REVIEW Alcohol Consumption and Risk of Stroke A Meta-analysis Kristi Reynolds, MPH Context Observational studies suggest that heavy alcohol consumption may in- L. Brian Lewis, MPH crease the risk of stroke while moderate consumption may decrease the risk. John David L. Nolen, MD, PhD, MSPH Objective To examine the association between alcohol consumption and relative risk of stroke. Gregory L. Kinney, MPH Data Sources Studies published in English-language journals were retrieved by search- Bhavani Sathya, MPH ing MEDLINE (1966–April 2002) using Medical Subject Headings alcohol drinking, Jiang He, MD, PhD ethanol, cerebrovascular accident, cerebrovascular disorders, and intracranial embo- lism and thrombosis and the key word stroke; Dissertation Abstracts Online using the S TROKE IS THE THIRD LEADING keywords stroke and alcohol; and bibliographies of retrieved articles. cause of death and a major cause Study Selection From 122 relevant retrieved reports, 35 observational studies (co- of disability in the United hort or case control) in which total stroke, ischemic stroke, or hemorrhagic (intracerebral States.1,2 In 1999, 167366 deaths or total) stroke was an end point; the relative risk or relative odds and their variance (or in the United States resulted from stroke.1 data to calculate them) of stroke associated with alcohol consumption were reported; Approximately 30% of stroke survivors alcohol consumption was quantified; and abstainers served as the reference group. are permanently disabled and 20% re- Data Extraction Information on study design, participant characteristics, level of alco- quire institutionalized care.1 Stroke is also hol consumption, stroke outcome, control for potential confounding factors, and risk esti- a huge financial burden for patients, their mates was abstracted independently by 3 investigators using a standardized protocol. families, and the health care system. The Data Synthesis A random-effects model and meta-regression analysis were used cost of stroke in the United States in 2002 to pool data from individual studies. Compared with abstainers, consumption of more is estimated to be $49.4 billion, which than 60 g of alcohol per day was associated with an increased relative risk of total includes direct health expenditures and 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 consump- lost productivity resulting from morbid- tion of less than 12 g/d was associated with a reduced relative risk of total stroke, ity and mortality.1 0.83 (95%, CI, 0.75-0.91) and ischemic stroke, 0.80 (95% CI, 0.67-0.96), and con- Alcoholic beverages are consumed sumption of 12 to 24 g/d was associated with a reduced relative risk of ischemic stroke, widely throughout the world, and an 0.72 (95%, CI, 0.57-0.91). The meta-regression analysis revealed a significant non- association between alcohol consump- linear relationship between alcohol consumption and total and ischemic stroke and a tion and stroke could have considerable linear relationship between alcohol consumption and hemorrhagic stroke. public health and clinical implications. Conclusions These results indicate that heavy alcohol consumption increases the Over the past 2 decades, many observa- relative risk of stroke while light or moderate alcohol consumption may be protective tional epidemiologic studies3-37 have against total and ischemic stroke. examined the role of alcohol as both a JAMA. 2003;289:579-588 www.jama.com risk factor and a potential protective fac- tor for stroke. Heavy alcohol consump- hol consumption is positively related to Headings alcohol drinking, ethanol, cere- tion has been linked to an increased risk risk of stroke.3,25 brovascular accident, cerebrovascular dis- of total stroke,23,32 ischemic stroke,29,33 and We performed a meta-analysis of epi- orders, and intracranial embolism and hemorrhagic stroke.3,7,33,35 However, stud- demiologic studies to examine the rela- thrombosis and the keyword stroke was ies investigating the association between tive risk of stroke at various levels of performed. The search was restricted to moderate alcohol consumption and alcohol consumption. stroke have reported conflicting results. Author Affiliations: Department of Epidemiology, Tu- Some studies have reported that mod- METHODS lane University School of Public Health and Tropical Study Selection Medicine, New Orleans, La. erate alcohol consumption is inversely Corresponding Author and Reprints: Kristi Rey- related to risk of total stroke,31 ischemic A literature search of the MEDLINE da- nolds, MPH, Department of Epidemiology, Tulane Uni- versity Health Sciences Center, School of Public Health stroke,27,31,37 and hemorrhagic stroke,27,31 tabase (from January 1966 through and Tropical Medicine, 1430 Tulane Ave SL18, New while others found that moderate alco- April 2002) using the Medical Subject Orleans, LA 70112 (e-mail: email@example.com). ©2003 American Medical Association. All rights reserved. (Reprinted) JAMA, February 5, 2003—Vol 289, No. 5 579 ALCOHOL CONSUMPTION AND RISK OF STROKE studies published in English-language stroke. Five studies that lacked suffi- ment units of alcohol consumption (eg, journals and conducted in human sub- cient data for calculation of relative risk grams, milliliters, ounces, or drinks jects. We also conducted a search of ab- estimates were excluded.56-60 The remain- consumed every day, week, or month). stracts listed in Dissertation Abstracts ing 6 excluded reports did not use ab- Therefore, we first converted these dif- Online using the keywords stroke and stainers as the reference group.61-66 We ferent units of alcohol consumption to alcohol, and we performed a manual included 19 cohort studies and 16 case- grams per day. Among the 35 studies search of references cited in published control studies in our final analysis. included in our meta-analysis, 20 re- original study and relevant review ar- ported alcohol consumption as grams. ticles. 38-48 The contents of 122 ab- Data Abstraction We used the following conversion fac- stracts or full-text manuscripts identi- All data were independently abstracted tors for the 4 studies that reported al- fied during the literature search were in triplicate by means of a standardized cohol data as milliliters or ounces: 1 mL, reviewed independently by 2 investi- data-collection form. Discrepancies were 0.785 g; 1 fl oz, 28.41 mL (United King- gators in duplicate to determine resolved by discussion and referencing dom); and 1 fl oz, 29.58 mL (United whether they met the criteria for inclu- the original publication. We did not con- States). Two of the 11 studies that re- sion. When there were discrepancies be- tact authors to request additional infor- ported alcohol data as drinks provided tween investigators for inclusion or ex- mation. Study characteristics recorded conversion factors in their articles. The clusion, other investigators conducted were as follows: title, article’s first au- other 9 used common conversion fac- additional evaluation of the study and thor’s name, year, and source of publi- tors.67 In the latter, a drink was de- discrepancies were resolved in confer- cation, country of origin, study design fined as 12 g in the United States, 10 g ence. To be included in our meta- (cohort study or case-control study), in Australia and Europe, and 21.2 g in analysis, a published study had to meet characteristics of the study population Japan, which is the standard drink vol- the following criteria: (1) observa- (sample size; sampling methods; and dis- ume in Japan.67 tional cohort or case-control study in tribution of age, sex, and race), mea- Alcohol consumption was reported which total stroke, ischemic stroke, or sures of outcome and exposure, dura- as categorical data with a range in all hemorrhagic (intracerebral or total) tion of follow-up (for prospective cohort studies. We assigned the mean of the stroke was an end point; (2) relative risk studies), confounding factors con- upper and lower bounds in each cat- or relative odds and their variance (or trolled for by matching or adjustment, egory as the average alcohol consump- data to calculate them) of stroke asso- and the relative risk (or relative odds) tion. An upper bound was not re- ciated with alcohol consumption were of stroke associated with alcohol con- ported in many studies for the category reported; (3) alcohol consumption was sumption and the corresponding con- of highest consumption, so we as- quantified; and (4) abstainers were used fidence interval (or SE). Relative risks sumed it to be the same amplitude as as the reference group. overall and in each subgroup, accord- the preceding category for calculation Fifty-three studies were identified and ing to sex, subtype of stroke, level of al- of average alcohol consumption in this abstracted. Four studies reported total cohol consumption, and type of alco- category. In our meta-analysis, alco- hemorrhagic stroke as the outcome, holic beverage, were abstracted. hol consumption was categorized into which includes intracerebral and sub- 5 groups: none (reference), less than 12, arachnoid hemorrhage.4,7,10,11 None of the Statistical Analysis 12 to 23, 24 to 60, and more than 60 studies reported information on subdu- Relative risk was used as a measure of g/d. We assigned the level of alcohol ral hemorrhagic strokes. We have used the relation between alcohol consump- consumption from each study to these the term hemorrhagic stroke through- tion and risk of stroke. For case- groups based on the calculated aver- out the article. Two reports consisted of control studies, relative odds were used age consumption of alcohol. In some the same case patients but different con- as a surrogate measure of the corre- studies, the average alcohol consump- trols and were treated as 2 separate stud- sponding relative risk. Because the ab- tion from more than 1 category fell into ies.23,24 From the 53 studies, 18 were fur- solute risk of stroke is low, the rela- the same group of alcohol consump- ther excluded for various reasons. Two tive odds approximate the relative risk. tion in our meta-analysis. When this oc- studies were excluded because com- Relative risks from individual studies curred, we pooled the relative risks bined risk estimates were reported for for each level of alcohol consumption within each category for each study and men and women but levels of alcohol and the corresponding SEs were trans- then we pooled across all studies. consumption were not the same for men formed to their natural logarithms to Both fixed-effects and DerSimonian as for women.49,50 We excluded 5 stud- stabilize the variances and to normal- and Laird random-effects models68 were ies that examined only the effect of binge ize the distributions. The SEs were used to calculate the pooled relative risk drinking or acute alcohol consumption derived from the confidence intervals across levels of alcohol consumption. Al- (within 24 hours before stroke)51-55 be- provided in each study. though both models yielded similar find- cause our study assessed habitual alco- The studies included in our meta- ings, results from the random-effects hol consumption and relative risk of analysis often differed in the measure- model are presented herein because 580 JAMA, February 5, 2003—Vol 289, No. 5 (Reprinted) ©2003 American Medical Association. All rights reserved. ALCOHOL CONSUMPTION AND RISK OF STROKE Table 1. Characteristics of 19 Cohort Studies of Alcohol Consumption and Risk of Stroke Study Exposure Duration of Follow-up Outcome No. of Source Participants Assessment Follow-up, y Process Assessment Stroke Cases Controlled Variables Donahue et al,3 7878 Men aged In-person 12 Clinical Hospital discharge 290 Age, BMI, cigarette smoking, 1986 45-69 y in interview examinations diagnosis, clinical hypertension, serum Hawaii at years 2 and diagnosis, death cholesterol, uric acid, 6 and certificate, or glucose level, hematocrit continued autopsy record surveillance Kono et al,4 5135 Men in Self-administered 19 Vital status Death certificate 230 Age, cigarette smoking 1986 Japan questionnaire ascertained by medical association Gordon and 1910 Men aged Self-administered 29 Vital statistics Proxy reports or 33 None Doyle,5 38-55 y in questionnaire records, death certificate 1987 New York newspapers, or reports from proxies Stampfer et al,6 87 526 US Self-administered 4 Biennial Medical records 120 Age, cigarette smoking, 1988 women questionnaire question- hypertension, DM, serum aged naires cholesterol level, obesity, 34-59 y exercise, cholesterol intake, saturated and polyunsaturated fat intake, parental history of MI before age 60 y, menopausal status, hormone use, study period Klatsky et al,7 107 137 US Self-administered 6 Surveillance of Clinical diagnosis 674 Age, sex, race, cigarette 1989 men and questionnaire hospital smoking, SBP, coffee women discharges consumption, BMI, aged 50 y baseline disease Shaper et al,8 7735 UK men In-person 8 Death register Clinical diagnosis or 110 Age, cigarette smoking, SBP 1991 aged interview death certificate 40-59 y Goldberg et al,9 6069 Men aged In-person 15 Clinical Hospital discharge 70 Age; cigarette smoking; SBP; 1994 51-75 y in interview examinations diagnosis, clinical serum cholesterol, serum Hawaii at years 2 and diagnosis, or triglyceride, and serum uric 6 and death certificate acid levels, coffee continued consumption, total caloric surveillance intake Hansagi et al,10 15 077 Men and Self-administered 20 Death register Death certificate 769 Age, cigarette smoking 1995 women questionnaire aged 40 y in Sweden Iso et al,11 1995 2890 Men aged In-person 10.5 Not specified Clinical diagnosis and 178 Age, cigarette smoking, 40-69 y in interview CT scan hypertension, serum total Japan cholesterol level, DM Kiyohara et al,12 1621 Men and In-person 26 Biennial Neurological 304 Age, sex, hypertension 1995 women interview examinations, examination, CT aged 40 y mail, or scan, in Japan telephone angiography, lumbar puncture, or autopsy Palmer et al,13 6369 Men and In-person 22 Questionnaire Death certificate 159 Age, sex, cigarette smoking, 1995 women interview every 1-2 y SBP aged (1971-1976) 18-90 y in Self-administered England questionnaire (after 1976) Yuan et al,14 18 244 Men In-person 9 Annual contact Death certificate 269 Age, cigarette smoking, 1997 aged interview educational level 45-64 y in China Maskarinec et 27 678 Men and In-person 20 Passive follow-up Death certificate 433 Age, BMI, cigarette smoking, al,15 1998 women interview ethnicity, educational level aged 30 y in Hawaii Hart et al,16 5766 Men aged In-person 21 NHS death Death certificate 133 Age, BMI, cigarette smoking, 1999 35-64 y in interview register DBP, serum cholesterol Scotland level, educational level, social class, father’s social class, car use, siblings, deprivation category, adjusted FEV, angina, ischemia on ECG, bronchitis (continued) ©2003 American Medical Association. All rights reserved. (Reprinted) JAMA, February 5, 2003—Vol 289, No. 5 581 ALCOHOL CONSUMPTION AND RISK OF STROKE Table 1. Characteristics of 19 Cohorts Studies of Alcohol Consumption and Risk of Stroke (cont) Study Exposure Duration of Follow-up Outcome No. of Source, y Participants Assessment Follow-up, y Process Assessment Stroke Cases Controlled Variables Leppälä et al,17 26 556 Men Self-administered 6.1 National hospital Clinical diagnosis or 960 Age, BMI, cigarette smoking, 1999 aged questionnaire discharge death certificate serum cholesterol level, 50-69 y in register and DM, educational level, Finland national death leisure time physical register activity, heart disease, supplementation with -tocopherol or beta carotene Romelsjö et al,18 49 618 Men Self-administered 25 Inpatient care Clinical diagnosis or 223 BMI, cigarette smoking, BP, 1999 aged questionnaire register and death certificate father’s social class, 17-45 y in death register running away from home, Sweden poor school well-being, parental divorce, poor emotional control, few friends, unemployment 3 mo during life, poor health Gaziano et al,19 89 299 US men Self-administered 5.5 National Death Death certificates 150 Age, BMI, cigarette smoking, 2000 aged questionnaire Index search DM, exercise 40-84 y Jousilahti et al,20 14 874 Men Self-administered 12 National hospital Clinical diagnosis or 470 Age, BMI, cigarette smoking, 2000 and women questionnaire discharge death certificates serum total cholesterol, aged register or SBP, DBP, and study year 25-64 y in central Finland statistical office of Finland Djousse et al,21 ´ 5209 In-person 30 Biennial Clinical diagnosis and 441 Age, BMI, cigarette smoking, 2002 Framing- interview examinations radiographic DM ham, Mass, images men and women 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 age due to the lack of such detailed in- ported total stroke as the outcome. In among studies.68 A weighted meta- formation in most studies. addition, 7 studies reported ischemic regression analysis with no intercept term To assess the potential for publica- stroke, and 7 studies reported hemor- was performed to examine the associa- tion bias, we constructed a funnel plot rhagic stroke as the outcome. The fol- tion between alcohol consumption and in which the log relative risks were plot- low-up period ranged from 4 to 30 the natural logarithm of the relative risk ted against their SEs.70 In addition, a years. The study population in 7 co- of stroke. We used the “pool-first” rank correlation for the association be- hort studies consisted of men and method proposed by Greenland and tween standardized log relative risks women, 1 consisted entirely of women, Longnecker.69 This method was chosen and their SEs was conducted using the and 11 consisted of only men. because several studies reported find- Kendall correlation coefficient. The Twelve of the 16 case-control stud- ing a nonlinear, J- or U-shaped relation- correlation between sample size and ies were conducted outside the United ship between alcohol consumption and relative risk would be high if small stud- States (TABLE 2). The number of case relative risk of stroke. This method is ad- ies with null results were less likely to subjects enrolled in these studies vantageous because it can easily be ex- be published. A significant correlation ranged from 89 in the study by Hen- tended to test nonlinearity and identify between sample size and relative risk rich and Horwitz26 to 677 in the study J- or U-shaped curves, or other relation- would not exist in the absence of this by Sacco et al,34 and the corresponding ships between exposure levels and rela- type of publication bias.70 number of control subjects ranged tive risks. For each included study, we from 153 in the study by Palomäki et performed an initial fit of a quadratic RESULTS al29 to 1139 in the study by Sacco et curve. When a nonsignificant term was The characteristics of the study sub- al.34 Total stroke was the study out- found in the initial model, a subse- jects and design of the cohort studies come in 9 studies, whereas 8 studies quent fit of a simpler model (linear or are presented in TABLE 1. Of the 19 co- collected data on ischemic stroke and solitary square term) was conducted. hort studies, 8 were conducted in the 5 collected data on hemorrhagic Prestated subgroup analyses were United States. The number of subjects stroke. Fourteen of the 16 case-control conducted by subtype of stroke and sex in the cohort studies ranged from 1621 studies were composed of both men for the different levels of alcohol con- in the study by Kiyohara et al 12 to and women, 1 case-control study con- sumption. Subgroup analyses were not 107 137 in the study by Klatsky et al.7 sisted of only women, and 1 case- performed by type of alcoholic bever- Among the 19 cohort studies, 15 re- control study consisted of only men. 582 JAMA, February 5, 2003—Vol 289, No. 5 (Reprinted) ©2003 American Medical Association. All rights reserved. ALCOHOL CONSUMPTION AND RISK OF STROKE Table 2. Characteristics of 16 Case-Control Studies of Alcohol Consumption and Risk of Stroke Exposure Source, y Stroke Cases Controls Case Assessment Assessment Controlled Variables Herman et al,22 132 Male and female 239 Patients from the Clinical examination In-person interview Age, sex 1983 patients with same hospital incident stroke event in 2 hospitals in the Netherlands Gill et al,23 1986 230 Male and female 230 Hospital patients Clinical examination, In-person interview Age, sex, race, cigarette patients with CT scan, smoking, treatment of stroke diagnosis in angiography, and hypertension, medication the district hospital postmortem in England examinations, or lumbar puncture Gill et at,24 1988 230 Male and female 577 Male and female Clinical examination, In-person interview Age, race, cigarette smoking, patients with industrial workers in CT scan, treatment of hypertension, stroke diagnosis in the same angiography, and social class, drug therapy the district hospital community postmortem in England examinations, or lumbar puncture Gorelick et al,25 205 Male and female 410 Outpatient clinic Clinical diagnosis and In-person interview Age, sex, race, cigarette 1989 patients with patients CT scan smoking, hypertension, incident ischemic method of hospital stroke in 3 medical payment centers in Chicago Henrich and 89 Male and female 178 Patients Clinical examination Telephone interview None Horwitz,26 hospitalized discharged from the and CT scan 1989 patients with same hospital ischemic stroke in Connecticut Gill et al,27 1991 621 Male and female 573 Male and female Clinical examination, In-person interview Age, sex, race, cigarette hospitalized industrial workers in CT scan, smoking, hypertension, patients with the same angiography and social class, medication stroke diagnosis in community postmortem 2 centers in examination, or England lumbar puncture Ben-Shlomo 115 Male and female 165 Generally matched, Clinical examination, Cases, in-person General and selective controls: et al,28 1992 hospitalized 115 selectively CT scan, or taped interview age, sex, cigarette patients with matched, and 752 lumbar puncture Controls, smoking, hypertension, incident stroke in 3 community controls self-administered DM, heart disease hospitals in the questionnaire Community controls: age, United Kingdom sex, cigarette smoking, hypertension, and social class Palomäki et al,29 156 Male hospitalized 153 Hospital patients Clinical diagnosis In-person interview Age, BMI, cigarette smoking, 1993 patients with hypertension, DM, ischemic stroke in coronary heart disease, Finland history of snoring Shinton et al,30 125 Male and female 198 Community Clinical examination, Alcohol diary Age, sex, history of 1993 patients with controls CT scan, or cardiovascular disease incident stroke in autopsy 11 general practice partnerships in England Jamrozik et al,31 501 Male and female 931 Community Clinical examination, In-person interview Age, sex, cigarette smoking, 1994 patients with controls from the CT scan, MRI, or hypertension, DM, stroke diagnosis in electoral roles autopsy previous stroke or TIA, Australia 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 Beghi et al,32 200 Male and female 170 Patients in the Clinical examination, In-person interview Age, sex 1995 hospitalized same hospital and CT scan, or patients with 202 community neurological stroke in Italy controls consultation Caicoya et al,33 467 Male and female 477 Residents of the Clinical examination or In-person interview Age, sex, cigarette smoking, 1999 patients with same community CT scan hypertension, DM, incident stroke in hypercholesterolemia, Spain cardiac disease (continued) ©2003 American Medical Association. All rights reserved. (Reprinted) JAMA, February 5, 2003—Vol 289, No. 5 583 ALCOHOL CONSUMPTION AND RISK OF STROKE Table 2. Characteristics of 16 Case-Control Studies of Alcohol Consumption and Risk of Stroke (cont) Exposure Source Stroke Cases Controls Case Assessment Assessment Controlled Variables Sacco et al,34 677 Men and women with 1139 Community Brain imaging and In-person interview Age, sex, race, BMI, cigarette 1999 incident cerebral controls clinical diagnosis smoking, hypertension, infarction in the DM, cardiac disease, community in educational level New York Thrift et al,35 331 Male and female 331 Residents from the CT scan, MRI, or In-person interview Age, sex, BMI, cigarette 1999 patients with primary same neighborhood autopsy smoking, DM, serum hemorrhagic stroke cholesterol level, SES, from 13 hospitals in educational level, exercise, Melbourne, Australia cardiovascular disease, hormone replacement therapy Zodpey et al,36 166 Male and female 166 Patients from the CT scan In-person interview Age, sex 2000 hospitalized patients same hospital with incident hemorrhagic stroke in India Malarcher et al,37 224 Female patients with 392 Female community Hospital discharge In-person interview Age, race, BMI, cigarette 2001 incident cerebral residents diagnosis, clinical smoking, hypertension, infarction in 59 diagnosis, DM, total cholesterol, HDL hospitals in neuroimaging cholesterol level, Baltimore-Washington results, or autopsy geographic region of region in the United reports residence, educational States 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 random- 60 g/d, or more then 5 drinks per day, important confounders, or studies that effects model and the meta-regression had the highest relative risk. did not exclude prevalent stroke cases analysis test for trend are presented in The association between alcohol con- at baseline. TABLE 3. The overall results indicate a sumption and relative risk of total There was no evidence of publica- nonlinear association between alco- stroke was similar in men and women tion bias in our study as indicated by a hol consumption and relative risk of (Table 3 and FIGURE 2) although the funnel plot (FIGURE 3) and the Ken- total stroke (P = .002 for nonlinear relative risk was somewhat lower in dall correlation coefficient. The Ken- trend). Compared with the reference women consuming less than 12 g/d, or dall correlation coefficient for the SE group of abstainers, alcohol consump- less than 1 drink per day, than in men. and the standardized log relative risk tion of less than 12 g/d, or less than 1 Likewise, the association was similar in was −0.072 (P = .17) for all studies. drink per day based on US conver- case-control studies and cohort stud- When the outliers were excluded, the sions, was significantly associated with ies, with alcohol consumption of less Kendal correlation coefficient for the a decreased relative risk of total stroke, than 12 g/d, or less than 1 drink per day, SE and the standardized log relative risk while alcohol consumption of more among cohort studies and alcohol con- became −0.053 (P=.32). than 60 g/d, or more than 5 drinks per sumption of less than 24 g/d, or less day, was significantly associated with than 2 drinks per day, among case- COMMENT an increased relative risk of total stroke. control studies associated with a sig- Several large epidemiologic studies that The association between alcohol con- nificant reduced relative risk while al- have examined the effect of alcohol con- sumption and relative risk of ischemic cohol consumption of more than 60 g/d, sumption on the risk of stroke have pro- stroke was J-shaped with the lowest risk or more than 5 drinks per day, was as- vided inconsistent findings. In our cur- among those consuming less than 12 sociated with an increased relative risk. rent meta-analysis, we found a J-shaped g/d, or less than 1 drink per day, or 12 The findings from the sensitivity association between alcohol consump- to 24 g/d, or 1 to 2 drinks per day, and analyses that excluded studies based on tion and the relative risk of total and the highest risk among those consum- different inclusion criteria are pre- ischemic stroke and a linear associa- ing more than 60 g/d, or more than 5 sented in T ABLE 4. Risk estimates tion between alcohol consumption and drinks per day, (FIGURE 1). Relative risk changed very little after the exclusion the relative risk of hemorrhagic stroke. of hemorrhagic stroke increased lin- of outliers, studies without computed Moderate alcohol consumption was as- early with increasing alcohol consump- tomographic scans or other imaging sociated with a reduced relative risk of tion, and those consuming more than measures, studies that did not adjust for total and ischemic stroke while heavy 584 JAMA, February 5, 2003—Vol 289, No. 5 (Reprinted) ©2003 American Medical Association. All rights reserved. ALCOHOL CONSUMPTION AND RISK OF STROKE alcohol consumption was associated The relationship between alcohol con- alcohol-induced hypertension, cardio- with an increased relative risk of total, sumption and stroke is believed to in- myopathy, coagulation disorders, atrial ischemic, and hemorrhagic stroke. volve various mechanisms including 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 Test for Linear Test for Nonlinear Studies 12 12-24 24-60 60 Association* Association Overall 35 0.83 (0.75-0.91) 0.91 (0.78-1.06) 1.10 (0.97-1.24) 1.64 (1.39-1.93) .002 Type of stroke Ischemic 15 0.80 (0.67-0.96) 0.72 (0.57-0.91) 0.96 (0.79-1.18) 1.69 (1.34-2.15) .004 Hemorrhagic 12 0.79 (0.60-1.05) 0.98 (0.77-1.25) 1.19 (0.80-1.79) 2.18 (1.48-3.20) .004 .17 Sex Men 27 0.89 (0.79-1.01) 0.94 (0.84-1.05) 1.08 (0.96-1.21) 1.76 (1.57-1.98) .001 Women 16 0.66 (0.61-0.71) 0.79 (0.56-1.11) 0.80 (0.49-1.30) 4.29 (1.30-14.14) .001 Study design Cohort 19 0.82 (0.73-0.92) 0.94 (0.84-1.05) 1.06 (0.90-1.23) 1.63 (1.49-1.79) .02 Case control 16 0.80 (0.67-0.97) 0.65 (0.44-0.96) 1.12 (0.92-1.37) 1.98 (1.35-2.92) .03 *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 Ischemic Stroke Hemorrhagic Stroke 3 2 Natural Logarithm Relative Risk 1 0 –1 –2 –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 Men Women 3 2 Natural Logarithm Relative Risk 1 0 –1 –2 –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. ©2003 American Medical Association. All rights reserved. (Reprinted) JAMA, February 5, 2003—Vol 289, No. 5 585 ALCOHOL CONSUMPTION AND RISK OF STROKE 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 12 12-24 24-60 60 All studies 0.83 (0.75-0.91) 0.91 (0.78-1.06) 1.10 (0.97-1.24) 1.64 (1.39-1.93) All studies except outliers* 0.83 (0.75-0.91) 0.91 (0.78-1.06) 1.11 (0.98-1.26) 1.62 (1.46-1.81) Studies that used computed tomography scans or 0.84 (0.75-0.94) 0.86 (0.71-1.05) 1.14 (1.01-1.35) 1.74 (1.37-2.21) other imaging measures as an outcome measure† Studies that controlled for important stroke risk factors‡ 0.81 (0.71-0.92) 0.80 (0.64-1.00) 1.12 (0.94-1.33) 1.62 (1.19-2.21) Cohort studies that used incident stroke events§ 0.83 (0.73-0.95) 0.91 (0.77-1.07) 1.02 (0.83-1.26) 1.58 (1.43-1.73) *The 24 to 60 and 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 cluded in our analysis. Our study may among studies. For instance, some stud- Figure 3. Funnel Plot of Log Relative Risk vs Variance of Log Relative Risks Among All inherit the problems of potential bias ies used the lowest consumption level Studies and confounding effects associated with as the reference group while others used observational studies. However, a ran- abstainers. In an effort to avoid com- 100 domized controlled trial of alcohol con- bining studies that were not compa- 80 sumption and stroke has not been per- rable, we chose to include only those formed and is unlikely to be conducted studies that used abstainers as the ref- Variance 60 in the future. Consequently, we must erence group. It has been suggested that 40 rely on data from observational stud- the U- or J-shaped association be- 20 ies to draw conclusions and make rec- tween alcohol consumption and mor- 0 ommendations. tality from cardiovascular disease may –2.5 –1.5 –0.5 0.5 1.5 2.5 Second, computed tomographic be due to the inclusion of ex-drinkers Natural Logarithm Relative Risk scans and other imaging techniques in the reference group of abstainers. Ex- were not available for some early stud- drinkers may have stopped alcohol con- Most studies provided more than 1 relative risk esti- mate for multiple levels of alcohol consumption. ies. Furthermore, several studies only sumption due to health problems and used death certificates or death regis- they are at increased risk for death from ter data for diagnosis of stroke out- cardiovascular disease. 47,75,76 How- blood flow.37,46,71,72 A plausible explana- come. However, our findings were un- ever, several studies have examined this tion of a reduced risk of ischemic stroke likely due to misclassification of potential bias and concluded that the with moderate alcohol consumption is outcome because the relative risks of J- or U-shaped relationship between al- that alcohol increases high-density li- stroke associated with alcohol con- cohol consumption and risk of cardio- poprotein cholesterol levels and de- sumption did not change after exclu- vascular disease mortality held creases platelet aggregation and fibri- sion of studies that did not use com- true.6,13,27,77 Moreover, we conducted a nolytic activity.6,71,72 Epidemiologic puted tomography or other imaging sensitivity analysis in which only pro- studies also have consistently observed techniques for diagnosis. Our find- spective cohort studies that excluded a protective effect of moderate alcohol ings were also unlikely due to con- prevalent stroke cases at baseline were consumption on coronary heart dis- founding effects because the relative included, and we found that the shape ease.73,74 Alcohol-induced hyperten- risks of stroke associated with alcohol of association remained unchanged. sion and coagulation disorders are prob- consumption were similar among all Second, the health effects of binge able underlying mechanisms for studies and only those studies that con- drinking may be different than those for hemorrhagic stroke.27,45,71 The antico- trolled for important risk factors for regular drinkers. The failure to differ- agulant effects of alcohol, although they stroke, such as cigarette smoking and entiate between these 2 groups could appear to be beneficial for decreasing the hypertension. Additionally, our re- possibly obscure the observation of any risk of ischemic stroke, may play an im- sults were unlikely to result from pub- true association. Therefore, we only in- portant role in increasing the risk of lication bias as demonstrated by the fun- cluded studies that examined the effect hemorrhagic stroke.71,74 nel plot and rank correlation analysis. of usual alcohol consumption rather There are several potential limita- Several methodological issues re- than acute alcohol consumption. Third, tions in our study. First, our study is a garding epidemiologic research on the the measurement units, especially the meta-analysis of observational stud- health impact of alcohol consumption definition of an alcohol drink, varies ies. The quality of our study depends are worth considering. First, the selec- among studies. We attempted to over- on data from original publications in- tion of the reference group may vary come this problem by applying a com- 586 JAMA, February 5, 2003—Vol 289, No. 5 (Reprinted) ©2003 American Medical Association. All rights reserved. ALCOHOL CONSUMPTION AND RISK OF STROKE monly used and validated method sug- moderate alcohol consumption re- tension Care Computing Project. J Hypertens. 1995; 13:957-964. gested by Turner.67 Finally, assessment duces risk of ischemic stroke. How- 14. Yuan JM, Ross RK, Gao YT, Henderson BE, Yu MC. methods for alcohol consumption may ever, the implications of these find- Follow up study of moderate alcohol intake and mor- tality among middle aged men in Shanghai, China also vary among studies. The assess- ings should be examined cautiously. [comments]. BMJ. 1997;314:18-23. ment of alcohol consumption is usu- Any advice regarding the consump- 15. Maskarinec G, Meng L, Kolonel L. Alcohol in- ally based on self-reported alcohol hab- tion of alcohol should be tailored to the take, body weight, and mortality in a multiethnic pro- spective cohort. Epidemiology. 1998;9:654-661. its. Such data are subject to errors of individual patient’s risks and poten- 16. Hart CL, Smith GD, Hole DJ, Hawthorne VM. Al- recall. For example, heavy drinkers may tial benefits. cohol consumption and mortality from all causes, coro- nary heart disease, and stroke: results from a prospec- be more likely to underreport their al- tive cohort study of Scottish men with 21 years of Author Contributions: Study concept and design: cohol consumption. The majority of Reynolds, Lewis, Nolen, Kinney, Sathya, He. follow up [comments]. BMJ. 1999;318:1725-1729. ¨ ¨ 17. Leppala JM, Paunio M, Virtamo J, et al. Alcohol studies in this meta-analysis used in- Acquisition of data: Reynolds, Lewis, Nolen, Kinney, consumption and stroke incidence in male smokers. Sathya. person interviews, while 11 studies used Analysis and interpretation of data: Reynolds, Lewis, Circulation. 1999;100:1209-1214. self-administered questionnaires, 1 Nolen, Kinney, Sathya, He. ¨ 18. Romelsjo A, Leifman A. Association between al- Drafting of the manuscript: Reynolds, Nolen, Kinney, cohol consumption and mortality, myocardial infarc- study conducted telephone inter- Sathya. tion, and stroke in 25 year follow up of 49618 young views, and 1 study used alcohol con- Critical revision of the manuscript for important in- Swedish men. BMJ. 1999;319:821-822. tellectual content: Reynolds, Lewis, Nolen, Kinney, 19. Gaziano JM, Gaziano TA, Glynn RJ, et al. Light- sumption diaries. to-moderate alcohol consumption and mortality in the Sathya, He. There are several advantages of our Statistical expertise: Reynolds, Nolen, Kinney, He. Physicians’ Health Study enrollment cohort. J Am Coll study. The discrepancies among stud- Obtained funding: He. Cardiol. 2000;35:96-105. 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Monforte R, Estruch R, Graus F, Nicolas JM, Ur- Glynn RJ, Manson JE, Stampfer MJ. Prospective 78. National Institute on Alcohol Abuse and Alcohol- bano-Marquez A. High ethanol consumption as risk study of moderate alcohol consumption and mortal- ism. 10th Special Report to the US Congress on Al- factor for intracerebral hemorrhage in young and ity in US male physicians. Arch Intern Med. 1997;157: cohol and Health. Rockville, Md: US Dept of Health middle-aged people. Stroke. 1990;21:1529-1532. 79-85. and Human Services; 2000. 588 JAMA, February 5, 2003—Vol 289, No. 5 (Reprinted) ©2003 American Medical Association. All rights reserved. LETTERS widely, with particularly high rates of use by internists and physicians in the Northeast and the South. CORRECTIONS Michael A. Steinman, MD Name Omitted: In the Original Contribution entitled “Combination Therapy With C. Seth Landefeld, MD Hormone Replacement and Alendronate for Prevention of Bone Loss in Elderly San Francisco VA Medical Center Women: A Randomized Controlled Trial” published in the May 21, 2003, issue of San Francisco, Calif 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 Ralph Gonzales, MD, MSPH Peggy A. Norton, MD. University of California, San Francisco 1. Gonzales R, Steiner JF, Lum A, Barrett PH Jr. Decreasing antibiotic use in am- bulatory practice: impact of a multidimensional intervention on the treatment of Error in Author’s Name: In the Review article entitled “Alcohol Consumption and uncomplicated acute bronchitis in adults. JAMA. 1999;281:1512-1519. Risk of Stroke: A Meta-analysis” published in the February 5, 2003, issue of THE 2. Gonzales R, Malone DC, Maselli JH, Sande MA. Excessive antibiotic use for acute JOURNAL (2003;289:579-588) in the byline, the initial letter “L.” was incorrectly respiratory infections in the United States. Clin Infect Dis. 2001;33:757-762. 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. 2798 JAMA, June 4, 2003—Vol 289, No. 21 (Reprinted) ©2003 American Medical Association. All rights reserved.
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