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(Stroke. 1996;27:672-676.)
© 1996 American Heart Association, Inc.

Articles

Risk Factors for Death From Stroke in Middle-aged Lithuanian Men

Results From a 20-Year Prospective Study

Daiva Rastenyte, MD; Jaakko Tuomilehto, MD, MSocSc, PhD; Stanislava Domarkiene, MD, PhD; Zygimantas Cepaitis, MA Regina Reklaitiene, MD, PhD

From the Kaunas Medical Academy, Institute of Cardiology, Lithuania (D.R., S.D., R.R.), and the National Public Health Institute, Department of Epidemiology and Health Promotion, Helsinki, Finland (J.T., Z.C.).

Correspondence to Dr Daiva Rastenyte, Institute of Cardiology, St Sukileliu 17, LIT-3007 Kaunas, Lithuania.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose Although in eastern Europe, mortality from stroke at present is the highest in the world, no previous prospective study of the risk factors for stroke has been reported from this part of the world. The aim of our study, therefore, was to evaluate the relations between blood pressure, serum total cholesterol, glucose intolerance, body mass index, and cigarette smoking and the risk of death from stroke in middle-aged men in Kaunas, Lithuania.

Methods We conducted a prospective study with an average follow-up of 17.5 years of 2295 men who had participated in risk factor surveys within the framework of the World Health Organization Kaunas-Rotterdam Intervention Study from 1972 to 1974. Risk factors included in the current analyses were smoking, blood pressure, serum total cholesterol, glucose intolerance, diabetes, and body mass index. Age- and risk factor–adjusted relative risks (RR) for death of stroke were determined by use of the Cox proportional hazards model.

Results The strongest risk factors for death from stroke in middle-aged men were systolic blood pressure (RR=1.02; P=.0001), diabetes (RR=4.17; P=.02), and smoking (RR=2.01; P=.004). Serum cholesterol, impaired glucose tolerance, and body mass index were not related to the risk of death from stroke. Twenty-five percent and 19% of stroke deaths were attributed to hypertension and smoking, respectively.

Conclusions Prevention and effective control of hypertension, smoking, and diabetes are the key elements in primary prevention of stroke in eastern Europe, where stroke mortality remains high.

Key Words: mortality • prospective studies • risk factors • Lithuania

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In most eastern European countries, an increasing trend in stroke mortality was observed during the last two decades.^{1 2 3} We have recently shown in a community-based stroke-register study in Kaunas, Lithuania,⁴ that both incidence of and mortality from stroke are increasing. In addition, a comparative assessment of stroke incidence and mortality between the Nordic countries and Lithuania demonstrated that the risk of stroke in Kaunas is indeed high.⁵ Efforts to reduce the incidence of stroke are essential for the improvement of public health. Such attempts should be based on knowledge about risk factors that are subject to intervention. Several epidemiological studies of risk factors for stroke have been performed throughout the world.^{6 7 8 9 10} Although there is good agreement about the major risk factors for stroke, the relative importance of different risk factors seems to vary between populations. Thus, data on risk factors for stroke should be examined in different ethnic groups and geographic regions. No previous prospective study has been reported from eastern Europe. On the basis of the cohort of men screened in the Kaunas-Rotterdam Intervention Study in the early 1970s, we have evaluated the relations between BP, serum total cholesterol, glucose intolerance, diabetes, BMI, and cigarette smoking and the risk of death from stroke in middle-aged men in Kaunas, Lithuania.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
From 1972 to 1974, a cardiovascular screening program was carried out in Kaunas within the framework of the WHO Kaunas-Rotterdam Intervention Study.¹¹ A sample of 3542 randomly selected men aged 45 to 59 years who represented various socioeconomic strata of an urban population was identified. In more detail, three districts were selected on the basis of the type of housing found in each district. We subsequently checked the homogeneity of each district by selecting at random 100 men and comparing their occupation, education, marital status, and type of housing. The first district consisted mainly of small private homes in an area close to the screening center. The second district was located in the downtown area, where old apartment houses predominated. In the third district, on the outskirts of Kaunas, there were only new high-rise buildings. Street lists of the city population were used, starting with the street at the center of each district and working out toward the periphery until the desired number of male candidates had been obtained.¹¹ Of these candidates, 2452 (69.2%) participated in the screening. The eligibility criteria for the present prospective analysis were no previous history of stroke at entry and availability of all study parameters. Thus, the final cohort comprised 2295 men.

Almost one third of all randomly selected men refused to take part in the initial screening. A participant/nonparticipant substudy was performed in Kaunas to reveal possible differences between participants and nonparticipants in the risk factor screening. This substudy showed that there was no significant difference between participants and nonparticipants in mean levels of the main risk factors, although both systolic and diastolic BPs, glucose level, and prevalence of smokers tended to be higher in the nonparticipant than in the participant group.¹¹

The methods used in the risk factor survey have been described in detail previously.¹¹ Briefly, Hawksley random zero sphygmomanometers were used for BP measurements. BP was measured from the right arm of the subject after 5 minutes' rest in a sitting position. The fifth phase of Korotkoff sounds was recorded as diastolic BP. The mean of two BP readings was used. We considered a person to have an elevated BP if systolic BP was 160 mm Hg or diastolic BP was 95 mm Hg or if the person had taken antihypertensive drugs within the previous 2 weeks. Weight was measured with a balance scale with subjects wearing light clothing and no shoes. Height was measured to the nearest centimeter, with subjects not wearing shoes. BMI, ie, weight (in kilograms) divided by height (in meters) squared, was used as a measure of relative body weight. Glucose tolerance was examined 1 hour after a 75-g glucose load. Participants with a history of diabetes mellitus were excluded from the glucose tolerance test. A 1-hour postload blood glucose level between 10.08 and 19.5 mmol/L was considered impaired glucose tolerance; a glucose level of 19.6 mmol/L or more was considered diabetes mellitus. Men who met this criterion of diabetes and those with a previous history of diabetes mellitus were considered diabetic in the present study. Serum total cholesterol was determined by use of the heparin-manganate precipitation method (Liebermann-Burchard). All serum samples were analyzed in the same laboratory. Information about smoking habits was obtained by use of a standard set of questions. Respondents were classified as smokers (men who smoked regularly for at least 1 year more than once a day, on average, and had smoked during the preceding 6 months) or nonsmokers (men who had never smoked and men who had smoked previously but stopped smoking 6 months or more before the survey). Self-reported information about previous history of stroke and myocardial infarction was also obtained on the questionnaire and was verified from medical records afterward.

The end point used in the present study was death from stroke. Mortality data were collected continually during the 20-year follow-up. The list of participants was checked monthly against mortality registration that covered the entire population of Kaunas. Throughout the follow-up period, the eighth revision of the ICD was used. All deaths that listed ICD codes 430 through 438 as the underlying cause of death were reviewed and checked against all available medical information (records in outpatient departments and hospitals, autopsy reports, and medicolegal reports) and were considered stroke in the present analyses. There were 75 stroke deaths (9.2% of all deaths) during the 20-year follow-up and 742 deaths from other causes: 249 (30.5%) from neoplasms, 369 (45.2%) from all cardiovascular disease, 230 (28.2%) from ischemic heart disease, 83 (10.2%) from external causes, and 116 (14.2%) from other causes. The 211 men who were lost to follow-up did not differ significantly from the remaining group with respect to cardiovascular risk factors, prevalent hypertension, diabetes, or smoking.

Statistical Analyses
Estimates of RR and 95% CIs were based on the Cox proportional hazards model.¹² The Cox proportional hazards model was also used to produce predicted survival curves and the survival function estimates and to compare different survival curves. In cases of uncensored observations, each subject was followed up until December 31, 1994, or until death from another cause, whichever came first. The average follow-up time was 17.5 years. All analyses were done with adjustment for age. The population-attributable risk was calculated according to the method of Breart and Padieu.¹³ Statistical analyses were performed with SAS (Statistical Analysis Systems) statistical software in a VAX computer at the National Public Health Institute in Helsinki, Finland.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Age-adjusted mean values of risk factors at baseline according to the subsequent analysis of data collected during our 20-year study are presented in Table 1. Men who died of stroke had significantly higher systolic and diastolic BPs and a higher prevalence of hypertension, diabetes, and cigarette smoking than men who were alive at the end of follow-up. Systolic BP (P=.02) and prevalence of hypertension (P=.05) and diabetes (P=.03) were also significantly higher among men who died of stroke than among men who died of other causes during follow-up.

View this table: [in this window] [in a new window]   Table 1. Age-Adjusted Risk Factor Levels at the 1972-1974 Baseline Visit According to Survival Status at End of Follow-up (December 31, 1994)

Results from the univariate and multivariate analyses are shown in Table 2. In the univariate analysis, diabetes was associated with a 5-fold increase in the risk of death from stroke (95% CI, 1.6 to 16.8; P=.005), hypertension was associated with a 2.4-fold increase in risk (95% CI, 1.5 to 3.7; P=.0002), and smoking was associated with a 1.8-fold increase in risk (95% CI, 1.2 to 2.9; P=.01). In addition, both systolic (P=.0001) and diastolic (P=.0006) BPs were strongly associated with the risk of death from stroke. Serum total cholesterol level, impaired glucose tolerance, and BMI were not significant risk factors.

View this table: [in this window] [in a new window]   Table 2. Effect of the Main Risk Factors From Risk of Death From Stroke Based on Univariate and Multivariate Analyses

To investigate whether some of the risk factors were independently associated with the risk of death from stroke, multivariate analysis was used (Table 2). Age (RR=1.11; P=.0001), systolic BP (RR=1.02; P=.0001), diabetes (RR=4.17; P=.02), and smoking (RR=2.01; P=.004) were found to be independent risk factors for death from stroke. The population-attributable risks of stroke related to hypertension, smoking status, diabetes, and glucose intolerance were 24.9%, 19.2%, 3.1%, and 4.9%, respectively.

Predicted survival curves estimated by the Cox proportional hazards model for nondiabetic versus diabetic men, nonsmokers versus smokers, and normotensive versus hypertensive men are shown in the Figure. After only 2 years of follow-up, the survival curve for diabetic men began to separate from the curve for nondiabetic men (Figure, panel A). Survival curves for nonsmokers and for normotensives began to separate from survival curves for smokers and for hypertensive men after about 3 and 4 years' follow-up, respectively (Figure, panels B and C). After adjustment for age, survival was significantly better in nondiabetic, nonsmoking, and normotensive men than in those who were diabetic (P=.02), smoked cigarettes (P=.004), or were hypertensive (P=.0001).

View larger version (30K): [in this window] [in a new window]   Figure 1. Cumulative mortality from stroke in Kaunas men aged 45 to 59 years at baseline, classified by diabetic status (A), smoking status (B), and presence or absence of hypertension (C), estimated by a life-table method with use of Cox regression models. Differences in relative hazards during follow-up were estimated with adjustment by age and use of the same models.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The present study confirmed that in middle-aged men in Kaunas, Lithuania, the strongest independent risk factors for stroke are systolic BP, diabetes, and smoking. In addition, hypertension was associated with a 2.4-fold increased risk of death from stroke in the univariate analysis. On the other hand, we failed to show that cholesterol level, impaired glucose tolerance, or BMI is related to the risk of death from stroke. Although these results are in keeping with findings from western countries, this is the first assessment of risk factors for stroke in eastern Europe, where mortality from stroke is presently the highest in the world and does not show a decline as in western countries.

Hypertension is the best-known risk factor for stroke. Hence, our findings are in accord with a large number of previous studies.^{8 9 14 15} It has been shown that the risk of stroke in hypertensive subjects can be effectively reduced by lowering BP levels with antihypertensive drugs.^{16 17} Our data stress the importance of primary prevention and more efficient hypertension control in Lithuania. The comparative data from the WHO MONICA project also show that BP levels in Kaunas are relatively high and that antihypertensive drug treatment is not very efficient.¹⁸ Furthermore, a statistically significant increase in mean level of BP among both men and women aged 35 to 64 years has been observed during the period from 1987 to 1993 in Kaunas.¹⁹ In addition, only one of every five men with elevated BP had been informed of his condition, and only one fourth of those subjects who were aware of their hypertension were receiving proper treatment.¹⁹ The population-attributable risk estimates indicate that it would be possible to prevent every fourth stroke death among men in Kaunas if the BPs of hypertensive men were normalized.

Several investigators have found diabetes to be an independent risk factor for stroke,^{14 19 20 21 22 23 24 25 26} but in some studies, diabetes did not remain an independent risk factor in multivariate analysis.^{27 28} Some recent studies have suggested that diabetes might be associated with the risk of ischemic stroke but not hemorrhagic stroke.^{23 24 29} Unfortunately, during the first half of the present study, no attempts were made to verify diagnosis of stroke subtype, and therefore we could not evaluate the effect of diabetes (or other risk factors) on ischemic and hemorrhagic stroke separately.

Impaired glucose tolerance appeared not to be associated with stroke mortality in the present study. This is in the conflict with the recent results from the Honolulu Heart Program^{20 23} and the Whitehall study,³⁰ in which glucose intolerance was shown to be an independent risk factor for stroke. In the present study, the postload glucose concentration was measured 1 hour after a 75-g glucose load only. It is therefore possible that some healthy persons were misclassified as having impaired glucose tolerance. Nevertheless, a similar 1-hour glucose tolerance test was also used in the Honolulu Heart Program.

The risk of diabetes and its complications vary among populations, and much of this variation is due to obesity. The population of Kaunas is one of the most obese in Europe, as seen from the mean BMI values in the present study and from the comparative data of the WHO MONICA project.¹⁸ Although BMI seems not to be an independent risk factor for stroke,¹⁵ it is important because of its associations with other risk factors, such as systolic and diastolic BPs, serum cholesterol level, and plasma glucose level.³¹ Some studies have demonstrated the importance of a central pattern of body fat distribution in predicting coronary heart disease after adjustment for BMI.^{32 33} It was suggested that the intra-abdominal tissue has a highly sensitive lipomobilization capacity that results in high portal free fatty acid concentrations, which in turn generate, through hepatic regulation, elevated risk factor levels for cardiovascular disease.³⁴ In other words, prevention and control of obesity is certainly one of the main issues in the prevention of cardiovascular diseases, hypertension, and diabetes and thereby indirectly in the prevention of stroke.

Although previously debated, it is now commonly agreed that smoking is an independent risk factor for stroke.^{35 36} In Kaunas, almost 20% of all stroke deaths in men could be attributed to smoking. Wider and more intensive public health policy and education about the harmful effects of smoking are needed in Lithuania. Prevention of smoking could help to prevent almost one fifth of stroke deaths in middle-aged men and obviously a large number of cases of coronary heart disease, lung cancer, and other chronic diseases.

We did not find serum total cholesterol level to be a significant risk factor for mortality in univariate analysis. The association between cholesterol and stroke seems to differ by the type of stroke, ie, a low serum total cholesterol level is associated with hemorrhagic stroke, whereas a high cholesterol level is associated with ischemic stroke.^{9 37} A recent overview of 10 prospective studies of the association between serum cholesterol concentrations >5.7 mmol/L and stroke risk found the pooled risk to be 1.31, which was statistically significant.³⁸ Findings from the Honolulu Heart Program¹⁰ suggested that the association between serum total cholesterol level and increased risk for thromboembolic stroke sometimes may be underestimated, in part because of shared or competing risk with coronary heart disease, the clinical manifestation of atherosclerosis that generally occurs earlier in life and with greater frequency than thromboembolic stroke.

In conclusion, our findings confirmed that BP, diabetes, and daily cigarette smoking were the main risk factors for death from stroke in the middle-aged, male Kaunas population. Both BP and smoking are modifiable risk factors for stroke, and the means for effective treatment of diabetes also exists. Since about half of stroke deaths can be attributed to these three risk factors, urgent measures aimed at changes of lifestyle are required in Lithuania, where increasing trends in incidence and mortality of stroke have been observed.

	Selected Abbreviations and Acronyms

 

BMI = body mass index BP = blood pressure CI = confidence interval ICD = International Classification of Diseases RR = relative risk WHO MONICA = World Health Organization Monitoring Trends and Determinants in Cardiovascular Disease

Received September 29, 1995; revision received November 27, 1995; accepted January 15, 1996.

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