REVIEW

Alcohol Consumption and Risk of Stroke

A Meta-analysis
Kristi Reynolds, MPH L. Brian Lewis, MPH John David L. Nolen, MD, PhD, MSPH Gregory L. Kinney, MPH Bhavani Sathya, MPH Jiang He, MD, PhD cause of death and a major cause of disability in the United States.1,2 In 1999, 167366 deaths in the United States resulted from stroke.1 Approximately 30% of stroke survivors are permanently disabled and 20% require institutionalized care.1 Stroke is also a huge financial burden for patients, their families, and the health care system. The cost of stroke in the United States in 2002 is estimated to be $49.4 billion, which includes direct health expenditures and lost productivity resulting from morbidity and mortality.1 Alcoholic beverages are consumed widely throughout the world, and an association between alcohol consumption and stroke could have considerable public health and clinical implications. Over the past 2 decades, many observational epidemiologic studies3-37 have examined the role of alcohol as both a risk factor and a potential protective factor for stroke. Heavy alcohol consumption has been linked to an increased risk of total stroke,23,32 ischemic stroke,29,33 and hemorrhagic stroke.3,7,33,35 However, studies investigating the association between moderate alcohol consumption and stroke have reported conflicting results. Some studies have reported that moderate alcohol consumption is inversely related to risk of total stroke,31 ischemic stroke,27,31,37 and hemorrhagic stroke,27,31 while others found that moderate alcoContext Observational studies suggest that heavy alcohol consumption may increase the risk of stroke while moderate consumption may decrease the risk. Objective To examine the association between alcohol consumption and relative risk of stroke. Data Sources Studies published in English-language journals were retrieved by searching MEDLINE (1966April 2002) using Medical Subject Headings alcohol drinking, ethanol, cerebrovascular accident, cerebrovascular disorders, and intracranial embolism and thrombosis and the key word stroke; Dissertation Abstracts Online using the keywords stroke and alcohol; and bibliographies of retrieved articles. Study Selection From 122 relevant retrieved reports, 35 observational studies (cohort or case control) in which total stroke, ischemic stroke, or hemorrhagic (intracerebral or total) stroke was an end point; the relative risk or relative odds and their variance (or data to calculate them) of stroke associated with alcohol consumption were reported; alcohol consumption was quantified; and abstainers served as the reference group. Data Extraction Information on study design, participant characteristics, level of alcohol consumption, stroke outcome, control for potential confounding factors, and risk estimates was abstracted independently by 3 investigators using a standardized protocol. Data Synthesis A random-effects model and meta-regression analysis were used to pool data from individual studies. Compared with abstainers, consumption of more than 60 g of alcohol per day was associated with an increased relative risk of total stroke, 1.64 (95% confidence interval [CI], 1.39-1.93); ischemic stroke, 1.69 (95% CI, 1.34-2.15); and hemorrhagic stroke, 2.18 (95% CI, 1.48-3.20), while consumption of less than 12 g/d was associated with a reduced relative risk of total stroke, 0.83 (95%, CI, 0.75-0.91) and ischemic stroke, 0.80 (95% CI, 0.67-0.96), and consumption of 12 to 24 g/d was associated with a reduced relative risk of ischemic stroke, 0.72 (95%, CI, 0.57-0.91). The meta-regression analysis revealed a significant nonlinear relationship between alcohol consumption and total and ischemic stroke and a linear relationship between alcohol consumption and hemorrhagic stroke. Conclusions These results indicate that heavy alcohol consumption increases the relative risk of stroke while light or moderate alcohol consumption may be protective against total and ischemic stroke.
JAMA. 2003;289:579-588 www.jama.com

TROKE IS THE THIRD LEADING

hol consumption is positively related to risk of stroke.3,25 We performed a meta-analysis of epidemiologic studies to examine the relative risk of stroke at various levels of alcohol consumption. METHODS
Study Selection

Headings alcohol drinking, ethanol, cerebrovascular accident, cerebrovascular disorders, and intracranial embolism and thrombosis and the keyword stroke was performed. The search was restricted to
Author Affiliations: Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, La. Corresponding Author and Reprints: Kristi Reynolds, MPH, Department of Epidemiology, Tulane University Health Sciences Center, School of Public Health and Tropical Medicine, 1430 Tulane Ave SL18, New Orleans, LA 70112 (e-mail: kreynol1@tulane.edu).

A literature search of the MEDLINE database (from January 1966 through April 2002) using the Medical Subject

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ALCOHOL CONSUMPTION AND RISK OF STROKE

studies published in English-language journals and conducted in human subjects. We also conducted a search of abstracts listed in Dissertation Abstracts Online using the keywords stroke and alcohol, and we performed a manual search of references cited in published original study and relevant review articles. 38-48 The contents of 122 abstracts or full-text manuscripts identified during the literature search were reviewed independently by 2 investigators in duplicate to determine whether they met the criteria for inclusion. When there were discrepancies between investigators for inclusion or exclusion, other investigators conducted additional evaluation of the study and discrepancies were resolved in conference. To be included in our metaanalysis, a published study had to meet the following criteria: (1) observational cohort or case-control study in which total stroke, ischemic stroke, or hemorrhagic (intracerebral or total) stroke was an end point; (2) relative risk or relative odds and their variance (or data to calculate them) of stroke associated with alcohol consumption were reported; (3) alcohol consumption was quantified; and (4) abstainers were used as the reference group. Fifty-three studies were identified and abstracted. Four studies reported total hemorrhagic stroke as the outcome, which includes intracerebral and subarachnoid hemorrhage.4,7,10,11 None of the studies reported information on subdural hemorrhagic strokes. We have used the term hemorrhagic stroke throughout the article. Two reports consisted of the same case patients but different controls and were treated as 2 separate studies.23,24 From the 53 studies, 18 were further excluded for various reasons. Two studies were excluded because combined risk estimates were reported for men and women but levels of alcohol consumption were not the same for men as for women.49,50 We excluded 5 studies that examined only the effect of binge drinking or acute alcohol consumption (within 24 hours before stroke)51-55 because our study assessed habitual alcohol consumption and relative risk of
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stroke. Five studies that lacked sufficient data for calculation of relative risk estimates were excluded.56-60 The remaining 6 excluded reports did not use abstainers as the reference group.61-66 We included 19 cohort studies and 16 casecontrol studies in our final analysis.
Data Abstraction

All data were independently abstracted in triplicate by means of a standardized data-collection form. Discrepancies were resolved by discussion and referencing the original publication. We did not contact authors to request additional information. Study characteristics recorded were as follows: title, articles first authors name, year, and source of publication, country of origin, study design (cohort study or case-control study), characteristics of the study population (sample size; sampling methods; and distribution of age, sex, and race), measures of outcome and exposure, duration of follow-up (for prospective cohort studies), confounding factors controlled for by matching or adjustment, and the relative risk (or relative odds) of stroke associated with alcohol consumption and the corresponding confidence interval (or SE). Relative risks overall and in each subgroup, according to sex, subtype of stroke, level of alcohol consumption, and type of alcoholic beverage, were abstracted.
Statistical Analysis

Relative risk was used as a measure of the relation between alcohol consumption and risk of stroke. For casecontrol studies, relative odds were used as a surrogate measure of the corresponding relative risk. Because the absolute risk of stroke is low, the relative odds approximate the relative risk. Relative risks from individual studies for each level of alcohol consumption and the corresponding SEs were transformed to their natural logarithms to stabilize the variances and to normalize the distributions. The SEs were derived from the confidence intervals provided in each study. The studies included in our metaanalysis often differed in the measure-

ment units of alcohol consumption (eg, grams, milliliters, ounces, or drinks consumed every day, week, or month). Therefore, we first converted these different units of alcohol consumption to grams per day. Among the 35 studies included in our meta-analysis, 20 reported alcohol consumption as grams. We used the following conversion factors for the 4 studies that reported alcohol data as milliliters or ounces: 1 mL, 0.785 g; 1 fl oz, 28.41 mL (United Kingdom); and 1 fl oz, 29.58 mL (United States). Two of the 11 studies that reported alcohol data as drinks provided conversion factors in their articles. The other 9 used common conversion factors.67 In the latter, a drink was defined as 12 g in the United States, 10 g in Australia and Europe, and 21.2 g in Japan, which is the standard drink volume in Japan.67 Alcohol consumption was reported as categorical data with a range in all studies. We assigned the mean of the upper and lower bounds in each category as the average alcohol consumption. An upper bound was not reported in many studies for the category of highest consumption, so we assumed it to be the same amplitude as the preceding category for calculation of average alcohol consumption in this category. In our meta-analysis, alcohol consumption was categorized into 5 groups: none (reference), less than 12, 12 to 23, 24 to 60, and more than 60 g/d. We assigned the level of alcohol consumption from each study to these groups based on the calculated average consumption of alcohol. In some studies, the average alcohol consumption from more than 1 category fell into the same group of alcohol consumption in our meta-analysis. When this occurred, we pooled the relative risks within each category for each study and then we pooled across all studies. Both fixed-effects and DerSimonian and Laird random-effects models68 were used to calculate the pooled relative risk across levels of alcohol consumption. Although both models yielded similar findings, results from the random-effects model are presented herein because

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ALCOHOL CONSUMPTION AND RISK OF STROKE

Table 1. Characteristics of 19 Cohort Studies of Alcohol Consumption and Risk of Stroke

Source Donahue et al,3 1986 Study Participants 7878 Men aged 45-69 y in Hawaii Exposure Assessment In-person interview Duration of Follow-up, y 12 Follow-up Process Clinical examinations at years 2 and 6 and continued surveillance Vital status ascertained by medical association Vital statistics records, newspapers, or reports from proxies Biennial questionnaires Outcome Assessment Hospital discharge diagnosis, clinical diagnosis, death certificate, or autopsy record Death certificate No. of Stroke Cases 290 Controlled Variables Age, BMI, cigarette smoking, hypertension, serum cholesterol, uric acid, glucose level, hematocrit

Kono et al,4 1986

5135 Men in Japan

Self-administered questionnaire

19

230

Age, cigarette smoking

Gordon and Doyle,5 1987

1910 Men aged 38-55 y in New York

Self-administered questionnaire

29

Proxy reports or death certificate

33

None

Stampfer et al,6 1988

87 526 US women aged 34-59 y

Self-administered questionnaire

Medical records

120

Age, cigarette smoking, hypertension, DM, serum cholesterol level, obesity, exercise, cholesterol intake, saturated and polyunsaturated fat intake, parental history of MI before age 60 y, menopausal status, hormone use, study period Age, sex, race, cigarette smoking, SBP, coffee consumption, BMI, baseline disease Age, cigarette smoking, SBP

Klatsky et al,7 1989

107 137 US men and women aged 50 y 7735 UK men aged 40-59 y 6069 Men aged 51-75 y in Hawaii

Self-administered questionnaire

Surveillance of hospital discharges Death register

Clinical diagnosis

674

Shaper et al,8 1991 Goldberg et al,9 1994

In-person interview In-person interview

Clinical diagnosis or death certificate Hospital discharge diagnosis, clinical diagnosis, or death certificate

110

15

Clinical examinations at years 2 and 6 and continued surveillance Death register

70

Age; cigarette smoking; SBP; serum cholesterol, serum triglyceride, and serum uric acid levels, coffee consumption, total caloric intake Age, cigarette smoking

Hansagi et al,10 1995

15 077 Men and women aged 40 y in Sweden 2890 Men aged 40-69 y in Japan 1621 Men and women aged 40 y in Japan

Self-administered questionnaire

20

Death certificate

769

Iso et al,11 1995

In-person interview In-person interview

10.5

Not specified

Clinical diagnosis and CT scan Neurological examination, CT scan, angiography, lumbar puncture, or autopsy Death certificate

178

Age, cigarette smoking, hypertension, serum total cholesterol level, DM Age, sex, hypertension

Kiyohara et al,12 1995

26

Biennial examinations, mail, or telephone

304

Palmer et al,13 1995

6369 Men and women aged 18-90 y in England 18 244 Men aged 45-64 y in China 27 678 Men and women aged 30 y in Hawaii 5766 Men aged 35-64 y in Scotland

In-person interview (1971-1976) Self-administered questionnaire (after 1976) In-person interview

22

Questionnaire every 1-2 y

159

Age, sex, cigarette smoking, SBP

Yuan et al,14 1997

Annual contact

Death certificate

269

Age, cigarette smoking, educational level

Maskarinec et al,15 1998

In-person interview

20

Passive follow-up

Death certificate

433

Age, BMI, cigarette smoking, ethnicity, educational level

Hart et al,16 1999

In-person interview

21

NHS death register

Death certificate

133

Age, BMI, cigarette smoking, DBP, serum cholesterol level, educational level, social class, fathers social class, car use, siblings, deprivation category, adjusted FEV, angina, ischemia on ECG, bronchitis
(continued)

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ALCOHOL CONSUMPTION AND RISK OF STROKE

Table 1. Characteristics of 19 Cohorts Studies of Alcohol Consumption and Risk of Stroke (cont)
Source, y Leppl et al,17 1999 Study Participants 26 556 Men aged 50-69 y in Finland Exposure Assessment Self-administered questionnaire Duration of Follow-up, y 6.1 Follow-up Process National hospital discharge register and national death register Outcome Assessment Clinical diagnosis or death certificate No. of Stroke Cases 960 Controlled Variables Age, BMI, cigarette smoking, serum cholesterol level, DM, educational level, leisure time physical activity, heart disease, supplementation with -tocopherol or beta carotene BMI, cigarette smoking, BP, fathers social class, running away from home, poor school well-being, parental divorce, poor emotional control, few friends, unemployment 3 mo during life, poor health Age, BMI, cigarette smoking, DM, exercise Age, BMI, cigarette smoking, serum total cholesterol, SBP, DBP, and study year

Romelsj et al,18 1999

49 618 Men aged 17-45 y in Sweden

Self-administered questionnaire

25

Inpatient care register and death register

Clinical diagnosis or death certificate

223

Gaziano et al,19 2000 Jousilahti et al,20 2000

89 299 US men aged 40-84 y 14 874 Men and women aged 25-64 y in Finland

Self-administered questionnaire Self-administered questionnaire

5.5

National Death Index search National hospital discharge register or central statistical office of Finland Biennial examinations

Death certificates

150

12

Clinical diagnosis or death certificates

470

Djousse et al,21 2002

5209 Framingham, Mass, men and women

In-person interview

30

Clinical diagnosis and radiographic images

441

Age, BMI, cigarette smoking, DM

Abbreviations: BMI, body mass index; CT, computed tomography; DBP, diastolic blood pressure; DM, diabetes mellitus; ECG, electrocardiogram; FEV, forced expiratory volume; MI, myocardial infarction; NHS, National Health Service; SBP, systolic blood pressure.

significant heterogeneity was identified among studies.68 A weighted metaregression analysis with no intercept term was performed to examine the association between alcohol consumption and the natural logarithm of the relative risk of stroke. We used the pool-first method proposed by Greenland and Longnecker.69 This method was chosen because several studies reported finding a nonlinear, J- or U-shaped relationship between alcohol consumption and relative risk of stroke. This method is advantageous because it can easily be extended to test nonlinearity and identify J- or U-shaped curves, or other relationships between exposure levels and relative risks. For each included study, we performed an initial fit of a quadratic curve. When a nonsignificant term was found in the initial model, a subsequent fit of a simpler model (linear or solitary square term) was conducted. Prestated subgroup analyses were conducted by subtype of stroke and sex for the different levels of alcohol consumption. Subgroup analyses were not performed by type of alcoholic bever582

age due to the lack of such detailed information in most studies. To assess the potential for publication bias, we constructed a funnel plot in which the log relative risks were plotted against their SEs.70 In addition, a rank correlation for the association between standardized log relative risks and their SEs was conducted using the Kendall correlation coefficient. The correlation between sample size and relative risk would be high if small studies with null results were less likely to be published. A significant correlation between sample size and relative risk would not exist in the absence of this type of publication bias.70 RESULTS The characteristics of the study subjects and design of the cohort studies are presented in TABLE 1. Of the 19 cohort studies, 8 were conducted in the United States. The number of subjects in the cohort studies ranged from 1621 in the study by Kiyohara et al 12 to 107 137 in the study by Klatsky et al.7 Among the 19 cohort studies, 15 re-

ported total stroke as the outcome. In addition, 7 studies reported ischemic stroke, and 7 studies reported hemorrhagic stroke as the outcome. The follow-up period ranged from 4 to 30 years. The study population in 7 cohort studies consisted of men and women, 1 consisted entirely of women, and 11 consisted of only men. Twelve of the 16 case-control studies were conducted outside the United States (TABLE 2). The number of case subjects enrolled in these studies ranged from 89 in the study by Henrich and Horwitz26 to 677 in the study by Sacco et al,34 and the corresponding number of control subjects ranged from 153 in the study by Palomki et al29 to 1139 in the study by Sacco et al.34 Total stroke was the study outcome in 9 studies, whereas 8 studies collected data on ischemic stroke and 5 collected data on hemorrhagic stroke. Fourteen of the 16 case-control studies were composed of both men and women, 1 case-control study consisted of only women, and 1 casecontrol study consisted of only men.

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Table 2. Characteristics of 16 Case-Control Studies of Alcohol Consumption and Risk of Stroke

Source, y Herman et al,22 1983 Stroke Cases 132 Male and female patients with incident stroke event in 2 hospitals in the Netherlands 230 Male and female patients with stroke diagnosis in the district hospital in England 230 Male and female patients with stroke diagnosis in the district hospital in England 205 Male and female patients with incident ischemic stroke in 3 medical centers in Chicago 89 Male and female hospitalized patients with ischemic stroke in Connecticut 621 Male and female hospitalized patients with stroke diagnosis in 2 centers in England 115 Male and female hospitalized patients with incident stroke in 3 hospitals in the United Kingdom Controls 239 Patients from the same hospital Case Assessment Clinical examination Exposure Assessment In-person interview Controlled Variables Age, sex

Gill et al,23 1986

230 Hospital patients

Gill et at,24 1988

577 Male and female industrial workers in the same community

Gorelick et al,25 1989

410 Outpatient clinic patients

Clinical examination, CT scan, angiography, and postmortem examinations, or lumbar puncture Clinical examination, CT scan, angiography, and postmortem examinations, or lumbar puncture Clinical diagnosis and CT scan

In-person interview

Age, sex, race, cigarette smoking, treatment of hypertension, medication

In-person interview

Age, race, cigarette smoking, treatment of hypertension, social class, drug therapy

In-person interview

Age, sex, race, cigarette smoking, hypertension, method of hospital payment None

Henrich and Horwitz,26 1989

178 Patients discharged from the same hospital

Clinical examination and CT scan

Telephone interview

Gill et al,27 1991

573 Male and female industrial workers in the same community

Ben-Shlomo et al,28 1992

165 Generally matched, 115 selectively matched, and 752 community controls

Clinical examination, CT scan, angiography and postmortem examination, or lumbar puncture Clinical examination, CT scan, or lumbar puncture

In-person interview

Age, sex, race, cigarette smoking, hypertension, social class, medication

Cases, in-person taped interview Controls, self-administered questionnaire

Palomki et al,29 1993

Shinton et al,30 1993

Jamrozik et al,31 1994

156 Male hospitalized patients with ischemic stroke in Finland 125 Male and female patients with incident stroke in 11 general practice partnerships in England 501 Male and female patients with stroke diagnosis in Australia

153 Hospital patients

Clinical diagnosis

In-person interview

198 Community controls

Clinical examination, CT scan, or autopsy

Alcohol diary

General and selective controls: age, sex, cigarette smoking, hypertension, DM, heart disease Community controls: age, sex, cigarette smoking, hypertension, and social class Age, BMI, cigarette smoking, hypertension, DM, coronary heart disease, history of snoring Age, sex, history of cardiovascular disease

931 Community controls from the electoral roles

Clinical examination, CT scan, MRI, or autopsy

In-person interview

Beghi et al,32 1995

Caicoya et al,33 1999

200 Male and female hospitalized patients with stroke in Italy 467 Male and female patients with incident stroke in Spain

170 Patients in the same hospital and 202 community controls 477 Residents of the same community

Clinical examination, CT scan, or neurological consultation Clinical examination or CT scan

In-person interview

Age, sex, cigarette smoking, hypertension, DM, previous stroke or TIA, previous MI, adding salt to food, consumption of fish 2 times/mo, claudication, use of reduced fat or skim milk, consumption of meat 4 times/wk Age, sex

In-person interview

Age, sex, cigarette smoking, hypertension, DM, hypercholesterolemia, cardiac disease

(continued)

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Table 2. Characteristics of 16 Case-Control Studies of Alcohol Consumption and Risk of Stroke (cont)
Source Sacco et al,34 1999 Stroke Cases 677 Men and women with incident cerebral infarction in the community in New York 331 Male and female patients with primary hemorrhagic stroke from 13 hospitals in Melbourne, Australia Controls 1139 Community controls Case Assessment Brain imaging and clinical diagnosis Exposure Assessment In-person interview Controlled Variables Age, sex, race, BMI, cigarette smoking, hypertension, DM, cardiac disease, educational level Age, sex, BMI, cigarette smoking, DM, serum cholesterol level, SES, educational level, exercise, cardiovascular disease, hormone replacement therapy Age, sex

Thrift et al,35 1999

331 Residents from the same neighborhood

CT scan, MRI, or autopsy

In-person interview

Zodpey et al,36 2000

Malarcher et al,37 2001

166 Male and female hospitalized patients with incident hemorrhagic stroke in India 224 Female patients with incident cerebral infarction in 59 hospitals in Baltimore-Washington region in the United States

166 Patients from the same hospital

CT scan

In-person interview

392 Female community residents

Hospital discharge diagnosis, clinical diagnosis, neuroimaging results, or autopsy reports

In-person interview

Age, race, BMI, cigarette smoking, hypertension, DM, total cholesterol, HDL cholesterol level, geographic region of residence, educational level, coronary heart disease

Abbreviations: BMI, Body mass index; CT, computed tomography; DM, diabetes mellitus; MI, myocardial infarction; MRI, magnetic resonance imaging; SES, socioeconomic status; TIA, transient ischemic attack.

The results from the randomeffects model and the meta-regression analysis test for trend are presented in TABLE 3. The overall results indicate a nonlinear association between alcohol consumption and relative risk of total stroke (P = .002 for nonlinear trend). Compared with the reference group of abstainers, alcohol consumption of less than 12 g/d, or less than 1 drink per day based on US conversions, was significantly associated with a decreased relative risk of total stroke, while alcohol consumption of more than 60 g/d, or more than 5 drinks per day, was significantly associated with an increased relative risk of total stroke. The association between alcohol consumption and relative risk of ischemic stroke was J-shaped with the lowest risk among those consuming less than 12 g/d, or less than 1 drink per day, or 12 to 24 g/d, or 1 to 2 drinks per day, and the highest risk among those consuming more than 60 g/d, or more than 5 drinks per day, (FIGURE 1). Relative risk of hemorrhagic stroke increased linearly with increasing alcohol consumption, and those consuming more than
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60 g/d, or more then 5 drinks per day, had the highest relative risk. The association between alcohol consumption and relative risk of total stroke was similar in men and women (Table 3 and FIGURE 2) although the relative risk was somewhat lower in women consuming less than 12 g/d, or less than 1 drink per day, than in men. Likewise, the association was similar in case-control studies and cohort studies, with alcohol consumption of less than 12 g/d, or less than 1 drink per day, among cohort studies and alcohol consumption of less than 24 g/d, or less than 2 drinks per day, among casecontrol studies associated with a significant reduced relative risk while alcohol consumption of more than 60 g/d, or more than 5 drinks per day, was associated with an increased relative risk. The findings from the sensitivity analyses that excluded studies based on different inclusion criteria are presented in T ABLE 4. Risk estimates changed very little after the exclusion of outliers, studies without computed tomographic scans or other imaging measures, studies that did not adjust for

important confounders, or studies that did not exclude prevalent stroke cases at baseline. There was no evidence of publication bias in our study as indicated by a funnel plot (FIGURE 3) and the Kendall correlation coefficient. The Kendall correlation coefficient for the SE and the standardized log relative risk was 0.072 (P = .17) for all studies. When the outliers were excluded, the Kendal correlation coefficient for the SE and the standardized log relative risk became 0.053 (P =.32). COMMENT Several large epidemiologic studies that have examined the effect of alcohol consumption on the risk of stroke have provided inconsistent findings. In our current meta-analysis, we found a J-shaped association between alcohol consumption and the relative risk of total and ischemic stroke and a linear association between alcohol consumption and the relative risk of hemorrhagic stroke. Moderate alcohol consumption was associated with a reduced relative risk of total and ischemic stroke while heavy

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alcohol consumption was associated with an increased relative risk of total, ischemic, and hemorrhagic stroke.

The relationship between alcohol consumption and stroke is believed to involve various mechanisms including

alcohol-induced hypertension, cardiomyopathy, coagulation disorders, atrial fibrillation, and reductions in cerebral

Table 3. Overall Relative Risk (95% Confidence Interval) of Stroke Associated With Alcohol Consumption and Test for Trend
P Value Alcohol Intake, g/d No. of Studies 35 15 12 27 16 19 16 12 0.83 (0.75-0.91) 0.80 (0.67-0.96) 0.79 (0.60-1.05) 0.89 (0.79-1.01) 0.66 (0.61-0.71) 0.82 (0.73-0.92) 0.80 (0.67-0.97) 12-24 0.91 (0.78-1.06) 0.72 (0.57-0.91) 0.98 (0.77-1.25) 0.94 (0.84-1.05) 0.79 (0.56-1.11) 0.94 (0.84-1.05) 0.65 (0.44-0.96) 24-60 1.10 (0.97-1.24) 0.96 (0.79-1.18) 1.19 (0.80-1.79) 1.08 (0.96-1.21) 0.80 (0.49-1.30) 1.06 (0.90-1.23) 1.12 (0.92-1.37) 60 1.64 (1.39-1.93) 1.69 (1.34-2.15) 2.18 (1.48-3.20) 1.76 (1.57-1.98) 4.29 (1.30-14.14) 1.63 (1.49-1.79) 1.98 (1.35-2.92) Test for Linear Association* Test for Nonlinear Association .002 .004 .17 .001 .001 .02 .03

Overall Type of stroke Ischemic Hemorrhagic Sex Men Women Study design Cohort Case control

.004

*Tests for linear associations were performed only when nonlinear associations were not statistically significant.

Figure 1. Scatterplot of Log Relative Risk and Meta-Regression Curve of Stroke Associated With Alcohol Consumption by Subtypes of Stroke
3

Ischemic Stroke

Hemorrhagic Stroke

Natural Logarithm Relative Risk

3 0 20 40 60 80 100 120 140 160 180 0 20 40 60 80 100 120 140 160 180

Alcohol Intake, g/d

Alcohol Intake, g/d

Most studies provided more than 1 relative risk estimate for multiple levels of alcohol consumption.

Figure 2. Scatterplot of Log Relative Risk and Meta-Regression Curve of Stroke Associated With Alcohol Consumption by Sex
3

Men

Women

Natural Logarithm Relative Risk

3 0 20 40 60 80 100 120 140 0 10 20 30 40 50 60 70 80

Alcohol Intake, g/d

Alcohol Intake, g/d

Most studies provided more than 1 relative risk estimate for multiple levels of alcohol consumption.

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Table 4. Overall Relative Risk (95% Confidence Interval) of Stroke Associated With Alcohol Consumption According to Different Exclusion Criteria*
Alcohol Intake, g/d Studies Included in Analysis All studies All studies except outliers* Studies that used computed tomography scans or other imaging measures as an outcome measure Studies that controlled for important stroke risk factors Cohort studies that used incident stroke events
*The 24 to 60 and

12 0.83 (0.75-0.91) 0.83 (0.75-0.91) 0.84 (0.75-0.94) 0.81 (0.71-0.92) 0.83 (0.73-0.95)

12-24 0.91 (0.78-1.06) 0.91 (0.78-1.06) 0.86 (0.71-1.05) 0.80 (0.64-1.00) 0.91 (0.77-1.07)

24-60 1.10 (0.97-1.24) 1.11 (0.98-1.26) 1.14 (1.01-1.35) 1.12 (0.94-1.33) 1.02 (0.83-1.26)

60 1.64 (1.39-1.93) 1.62 (1.46-1.81) 1.74 (1.37-2.21) 1.62 (1.19-2.21) 1.58 (1.43-1.73)

60 g/d levels in the study by Caicoya et al33 were excluded because they were outliers. Studies that solely used death certificates or death registries for the outcome assessment were excluded.4,5,10,13-16,19 Studies that did not control for age, cigarette smoking or hypertension were excluded.4,5,10,12,14,15,17-19,21,22,26,30,32,35,36 Cohort studies that did not exclude prevalent stroke events were excluded.4,5,8,10,13-16

Figure 3. Funnel Plot of Log Relative Risk vs Variance of Log Relative Risks Among All Studies
100 80

60 40 20 0 2.5 1.5 0.5 0.5 1.5 2.5

Natural Logarithm Relative Risk

Most studies provided more than 1 relative risk estimate for multiple levels of alcohol consumption.

blood flow.37,46,71,72 A plausible explanation of a reduced risk of ischemic stroke with moderate alcohol consumption is that alcohol increases high-density lipoprotein cholesterol levels and decreases platelet aggregation and fibrinolytic activity.6,71,72 Epidemiologic studies also have consistently observed a protective effect of moderate alcohol consumption on coronary heart disease.73,74 Alcohol-induced hypertension and coagulation disorders are probable underlying mechanisms for hemorrhagic stroke.27,45,71 The anticoagulant effects of alcohol, although they appear to be beneficial for decreasing the risk of ischemic stroke, may play an important role in increasing the risk of hemorrhagic stroke.71,74 There are several potential limitations in our study. First, our study is a meta-analysis of observational studies. The quality of our study depends on data from original publications in586

cluded in our analysis. Our study may inherit the problems of potential bias and confounding effects associated with observational studies. However, a randomized controlled trial of alcohol consumption and stroke has not been performed and is unlikely to be conducted in the future. Consequently, we must rely on data from observational studies to draw conclusions and make recommendations. Second, computed tomographic scans and other imaging techniques were not available for some early studies. Furthermore, several studies only used death certificates or death register data for diagnosis of stroke outcome. However, our findings were unlikely due to misclassification of outcome because the relative risks of stroke associated with alcohol consumption did not change after exclusion of studies that did not use computed tomography or other imaging techniques for diagnosis. Our findings were also unlikely due to confounding effects because the relative risks of stroke associated with alcohol consumption were similar among all studies and only those studies that controlled for important risk factors for stroke, such as cigarette smoking and hypertension. Additionally, our results were unlikely to result from publication bias as demonstrated by the funnel plot and rank correlation analysis. Several methodological issues regarding epidemiologic research on the health impact of alcohol consumption are worth considering. First, the selection of the reference group may vary

among studies. For instance, some studies used the lowest consumption level as the reference group while others used abstainers. In an effort to avoid combining studies that were not comparable, we chose to include only those studies that used abstainers as the reference group. It has been suggested that the U- or J-shaped association between alcohol consumption and mortality from cardiovascular disease may be due to the inclusion of ex-drinkers in the reference group of abstainers. Exdrinkers may have stopped alcohol consumption due to health problems and they are at increased risk for death from cardiovascular disease. 47,75,76 However, several studies have examined this potential bias and concluded that the J- or U-shaped relationship between alcohol consumption and risk of cardiovascular disease mortality held true.6,13,27,77 Moreover, we conducted a sensitivity analysis in which only prospective cohort studies that excluded prevalent stroke cases at baseline were included, and we found that the shape of association remained unchanged. Second, the health effects of binge drinking may be different than those for regular drinkers. The failure to differentiate between these 2 groups could possibly obscure the observation of any true association. Therefore, we only included studies that examined the effect of usual alcohol consumption rather than acute alcohol consumption. Third, the measurement units, especially the definition of an alcohol drink, varies among studies. We attempted to overcome this problem by applying a com-

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monly used and validated method suggested by Turner.67 Finally, assessment methods for alcohol consumption may also vary among studies. The assessment of alcohol consumption is usually based on self-reported alcohol habits. Such data are subject to errors of recall. For example, heavy drinkers may be more likely to underreport their alcohol consumption. The majority of studies in this meta-analysis used inperson interviews, while 11 studies used self-administered questionnaires, 1 study conducted telephone interviews, and 1 study used alcohol consumption diaries. There are several advantages of our study. The discrepancies among studies regarding the association between alcohol consumption and relative risk of stroke also may be attributable to a small sample size in the individual studies, resulting in insufficient statistical power. This meta-analysis included a large number of people from different populations throughout the world. Additionally, we were able to assess the pattern of the association between level of alcohol consumption and relative risk of stroke with precision due to the large sample size. Finally, the association between alcohol consumption and relative risk of stroke was consistent among subgroups by study design, sex, and stroke subtype. Our findings have important clinical and public health implications. In the United States, 44% of adults, aged 18 years or older, are current drinkers who have consumed at least 12 drinks in the preceding year.78 Stroke is a major cause of death and disability in the United States and other countries.2 In the United States, there are approximately 600000 new stroke cases each year.1 Given the widespread consumption of alcohol in the general population and the recognized health and economic burdens of stroke, our findings are both important and timely. Our study strongly suggests that reducing alcohol consumption in heavy drinkers should be an important approach to prevention of stroke in the general population. Our study also suggests that

moderate alcohol consumption reduces risk of ischemic stroke. However, the implications of these findings should be examined cautiously. Any advice regarding the consumption of alcohol should be tailored to the individual patients risks and potential benefits.
Author Contributions: Study concept and design: Reynolds, Lewis, Nolen, Kinney, Sathya, He. Acquisition of data: Reynolds, Lewis, Nolen, Kinney, Sathya. Analysis and interpretation of data: Reynolds, Lewis, Nolen, Kinney, Sathya, He. Drafting of the manuscript: Reynolds, Nolen, Kinney, Sathya. Critical revision of the manuscript for important intellectual content: Reynolds, Lewis, Nolen, Kinney, Sathya, He. Statistical expertise: Reynolds, Nolen, Kinney, He. Obtained funding: He. Administrative, technical, or material support: Lewis, Kinney, Sathya. Study supervision: He. Funding/Support: This study was supported in part by grant R01HL60300 from the National Heart, Lung, and Blood Institute. REFERENCES 1. American Heart Association. 2002 Heart and Stroke Statistical Update. Dallas, Tex: American Heart Association; 2001. 2. Warlow CP. Epidemiology of stroke. Lancet. 1998; 352(suppl 3):1-4. 3. Donahue RP, Abbott RD, Reed DM, Yano K. Alcohol and hemorrhagic stroke: the Honolulu Heart Program. JAMA. 1986;255:2311-2314. 4. Kono S, Ikeda M, Tokudome S, Nishizumi M, Kuratsune M. Alcohol and mortality: a cohort study of male Japanese physicians. Int J Epidemiol. 1986;15: 527-532. 5. Gordon T, Doyle JT. Drinking and mortality: the Albany Study. Am J Epidemiol. 1987;125:263-270. 6. Stampfer MJ, Colditz GA, Willett WC, Speizer FE, Hennekens CH. A prospective study of moderate alcohol consumption and the risk of coronary disease and stroke in women. N Engl J Med. 1988;319:267273. 7. Klatsky AL, Armstrong MA, Friedman GD. Alcohol use and subsequent cerebrovascular disease hospitalizations. Stroke. 1989;20:741-746. 8. Shaper AG, Phillips AN, Pocock SJ, Walker M, Macfarlane PW. Risk factors for stroke in middle aged British men [comments]. BMJ. 1991;302:1111-1115. 9. Goldberg RJ, Burchfiel CM, Reed DM, Wergowske G, Chiu D. A prospective study of the health effects of alcohol consumption in middle-aged and elderly men: the Honolulu Heart Program. Circulation. 1994;89:651-659. 10. Hansagi H, Romelsjo A, Gerhardsson de Verdier M, Andreasson S, Leifman, A. Alcohol consumption and stroke mortality: 20-year follow-up of 15077 men and women. Stroke. 1995;26:1768-1773. 11. Iso H, Kitamura A, Shimamoto T, et al. Alcohol intake and the risk of cardiovascular disease in middleaged Japanese men. Stroke. 1995;26:767-773. 12. Kiyohara Y, Kato I, Iwamoto H, Nakayama K, Fujishima M. The impact of alcohol and hypertension on stroke incidence in a general Japanese population: the Hisayama Study. Stroke. 1995;26:368-372. 13. Palmer AJ, Fletcher AE, Bulpitt CJ, et al. Alcohol intake and cardiovascular mortality in hypertensive patients: report from the Department of Health Hyper-

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Light-tomoderate alcohol consumption and risk of stroke among US male physicians. N Engl J Med. 1999;341: 1557-1564. 62. Wannamethee SG, Shaper AG. Patterns of alcohol intake and risk of stroke in middle-aged British men. Stroke. 1996;27:1033-1039. 63. Camargo CA Jr, Hennekens CH, Gaziano JM, Glynn RJ, Manson JE, Stampfer MJ. Prospective study of moderate alcohol consumption and mortality in US male physicians. Arch Intern Med. 1997;157: 79-85. 64. Truelsen T, Gronbaek M, Schnohr P, Boysen G. Intake of beer, wine, and spirits and risk of stroke: the Copenhagen city heart study. Stroke. 1998;29:24672472. 65. Kissela B, Sauerbeck L, Woo D, et al. Subarachnoid hemorrhage: a preventable disease with a heritable component. Stroke. 2002;33:1321-1326. 66. Klatsky A, Armstrong M, Friedman G, Sidney S. Alcohol drinking and risk of hospitalization for ischemic stroke. Am J Cardiol. 2001;88:703-706. 67. Turner C. How much alcohol is in a standard drink: an analysis of 125 studies. 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LETTERS

widely, with particularly high rates of use by internists and physicians in the Northeast and the South.
Michael A. Steinman, MD C. Seth Landefeld, MD San Francisco VA Medical Center San Francisco, Calif Ralph Gonzales, MD, MSPH University of California, San Francisco
1. Gonzales R, Steiner JF, Lum A, Barrett PH Jr. Decreasing antibiotic use in ambulatory practice: impact of a multidimensional intervention on the treatment of uncomplicated acute bronchitis in adults. JAMA. 1999;281:1512-1519. 2. Gonzales R, Malone DC, Maselli JH, Sande MA. Excessive antibiotic use for acute respiratory infections in the United States. Clin Infect Dis. 2001;33:757-762.

CORRECTIONS
Name Omitted: In the Original Contribution entitled Combination Therapy With Hormone Replacement and Alendronate for Prevention of Bone Loss in Elderly Women: A Randomized Controlled Trial published in the May 21, 2003, issue of THE JOURNAL (2003;289:2525-2533), Michael McClurg, MD, should be added to the list of members of the Data and Safety Monitoring Board on page 2532 after Peggy A. Norton, MD.

Error in Authors Name: In the Review article entitled Alcohol Consumption and Risk of Stroke: A Meta-analysis published in the February 5, 2003, issue of THE JOURNAL (2003;289:579-588) in the byline, the initial letter L. was incorrectly placed in front of the name of author Brian Lewis, MPH.

CME ANNOUNCEMENT
Online CME to Begin in Mid-2003 In mid-2003, online CME will be available for JAMA/Archives journals and will offer many enhancements: Article-specific questions Hypertext links from questions to the relevant content Online CME questionnaire Printable CME certificates and ability to access total CME credits

We apologize for the interruption in CME and hope that you will enjoy the improved online features that will be available in mid-2003.

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widely, with particularly high rates of use by internists and physicians in the Northeast and the South.
Michael A. Steinman, MD C. Seth Landefeld, MD San Francisco VA Medical Center San Francisco, Calif Ralph Gonzales, MD, MSPH University of California, San Francisco
1. Gonzales R, Steiner JF, Lum A, Barrett PH Jr. Decreasing antibiotic use in ambulatory practice: impact of a multidimensional intervention on the treatment of uncomplicated acute bronchitis in adults. JAMA. 1999;281:1512-1519. 2. Gonzales R, Malone DC, Maselli JH, Sande MA. Excessive antibiotic use for acute respiratory infections in the United States. Clin Infect Dis. 2001;33:757-762.

CORRECTIONS
Name Omitted: In the Original Contribution entitled Combination Therapy With Hormone Replacement and Alendronate for Prevention of Bone Loss in Elderly Women: A Randomized Controlled Trial published in the May 21, 2003, issue of THE JOURNAL (2003;289:2525-2533), Michael McClurg, MD, should be added to the list of members of the Data and Safety Monitoring Board on page 2532 after Peggy A. Norton, MD.

Error in Authors Name: In the Review article entitled Alcohol Consumption and Risk of Stroke: A Meta-analysis published in the February 5, 2003, issue of THE JOURNAL (2003;289:579-588) in the byline, the initial letter L. was incorrectly placed in front of the name of author Brian Lewis, MPH.

CME ANNOUNCEMENT
Online CME to Begin in Mid-2003 In mid-2003, online CME will be available for JAMA/Archives journals and will offer many enhancements: Article-specific questions Hypertext links from questions to the relevant content Online CME questionnaire Printable CME certificates and ability to access total CME credits

We apologize for the interruption in CME and hope that you will enjoy the improved online features that will be available in mid-2003.

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