of studies in the meta-analysis, and the heterogeneity of the results for alcohol intake and hemorrhagic stroke is also somewhat surprising.”
Reviewer Van Velden was not sure whether hypertension was given adequate consideration in this study, adding that blood pressure is linked both to heavy alcohol consumption and to stroke mortality. Added reviewer Skovenborg, “The results of the sensitivity analysis excluding the studies that specifically included patients with hypertension were similar to the results of the overall analysis and the conclusions were not affected by the exclusion of these studies. However, it is worth a discussion whether hypertension is a confounding variable or whether it is an important factor in the mechanistic pathway of the effect of alcohol on risk of stroke. In subgroup analysis the associations between alcohol intake and stroke morbidity and mortality were largely unaffected whether the analysis was adjusted for blood pressure or not.”
Forum member Svilaas stated that “This paper presents a well-performed meta-analysis, with some limitations as recognized by the authors. However, the benefit of light alcohol use seems once more to be confirmed.”
References for Forum critique
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Most epidemiologic studies have shown a reduction in the risk of ischemic stroke (and total stroke, as ischemic stroke is by far the most common type in western countries) to be associated with light to moderate alcohol consumption. The present study, a meta-analysis, was based on 27 prospective studies; the authors categorized a reported intake of <15 g/day as light consumption, and 15-30 g/day as moderate consumption. The authors point out differences (greater smoking, larger amounts of alcohol) between Chinese subjects and those from other countries, which may explain some of the differences shown between alcohol’s effects in the different countries. They also point out that they had no data on the pattern of drinking (regular, moderate intake versus binge-drinking) or on the type of alcoholic beverage consumed.
The key results of the study are a significant 15% reduction in total stroke for low alcohol intake, no effect for moderate, and a 20% increased risk for heavy alcohol consumption (RR 1.20, 95% CI 1.01, 1.43). Analyses were also done according to type of stroke: for ischemic stroke and stroke mortality there were decreases for low alcohol intake, but no significant effects of either moderate or heavy intake. For hemorrhagic stroke, the RR for subjects reporting heavy alcohol intake was higher than that of abstainers, but none of the differences between drinkers and non-drinkers was statistically significant.
This meta-analysis supports previous findings of a decrease in the risk of most strokes with light drinking and a probable increase in the risk for heavy drinking. Forum members generally agreed with the conclusions of the authors: “Low alcohol intake is associated with a reduced risk of stroke morbidity and mortality, whereas heavy alcohol intake is associated with an increased risk of total stroke. The association between alcohol intake and stroke morbidity and mortality is J-shaped. An alcohol intake of 0-20 grams/day is associated with decreased rates of stroke morbidity and mortality.”
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Comments on this critique by the International Scientific Forum on Alcohol Research were provided by the following members:
Creina Stockley, PhD, MBA, Clinical Pharmacology, Health and Regulatory Information Manager, Australian Wine Research Institute, Glen Osmond, South Australia, Australia
Erik Skovenborg, MD, Scandinavian Medical Alcohol Board, Practitioner, Aarhus, Denmark
Yuqing Zhang, MD, DSc, Epidemiology, Boston University School of Medicine, Boston, MA, USA
Arne Svilaas, MD, PhD, general practice and lipidology, Oslo University Hospital, Oslo, Norway
Harvey Finkel, MD, Hematology/Oncology, Boston University Medical Center, Boston, MA, USA
Dominique Lanzmann-Petithory,MD, PhD, Nutrition/Cardiology, Praticien Hospitalier Hôpital Emile Roux, Paris, France
David Van Velden, MD, Dept. of Pathology, Stellenbosch University, Stellenbosch, South Africa
R. Curtis Ellison, MD, Section of Preventive Medicine & Epidemiology, Boston University School of Medicine, Boston, MA, USA