(Circulation. 1999;100:1209-1214.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Alcohol Consumption and Stroke Incidence in Male Smokers
From the Department of Public Health, University of Helsinki (J.M.L., M.P., O.P.H.); National Public Health Institute (J.V.); and Department of Clinical Neurosciences, Helsinki University Central Hospital (R.F.), Helsinki, Finland, and National Cancer Institute, Bethesda, Md (D.A., P.R.T.).
Correspondence to Jaana M. Leppälä, Department of Public Health, University of Helsinki, PO Box 41 (Mannerheimintie 172), 00014 Helsinki, Finland. E-mail jaana.leppala{at}helsinki.fi
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Abstract |
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Background—Studies on alcohol consumption and incidences of stroke subtypes have suggested distinct dose-response relationships. Blood pressure and HDL cholesterol mediate the effect of alcohol on coronary heart disease, but similar evidence on cerebrovascular diseases is not available.
Methods and Results—We studied the risk of stroke in 26 556 male
cigarette smokers 50 to 69 years of age without history of stroke. The
men were categorized as nondrinkers, light (
24 g/d), moderate (25 to
60 g/d), or heavy (>60 g/d) drinkers. A total of 960 men suffered from
incident stroke: 83 with subarachnoid and 95 with
intracerebral hemorrhage, 733 with cerebral
infarction, and 49 with unspecified stroke. The adjusted relative risk
of subarachnoid hemorrhage was 1.0 in light drinkers,
1.3 in moderate drinkers, and 1.6 in heavy drinkers compared with
nondrinkers. The respective relative risks of
intracerebral hemorrhage were 0.8, 0.6, and
1.8; of cerebral infarction, 0.9, 1.2, and 1.5. Systolic blood
pressure attenuated the effect of alcohol consumption in all subtypes
of stroke, whereas HDL cholesterol strengthened the effect
of alcohol in subarachnoid hemorrhage and cerebral
infarction but attenuated the effect in intracerebral
hemorrhage.
Conclusions—Alcohol consumption may have a distinct dose-response relationship within each stroke subtype—linear in subarachnoid hemorrhage, U-shaped in intracerebral hemorrhage, and J-shaped in cerebral infarction—but further studies are warranted. Systolic blood pressure and HDL cholesterol seem to mediate the effect of alcohol on stroke incidence, but evidently additional mechanisms are involved.
Key Words: alcohol • blood pressure • HDL cholesterol • stroke
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Introduction |
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The epidemiological evidence on the relation between alcohol consumption and risk of stroke has not been consistent.1 At least part of the inconsistency is due to differences in the assessment of the amount and pattern of alcohol consumption and selection of the reference group. The cutoff points for alcohol consumption categories have varied considerably. Sometimes ex-drinkers have been separated from lifelong abstainers; sometimes they have been pooled with the group of current nondrinkers. In addition, subtyping of stroke has varied; most often it has been entirely neglected.
Heavy drinking (>60 g/d) is related to increased risk of both
hemorrhagic2 3 4 5 6 7 and ischemic
stroke.2 4 8 9 10 It is somewhat unclear whether light
(24 g/d for men) and moderate (25 to 60 g/d for men) drinking
decreases the risk of stroke compared with nondrinking: The risk of
hemorrhagic strokes has increased, remained unchanged, or decreased,
and the risk of ischemic stroke has either diminished or
remained unchanged.1 In summary, the risk of hemorrhagic
stroke seems to increase steeply with increasing alcohol consumption,
but the risk of ischemic stroke seems to be J-shaped with
nondrinkers, and heavy drinkers have a higher risk than light
drinkers.11
Alcohol causes many changes in physiological functions that may modify the risk of stroke. Alcohol increases blood pressure12 and serum HDL cholesterol (HDL-C) level.13 14 15 16 Moderate alcohol consumption increases17 but ethanol intoxication decreases18 fibrinolytic activity. Immediate heavy alcohol intake decreases platelet aggregation,19 but in binge drinkers and alcoholics, platelet aggregation is increased after alcohol withdrawal.19 20 Cerebral blood flow is increased immediately after alcohol intake,21 and alcohol dilates cutaneous capillaries but constricts arteries when given intra-arterially.22 On the other hand, alcohol may cause spasm of cerebral arteries,23 and it increased peripheral but decreased coronary vascular resistance in animal studies.24
The association between alcohol consumption and risk of stroke has been suggested to be mediated, at least partly, by changes in blood pressure and serum HDL-C.11 High blood pressure is a strong risk factor for all types of stroke,25 26 but the relation between HDL-C and stroke is less well known. HDL-C has been inversely related to intracerebral hemorrhage (ICH),27 ischemic stroke,27 28 29 and cerebrovascular atherosclerosis.30
We examined the association of different levels of alcohol consumption with the incidence of stroke and the roles of systolic blood pressure (SBP) and HDL-C as possible mediators of the effect. The study comprised male cigarette smokers who participated in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study.31 32
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Methods |
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Setting
The ATBC Study was a randomized, double-blind, placebo-controlled, 2x2-factorial-design, primary prevention trial testing the hypothesis that
-tocopherol and ß-carotene
supplements reduce the incidence of lung and other cancers. During 1985
through 1988, a total of 29 133 male cigarette smokers (
5 cigarettes
per day) 50 to 69 years of age from southwestern Finland were
randomized to 1 of 4 treatment regimens: -tocopherol 50
mg/d, ß-carotene 20 mg/d, -tocopherol plus
ß-carotene, or placebo. Among the exclusion criteria were severe
angina on exertion, anticoagulant therapy, chronic renal insufficiency,
cirrhosis of the liver, and chronic alcoholism. Of the 29 133 men,
26 556 (91%) were included in the present study, and 2557 (9%)
were excluded; 614 men reported a previous stroke, and others provided
no information on alcohol consumption. An additional 38 men were
excluded from the pathway analysis because of a missing SBP or
HDL-C value. Follow-up lasted for a median of 6.1 years with 153 356
person-years. There were no losses to follow-up.
End Points
The primary end point was incident stroke. Strokes were
identified by record linkage to the National Hospital Discharge
Register and the National Register of Causes of Death, which both use
the International Classification of Diseases (ICD).33 34
The included diagnoses were ICD-8 codes 430 through 434 and 436 and
ICD-9 codes 430, 431, 433, 434, and 436. The ICD-8 codes 431.01 and
431.91 denoting subdural hemorrhage and ICD-9 codes 4330X,
4331X, 4339X, and 4349X denoting cerebral or precerebral artery
stenosis or occlusion without cerebral infarction (CI) were
excluded. On the basis of the validation study that used specified
diagnostic criteria,35 discharge diagnoses of
subarachnoid hemorrhage (SAH), ICH, and CI were
reliable in 79%, 82%, and 90%, respectively.
Baseline Characteristics
At baseline, the participants completed questionnaires on
general background characteristics and medical and smoking histories,
including a question about physician-diagnosed stroke, hypertension,
diabetes, and heart disease (coronary heart disease, myocardial
infarction, valvular disease, arrhythmia, cardiac
enlargement, or congestive heart failure). At the first visit, a
trained study nurse reviewed the questionnaire with the participant and
measured blood pressure, height, and weight. The men were given a
detailed dietary history questionnaire36 to be completed
at home that included questions about amounts of beer, long drinks,
wine, and strong alcoholic drinks consumed daily/weekly/monthly during
the previous 12 months. Mean daily alcohol intake (in grams of pure
ethanol) was calculated on basis of the dietary history
questionnaire.
A blood sample was drawn at the baseline visit after 12 hours of
fasting, and serum was stored at -70°C. Serum total
cholesterol and HDL-C were determined enzymatically
(CHOD-PAP method, Boehringer Mannheim). HDL-C was measured
after precipitation of VLDL and LDL with dextran sulfate and magnesium
chloride.
Statistical Analyses
The men were classified as nondrinkers, light (24.0 g/d),
moderate (24.1 to 60.0 g/d), or heavy (>60.0 g/d) drinkers. For
specific dose-response analyses, alcohol consumption was
categorized by standard drinks (1 standard drink is equivalent to
12 g pure ethanol) consumed daily (1/2, 1, 2, 3, 4, 5, >5
drinks per day). For effect-modification analyses, moderate and
heavy drinkers were combined into 1 group, and men were divided into
nonhypertensive and hypertensive (SBP <160 or 160 mm Hg) and
into 2 groups by median value of HDL-C (<1.15 or 1.15 mmol/L).
Body mass index was calculated. Leisure-time physical activity was
categorized as sedentary or active (strenuous exercise at least once a
week). Education level was categorized as primary school (<7 years),
secondary school (7 to 12 years), and university or other higher
education (>12 years). The trial supplementation was coded as
recipient or nonrecipient of -tocopherol and as
recipient or nonrecipient of ß-carotene.
The calculation of person-years of the follow-up ended at stroke, death, or April 30, 1993, the end of the trial. The crude incidence rates were calculated per 10 000 person-years. Unspecified stroke was not included in subtype analyses. Relative risks, holding nondrinkers or the lowest alcohol consumption level (half a drink per day or less) as the reference category, were adjusted for age, body mass index, serum total cholesterol, number of cigarettes smoked daily, education, leisure-time physical activity, diabetes, heart disease, and trial supplementation by use of the Cox proportional-hazards method. Baseline SBP and HDL-C were excluded from the models because of their suspected roles as mediators for the effects of alcohol. The multivariate-adjusted Cox models having alcohol as either a continuous variable or a set of categorical dummy variables were evaluated by comparing the log-likelihood test results. To test log-linear trend, alcohol was set in the multivariate-adjusted Cox models as a single categorical variable with even-spaced values for each alcohol consumption level. The effect modification by SBP and HDL-C was evaluated by both stratified multivariate-adjusted Cox models and comparison of multivariate-adjusted Cox models with and without an interaction term formed by alcohol and SBP or by alcohol and HDL-C. In pathway analysis, SBP and HDL-C were added to the regression model each at time after adjustment for potential confounding factors mentioned above.
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Results |
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The baseline characteristics by alcohol consumption are given in Table 1
. Most men (61%) were
light drinkers, 11% did not drink alcohol, and only 5% were heavy
drinkers. Of the 23 625 men who reported any alcohol consumption, 25%
consumed at most 5 g/d; the median consumption was 13 g/d, and the
overall range was 0.04 to 278 g/d. Alcohol consumption correlated
inversely with age and previous heart disease and directly with SBP,
diastolic blood pressure, previous hypertension, HDL-C,
number of cigarettes smoked per day, and higher education.
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A total of 960 incident strokes occurred during the follow-up: 83 SAHs,
95 ICHs, 733 CIs, and 49 unspecified strokes (Table 2). The adjusted relative risk of SAH
increased linearly with increasing alcohol consumption, whereas the
association between alcohol consumption and the risk of ICH was
U-shaped, with the lowest risk among light to moderate drinkers and
heavy consumers showing the highest risk. The association between
alcohol consumption and the risk of CI was J-shaped, with the lowest
risk among light drinkers. The log-linear trend test was significant in
CI (P=0.002), yet the only statistically significant
difference in the adjusted relative risks of stroke subtypes was in CI
between nondrinkers and heavy drinkers. Repeating the analyses
in quartiles of alcohol use had no material effect on the results,
except the risk of ICH became less steep.
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Dose-response relationships between alcohol consumption and stroke risk
were also examined in drinkers, with men with an alcohol intake of at
most half a drink per day as the reference category (Table 3). The relationship was almost linear in
SAH and CI, but there was no consistent relationship in ICH.
The log-linear trend test was significant in CI
(P<0.001).
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In effect-modification analyses, there were no significant or
consistent findings that the risk of stroke caused by alcohol
consumption would be different for men with SBPs 160 mm Hg
compared with men with lower SBPs or for men with HDL-C 1.15
mmol/L compared with men with lower HDL-C levels.
In pathway analyses, inclusion of SBP in the regression model
diminished the effect of alcohol in all stroke subtypes: in SAH by 7%
to 37%, in ICH by 5% to 35%, and in CI by 3% to 19% (the
Figure). When HDL-C was added, the effect
of alcohol was strengthened in SAH by 6% to 31% and in CI by 3% to
16% but attenuated in ICH by 5% to 31%. When both SBP and HDL-C were
included in the model, the net effect of alcohol was practically the
same as the effect in the model without them in SAH and CI. The effect
of alcohol in ICH was instead diminished by 9% to 55%.
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Discussion |
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The analyses in the present study were based on the hypothesis that each stroke subtype has a distinct dose-response relationship with alcohol consumption, as suggested by Camargo in his review.1 Furthermore, this study elucidates the mediator role of blood pressure and HDL-C in the effects of alcohol on stroke incidence, as described in coronary heart disease.13 14
Alcohol consumption was self-reported at study baseline. Because we had no information on past drinking habits, we assumed that the reference group, the nondrinkers, probably included both lifelong abstainers and ex-drinkers. Neither did we have information on the pattern of consumption, eg, binge drinking versus regular drinking, or on the possible changes on alcohol habits during the follow-up. However, in a random sample of about 3700 men who recompleted the dietary questionnaire at some point during the follow-up, alcohol consumption remained unchanged.
The reliability of stroke diagnosis varied from 79% to 90%, depending on stroke subtype, in the ATBC Study.35 Bias caused by possible differential reliability of stroke subtype diagnoses cannot be totally excluded. However, in the sample of diagnoses reviewed for the validation study, the reliability of stroke diagnosis did not depend on the level of alcohol consumption; thus, this kind of bias was not evident.
The nondrinkers more often reported diabetes and heart disease than the drinkers, which may indicate that some of the nondrinkers had stopped drinking because of the diseases. They may, however, have a higher stroke risk than the true lifelong abstainers. This bias might erroneously lead to a conclusion of a J-shaped dose-response relationship, suggesting that light drinking protects from stroke. On the other hand, the risks caused by alcohol consumption were not different among those with compared with those without previous heart disease. Chronic alcoholics with the highest consumption level of alcohol were excluded from the ATBC Study, which probably attenuated the risk of stroke in heavy drinkers.
Other studies concerning alcohol consumption have met similar unavoidable methodological problems.11 37 Men tend to underestimate their alcohol consumption, and the underreporting may weaken the true effects of alcohol on stroke risk. Unless the underreporting was not grossly differential, the dose-response patterns by alcohol consumption would reflect reality. However, underreporting is most likely differential,38 especially in that heavy drinkers do not report as nondrinkers but as light or moderate drinkers, which consequently may make the slope of the risk of hemorrhagic stroke more gentle and level off the bottom of the J-shaped curve of the CI risk. It is unlikely that differential reporting of drinking habits differs by stroke subtype. Thus, the specific response curves for each subtype would still differ even if biased by differential reporting. Despite equal average weekly consumption, irregular drinking, including binge drinking, may be more harmful than daily drinking.9
The association between alcohol consumption and the risk of SAH was nearly linear; in ICH, U-shaped; and in CI, J-shaped. There was a significant log-linear trend in CI; the trend in SAH was similar but nonsignificant, probably because of lack of power, whereas there was no trend in ICH. Heavy drinking clearly increased the risk of all stroke subtypes, as has been confirmed in many previous studies.2 3 4 5 6 7 8 9 Light drinking, on the other hand, had no effect on the risk of SAH and decreased the risks of ICH and CI compared with nondrinking. In the literature, light drinking has decreased4 or increased2 5 6 the risk of SAH; decreased4 or increased2 7 the risk of ICH; and decreased,4 9 increased,8 or had no effect2 10 on the risk of CI. The true effects of light to moderate drinking still seem to be unsettled, but the beneficial effects, if any, are most likely weak. In addition to the methodological problems related to studies on alcohol and stroke subtypes, another problem has been the low power of the studies. In only 3 of 31 studies reviewed by Camargo11 has the total number of stroke cases been >300; the highest number of patients with SAH has been 1934 and that for patients with ICH has been 156.9
SBP and HDL-C did not seem to modify the effect of alcohol on stroke risk. Instead, in pathway analysis, inclusion of SBP in the regression model consistently decreased the effect of alcohol in all subtypes of stroke, indicating that alcohol increases the risk of stroke by raising SBP. When HDL-C was added to the regression model, the effect of alcohol was strengthened in SAH and CI, indicating that HDL-C may mediate the beneficial effects of alcohol as in coronary heart disease.13 14 39 The effect of alcohol, however, was attenuated in ICH, suggesting that the HDL-C changes caused by alcohol are harmful in ICH, especially as the finding was consistent between the levels of alcohol consumption. One very speculative explanation could be weakening of the endothelium of smaller intracerebral arteries because of low serum total cholesterol levels further aggravated by hypertension, as suggested by Bronner et al.40 The fact that SBP and HDL-C affect SAH and CI in opposite directions indicates that there are still other mediators for the effect of alcohol on the risk of stroke.
This study was done among male smokers only. It is known that smokers have a slightly lower blood pressure41 and that their serum total cholesterol is increased and HDL-C is reduced42 compared with nonsmokers. It is also known that smoking and alcohol consumption are associated with each other, which was seen in this study. Our findings apply only to male smokers; the shapes of the stroke risk curves may be different in women and in nonsmokers. Nevertheless, it is unlikely that the hypothesized mediator roles of SBP and HDL-C were different by sex or smoking status.
In conclusion, light drinking had no effect on the risk of SAH but decreased slightly the risk of ICH and CI. Heavy drinking increased the risk of all subtypes of stroke. Blood pressure and HDL-C seemed to be involved in the development of stroke. They did not, however, thoroughly explain the association between alcohol consumption and the risk of stroke; thus, the mechanisms of alcohol in stroke are basically still unexplained.
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Acknowledgments |
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The ATBC Study was supported by a contract (N01-CN-45165) from the National Cancer Institute, Bethesda, Md.
Received April 14, 1999; revision received June 1, 1999; accepted June 14, 1999.
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D. A. Fiellin, M. C. Reid, and P. G. O'Connor Outpatient Management of Patients with Alcohol Problems Ann Intern Med, November 21, 2000; 133(10): 815 - 827. [Abstract] [Full Text] [PDF]
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