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(Circulation. 1999;100:1209-1214.)
© 1999 American Heart Association, Inc.

Clinical Investigation and Reports

Alcohol Consumption and Stroke Incidence in Male Smokers

Jaana M. Leppälä, MD; Mikko Paunio, MD; Jarmo Virtamo, MD; Rainer Fogelholm, MD; Demetrius Albanes, MD; Philip R. Taylor, MD, DSc; Olli P. Heinonen, MD

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

	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

	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 hemorrhagic^{2 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}

	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.

	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.

View this table: [in this window] [in a new window]   Table 1. Baseline Characteristics by Alcohol Consumption

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.

View this table: [in this window] [in a new window]   Table 2. Crude Incidence Rates and Adjusted Relative Incidences of Stroke Subtypes by Alcohol Consumption

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).

View this table: [in this window] [in a new window]   Table 3. Adjusted Relative Incidences of Stroke Subtypes by Alcohol Consumption in Men Reporting Any Alcohol Consumption (Nondrinkers Excluded)

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%.

View larger version (12K): [in this window] [in a new window]   Figure 1. Alcohol consumption and risk of stroke. Relative risks were adjusted for age, body mass index, serum total cholesterol, number of cigarettes smoked daily, history of diabetes, history of heart disease, education, leisure-time activity, and supplementation with -tocopherol or ß-carotene. SBP and HDL-C were added separately to multivariate-adjusted Cox proportional-hazards model to examine effect of alcohol on stroke through these factors (logarithmic scale).

	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 increased^{2 5 6} the risk of SAH; decreased⁴ or increased^{2 7} the risk of ICH; and decreased,^{4 9} increased,⁸ or had no effect^{2 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.

	Acknowledgments

 
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.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Camargo CA Jr. Case-control and cohort studies of moderate alcohol consumption and stroke. Clin Chim Acta. 1996;246:107–119.[Medline] [Order article via Infotrieve]
   
2. Donahue RP, Abbott RD, Reed DM, Yano K. Alcohol and hemorrhagic stroke: the Honolulu Heart Program. JAMA. 1986;255:2311–2314.[Abstract]
   
3. Monforte R, Estruch R, Graus F, Nicolas JM, Urbano-Marquez A. High ethanol consumption as risk factor for intracerebral hemorrhage in young and middle-aged people. Stroke. 1990;21:1529–1532.[Abstract/Free Full Text]
   
4. Gill JS, Shipley MJ, Tsementzis SA, Hornby RS, Gill SK, Hitchcock ER, Beevers DG. Alcohol consumption: a risk factor for hemorrhagic and non-hemorrhagic stroke. Am J Med. 1991;90:489–497.[Medline] [Order article via Infotrieve]
   
5. Longstreth WT Jr, Nelson LM, Koepsell TD, van Belle G. Cigarette smoking, alcohol use, and subarachnoid hemorrhage. Stroke. 1992;23:1242–1249.[Abstract/Free Full Text]
   
6. Juvela S, Hillbom M, Numminen H, Koskinen P. Cigarette smoking and alcohol consumption as risk factors for aneurysmal subarachnoid hemorrhage. Stroke. 1993;24:639–646.[Abstract/Free Full Text]
   
7. Juvela S, Hillbom M, Palomäki H. Risk factors for spontaneous intracerebral hemorrhage. Stroke. 1995;26:1558–1564.[Abstract/Free Full Text]
   
8. Gorelick PB, Rodin MB, Langenberg P, Hier DB, Costigan J. Weekly alcohol consumption, cigarette smoking, and the risk of ischemic stroke: results of a case-control study at three urban medical centers in Chicago, Illinois. Neurology. 1989;39:339–343.[Abstract/Free Full Text]
   
9. Palomäki H, Kaste M. Regular light-to-moderate intake of alcohol and the risk of ischemic stroke: is there a beneficial effect? Stroke. 1993;24:1828–1832.[Abstract/Free Full Text]
   
10. Numminen H, Hillbom M, Juvela S. Platelets, alcohol consumption, and onset of brain infarction. J Neurol Neurosurg Psychiatry. 1996;61:376–380.[Abstract]
    
11. Camargo CA Jr. Moderate alcohol consumption and stroke: the epidemiologic evidence. Stroke. 1989;20:1611–1626.[Abstract/Free Full Text]
    
12. Klatsky AL. Alcohol and hypertension. Clin Chim Acta. 1996;246:91–105.[Medline] [Order article via Infotrieve]
    
13. Suh I, Shaten BJ, Cutler JA, Kuller LH. Alcohol use and mortality from coronary heart disease: the role of high-density lipoprotein cholesterol. Ann Intern Med. 1992;116:881–887.
    
14. Gaziano JM, Buring JE, Breslow JL, Goldhaber SZ, Rosner B, VanDenburgh M, Willett W, Hennekens CH. Moderate alcohol intake, increased levels of high-density lipoprotein and its subfractions, and decreased risk of myocardial infarction. N Engl J Med. 1993;329:1829–1834.[Abstract/Free Full Text]
    
15. Linn S, Carroll M, Johnson C, Fulwood R, Kalsbeek W, Briefel R. High-density lipoprotein cholesterol and alcohol consumption in US white and black adults: data from NHANES II. Am J Public Health. 1993;83:811–816.[Abstract/Free Full Text]
    
16. Paunio M, Heinonen OP, Virtamo J, Klag MJ, Manninen V, Albanes D, Comstock GW. HDL cholesterol and mortality in Finnish men with special reference to alcohol intake. Circulation. 1994;90:2909–2918.[Abstract/Free Full Text]
    
17. Hendriks HFJ, Veenstra J, Velthuis-te Wierik EJM, Schaafsma G, Kluft C. Effect of moderate dose of alcohol with evening meal on fibrinolytic factors. BMJ. 1994;308:1003–1006.[Abstract/Free Full Text]
    
18. Hillbom M, Kaste M, Rasi V. Can ethanol intoxication affect hemocoagulation to increase the risk of brain infarction in young adults? Neurology. 1983;33:381–384.[Abstract/Free Full Text]
    
19. Renaud SC, Ruf JC. Effects of alcohol on platelet functions. Clin Chim Acta. 1996;246:77–89.[Medline] [Order article via Infotrieve]
    
20. Hillbom M, Kangasaho M, Kaste M, Numminen H, Vapaatalo H. Acute ethanol ingestion increases platelet reactivity: is there a relationship to stroke? Stroke. 1985;16:19–23.[Abstract/Free Full Text]
    
21. Mathew RJ, Wilson WH. Regional cerebral blood flow changes associated with ethanol intoxication. Stroke. 1986;17:1156–1159.[Abstract/Free Full Text]
    
22. Gillespie JA. Vasodilator properties of alcohol. BMJ. 1967;2:274–277.
    
23. Altura BM, Altura BT, Gebrewold A. Alcohol-induced spasms of cerebral blood vessels: relation to cerebrovascular accidents and sudden death. Science. 1983;220:331–333.[Abstract/Free Full Text]
    
24. Ganz V. The acute effect of alcohol on the circulation and on the oxygen metabolism of the heart. Am Heart J. 1963;66:494–497.[Medline] [Order article via Infotrieve]
    
25. Dyken ML, Wolf PA, Barnett HJM, Bergan JJ, Hass WK, Kannel WB, Kuller L, Kurtzke JF, Sundt TM. Risk factors in stroke: a statement for physicians by the Subcommittee on Risk Factors and Stroke of the Stroke Council. Stroke. 1984;15:1105–1111.
    
26. MacMahon S, Peto R, Cutler J, Collins R, Sorlie P, Neaton J, Abbott R, Godwin J, Dyer A, Stamler J. Blood pressure, stroke, and coronary heart disease, part 1: prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet. 1990;335:765–774.[Medline] [Order article via Infotrieve]
    
27. Woo J, Lau E, Lam CWK, Kay R, Teoh R, Wong HY, Prall WY, Kreel L, Nicholls MG. Hypertension, lipoprotein(a), and apolipoprotein A-I as risk factors for stroke in the Chinese. Stroke. 1991;22:203–208.[Abstract/Free Full Text]
    
28. Gordon T, Kannel WB, Castelli WP, Dawber TR. Lipoproteins, cardiovascular disease, and death: the Framingham Study. Arch Intern Med. 1981;141:1128–1131.[Abstract]
    
29. Lindenstrom E, Boysen G, Nyboe J. Influence of total cholesterol, high density lipoprotein cholesterol, and triglycerides on risk of cerebrovascular disease: the Copenhagen City Heart Study. BMJ. 1994;309:11–15.[Abstract/Free Full Text]
    
30. Tell GS, Crouse JR, Furberg CD. Relation between blood lipids, lipoproteins, and cerebrovascular atherosclerosis: a review. Stroke. 1988;19:423–430.[Abstract/Free Full Text]
    
31. The ATBC Cancer Prevention Study Group. The Alpha-Tocopherol, Beta-Carotene Lung Cancer Prevention Study: design, methods, participant characteristics, and compliance. Ann Epidemiol. 1994;4:1–10.[Medline] [Order article via Infotrieve]
    
32. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med. 1994;330:1029–1035.[Abstract/Free Full Text]
    
33. Manual of the International Statistical Classification of Diseases, Injuries, and Causes of Death: Volume 1. 8th revision. Geneva, Switzerland: World Health Organization; 1967.
    
34. Manual of the International Statistical Classification of Diseases, Injuries, and Causes of Death: Volume 1. 9th revision. Geneva, Switzerland: World Health Organization; 1977.
    
35. Leppälä JM, Virtamo J, Heinonen OP. Validation of stroke diagnosis in the Hospital Discharge Register and the Register of Causes of Death in Finland. Eur J Epidemiol. 1999;15:155–160.[Medline] [Order article via Infotrieve]
    
36. Pietinen P, Hartman AM, Haapa E, Räsänen L, Haapakoski J, Palmgren J, Albanes D, Virtamo J, Huttunen JK. Reproducibility and validity of dietary assessment instruments, I: self-administered food use questionnaire with a portion size picture booklet. Am J Epidemiol. 1988;128:655–666.[Abstract/Free Full Text]
    
37. Midanik L. The validity of self-reported alcohol consumption and alcohol problems: a literature review. Br J Addiction. 1982;77:357–382.[Medline] [Order article via Infotrieve]
    
38. Paunio M, Virtamo J, Gref CG, Heinonen OP. Serum high density lipoprotein cholesterol, alcohol, and coronary mortality in male smokers. BMJ. 1996;312:1200–1203.[Abstract/Free Full Text]
    
39. Moore RD, Pearson TA. Moderate alcohol consumption and coronary artery disease: a review. Medicine. 1986;65:242–267.[Medline] [Order article via Infotrieve]
    
40. Bronner LL, Kanter DS, Manson JE. Primary prevention of stroke. N Engl J Med. 1995;333:1392–1400.[Free Full Text]
    
41. Omvik P. How smoking affects blood pressure. Blood Press. 1996;5:71–77.[Medline] [Order article via Infotrieve]
    
42. Krupski WC. The peripheral vascular consequences of smoking. Ann Vasc Surg. 1991;5:291–304.[Medline] [Order article via Infotrieve]
    

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