Background and Purpose This report examines the relationship between lung function and risk of major stroke events (fatal and nonfatal).
Methods We completed a prospective study of 7735 men aged 40 to 59 years at screening selected at random from one general practice in each of 24 British towns.
Results During the mean follow-up period of 14.8 years, there were 277 major stroke events in the 7650 men with data on forced expiratory volume in 1 second (FEV1). After exclusion of 499 men with definite myocardial infarction, stroke, or atrial fibrillation at screening, 7151 men experienced 239 major stroke events. Lower levels of FEV1 were associated with a significant increase in risk of stroke even after adjustment for age, smoking, social class, physical activity, alcohol intake, systolic blood pressure, antihypertensive treatment, diabetes, and preexisting ischemic heart disease. Relative risk in the low third (<3.10 L) versus high third (>3.65 L) was 1.4 (95% confidence interval, 1.0 to 2.0). The inverse association between FEV1 and stroke was only apparent in older men, current nonsmokers, hypertensive men, and men with preexisting ischemic heart disease. Lower FEV1 was associated with higher rates of stroke in hypertensive men irrespective of smoking status. Inclusion of FEV1 in a risk score for stroke provided only a small increase in the absolute risk or the yield of cases in the top fifth of the score distribution during the follow-up period.
Conclusions Lower levels of FEV1 are associated with an increased risk of stroke in those already at high risk, eg, those with ischemic heart disease or hypertension. However, the association is not strong enough to warrant the use of FEV1 in making clinical decisions regarding the treatment of hypertension as it relates to the prevention of stroke.
Diminished respiratory function expressed as FVC, FEV1, or peak expiratory flow has been shown to be an independent predictor of coronary and cardiovascular mortality and morbidity.1 2 3 4 5 6 7 8 Few studies have reported on a specific relationship between respiratory function and stroke. In all the studies that have done so, an inverse association has been reported,6 7 8 9 10 11 and some have found the association to be independent of smoking and other potential risk factors for stroke.7 10 11 Others have found the relationship to be nonsignificant after adjustment for potential confounders.6 8 9 In a prospective study of middle-aged male British civil servants (the Whitehall Study) followed up for 18 years, FEV1 at screening was found to be an independent predictor of stroke, and it was suggested that measurement of respiratory function might assist clinical decisions about the treatment of mild hypertension.10 We examined the relationship between FEV1 and risk of stroke during an average 14.8-year follow-up in a large prospective study of middle-aged men to assess the independent role of FEV1 and to consider its effect in hypertensive subjects.
Subjects and Methods
The British Regional Heart Study is a large prospective study of cardiovascular disease comprising 7735 men aged 40 to 59 years selected from the age/sex registers of one group general practice in each of 24 towns in England, Wales, and Scotland (78% response rate). The criteria for selecting the town, the general practice, and the subjects as well as the methods of data collection have been reported.12 Research nurses administered to each man a standard questionnaire that included questions on smoking habits, alcohol intake, physical activity, and medical history. Several physical measurements were made, and blood samples (nonfasting) were taken for biochemical and hematologic measurements. Classification methods for smoking status, alcohol consumption, occupation (social class), and body mass index have been reported.12
Alcohol consumption was recorded with the use of questions on frequency, quantity, and type, similar to those used in the 1978 General Household Survey. The men were classified into five groups based on weekly intake: none, occasional, light, moderate, and heavy.13 Heavy drinking was defined as drinking more than 6 units (1 UK unit=8 to 10 g alcohol) daily or on most days. The men were asked to indicate their usual pattern of physical activity, and a physical activity (exercise) score was derived for each man based on frequency and type (intensity) of the physical activity.14 The men were grouped into six broad categories based on their total score: inactive, occasional, light, moderate, moderately vigorous, and vigorous.
We measured FEV1 and FVC using a Vitalograph spirometer (model J49-B2) manufactured by Vitalograph Ltd Medical Instrumentation, with the subject seated. Two consecutive readings were made 15 seconds apart, and the greater of these two readings was used. The FEV1 and FVC values used are height standardized to 1.73 m, the average height of the men in this study. FEV1 and FVC measurements were not available on 85 men. Because of the high degree of correlation between FEV1 and FVC (r=.83) and because of the suggestion that FEV1 should be used in assessing subjects with mild hypertension for treatment,10 the focus of this report will be on FEV1, with additional comments on FVC and the ratio of FEV1 to FVC.
The men were classified according to their current smoking status into six groups: those who had never smoked cigarettes (never-smokers), ex–cigarette smokers, and four groups of current smokers (1 to 19, 20, 21 to 39, and ≥40 cigarettes per day). Those who had only smoked pipes or cigars were classified as never-smokers. Ex–cigarette smokers who currently smoked a pipe or cigars were classified as ex-smokers. For ex-smokers, data were also available on the number of cigarettes smoked previously and the total duration of smoking.15 In some analyses all current smokers are combined, and ex-smokers and those who had never smoked are combined as current nonsmokers.
Measurements of serum cotinine for validation of baseline smoking status were not available. However, blood cadmium, which is considered a strong biological marker of smoking and has been shown to be strongly associated with smoking status,16 17 was measured in this study. Mean levels of blood cadmium were shown to regress markedly within 1 to 2 years of quitting and then converged more slowly to the levels of never-smokers after 10 years of cessation.16
The London School of Hygiene sphygmomanometer was used to measure blood pressure twice in succession with the subjects seated and with the arm supported on a cushion. The mean of the two readings was used in the analysis, and all blood pressure readings were adjusted for observer variation within each town.18 Men with adjusted systolic blood pressure of 160 mm Hg or greater or adjusted diastolic blood pressure of 90 mm Hg or greater or subjects on regular antihypertensive treatment were regarded as hypertensive.
Preexisting IHD and Stroke
The men were asked whether a physician had ever told them that they had angina or myocardial infarction (heart attack, coronary thrombosis), stroke, or a number of other disorders. The WHO (Rose) chest pain questionnaire19 was administered to all men at the initial examination, and a three-lead ECG (orthogonal system) was recorded at rest.
Evidence of a previous stroke was determined by the subject’s recall of such a diagnosis made by a physician. There were 52 such men in the study.
In regard to IHD, the men were separated into three groups according to the evidence of IHD at screening. Group 1 comprised men with no evidence of IHD on WHO chest pain questionnaire or ECG and no recall of a physician’s diagnosis of IHD. Group 2 comprised men with evidence suggesting IHD short of a definite myocardial infarction. This group contained those with ECG evidence of possible or definite myocardial ischemia or possible myocardial infarction (asymptomatic) and those with angina or a possible myocardial infarction on WHO (Rose) chest pain questionnaire or who recalled a physician’s diagnosis of angina (symptomatic). Group 3 comprised men with a previous definite myocardial infarction on ECG or who recalled a physician’s diagnosis of myocardial infarction (“heart attack”).
A complex diagnostic tree, which was part of a larger set of criteria used in interpreting the ECG as a whole, was used to make the interpretation.20 All ECGs in the study were reviewed by an experienced electrocardiographer, and if any errors in the computer-based rhythm interpretation were detected, they were corrected before results were entered into the database. A normal rhythm was defined as sinus rhythm, coronary sinus rhythm, or sinus arrhythmia. All other statements of rhythm were treated as an arrhythmia, eg, sinus rhythm with ventricular extrasystoles. As expected, 97.8% of the men in the study were in sinus rhythm. Only 0.7% were in atrial fibrillation.
All men were followed up for all-cause mortality and for cardiovascular morbidity.21 All stroke events occurring in the period up to December 1993 are included in the study, with an average follow-up of 14.8 years (range, 13.5 to 16.0 years). Follow-up has been achieved for 99% of the cohort. Information on death was collected through the established “tagging” procedures provided by the National Health Service registers in Southport (England and Wales) and Edinburgh (Scotland). Nonfatal stroke events were those that produced a neurological deficit that was present for more than 24 hours. Evidence regarding such episodes was obtained by reports from general practitioners, from personal questionnaires to surviving subjects at years 5 and 12 after the initial examination, and by semiannual reviews of the patients’ notes through the end of the study period. This combination of reporting acute events as they occurred, personal recall of events in the first 5 years and 12 years later, and regular scrutiny of the records, which included all correspondence and reports relating to hospital admissions and attendance, is presumed to provide information that is as complete and as unbiased as possible in prospective studies. Fatal stroke episodes were those coded on the death certificate as International Classification of Diseases codes 430 through 438. All death certificates in which it appeared that coding as stroke was not appropriate or in which stroke was not the attributed code when it might have been were explored by correspondence with the certifying doctor and the hospital concerned. No information on the type of stroke was available.
The Cox proportional hazards model was used to assess the independent contributions of FEV1 to the risk of stroke and to obtain the RRs adjusted for age and other risk factors.22 We assessed tests for trend fitting the FEV1 in its original continuous form. In the adjustment, age, blood cholesterol, and systolic blood pressure were fitted as continuous variables. Alcohol (5 levels), smoking (6 levels), physical activity (6 levels), social class (3 groups), diabetes (yes/no), and preexisting IHD on WHO (Rose) questionnaire/ECG (group 2, yes/no) were fitted as categorical variables. In some of the analyses, all current smokers were combined. Direct standardization was used to obtain age-adjusted stroke rates per 1000 person-years for FEV1 groups by current smoking status in hypertensive men, with the whole study population as the standard. A test for interaction to assess whether the relationship between FEV1 and stroke differed by current smoking status was assessed by fitting an FEV1-smoking interaction term in the model with all current smokers combined. Similar analyses using interaction terms were performed to assess whether the association between FEV1 and stroke differed by age, presence of hypertension, and preexisting IHD.
During the mean follow-up period of 14.8 years, 277 major stroke events (63 fatal and 214 nonfatal) occurred in the 7650 men with available data on FEV1. Since the presence of definite myocardial infarction or stroke may strongly influence lung function (FEV1) and since such diagnosis (n=457) or the presence of atrial fibrillation (n=54, of whom 12 also had a diagnosis of stroke or myocardial infarction) on ECG may influence the risk of stroke, all such subjects have been excluded from the initial analysis (n=499). This group experienced 38 stroke cases, ie, 6.7/1000 person-years. In the 7151 men with no definite myocardial infarction/stroke or evidence of atrial fibrillation, 239 major stroke events (52 fatal and 187 nonfatal) occurred, representing a rate of 2.4/1000 person-years.
FEV1 and Risk of Stroke
Table 1⇓ shows the crude rates per 1000 person-years and the age-adjusted RR of stroke by thirds of the ranked FEV1 distribution. Men in the highest third were used as the reference group. A significant inverse association was seen after adjustment for age. FEV1 is strongly associated with smoking, which is a strong independent risk factor for stroke.23 Adjustment for smoking status reduced the trend slightly, but the association remained significant. Men in the lowest third showed a 50% increase in risk of stroke compared with men in the highest third (RR, 1.5; 95% CI, 1.1 to 2.2). Further adjustment for other factors known to be associated with stroke risk, eg, physical activity, alcohol intake, systolic blood pressure, diabetes, preexisting IHD short of myocardial infarction (group 2), social class, and antihypertensive treatment, reduced the inverse trend further, but risk was still significantly elevated in the lowest third of the FEV1 distribution, and the trend was marginally significant (P=.05).
Analysis using FVC instead of FEV1 yielded almost identical results, with fully adjusted RRs of 1.4 (95% CI, 1.0 to 2.0), 1.2 (95% CI, 0.8 to 1.7), and 1.0 for the thirds of the FVC distribution (test for trend, P=.03). Since FEV1 and FVC behaved so similarly, no association was seen with the ratio of FEV1 to FVC. The adjusted RRs were 1.1, 1.0, and 1.0, respectively, for the thirds of the FEV1/FVC distribution.
Age, Smoking, and Hypertension
The relationship between FEV1 and stroke was examined by levels of risk factors, eg, age, smoking, and hypertension (Table 2⇓). Because of the small number of stroke cases (n=28) in men who had never smoked, we divided the smoking categories into current smokers and non–current smokers, the latter including both ex–cigarette smokers (n=2483) and never-smokers (n=1738). The inverse association between FEV1 and risk of stroke was seen only in older men (aged 50 to 59 years), current nonsmokers, and hypertensive subjects. A formal test for interaction (see “Subjects and Methods”) confirmed a significant difference in the relationship between FEV1 and stroke by levels of these risk factors.
Among the current nonsmokers, men with low FEV1 were more likely to be past heavier smokers (≥20 cigarettes per day) or secondary pipe or cigar smokers than men with high FEV1. However, further adjustment for past cigarette smoking and secondary pipe or cigar smoking did not make a major difference to the significant inverse association seen between FEV1 and stroke in current nonsmokers. We also examined the relationship separately in ex–cigarette smokers and never-smokers. In the never-smokers, no apparent association was seen between FEV1 and stroke after adjustment, as shown in Table 2⇑. In ex-smokers, the inverse association was clearly seen even after we adjusted for past heavy smoking and secondary pipe or cigar smoking.
Men With Preexisting IHD
The relationship between FEV1 and stroke was also examined separately in men with and without preexisting IHD short of a myocardial infarction (group 2). The inverse association was seen only in men with evidence of preexisting IHD short of a myocardial infarction (Table 3⇓). We further separated men with preexisting IHD (group 2) into those with symptomatic (those who reported angina or possible myocardial infarction on the WHO [Rose] questionnaire or who recalled a physician’s diagnosis of angina irrespective of ECG findings) and asymptomatic IHD (those with ischemic ECG abnormalities but who did not report any chest pain). The inverse association was seen in both groups (data not shown).
We also examined the relationship between FEV1 and risk of stroke in the small group of men (n=499) with previous definite myocardial infarction/stroke or evidence of atrial fibrillation, who were excluded from all the previous analyses. FEV1 was significantly inversely associated with risk of stroke in this group (test for trend; P=.01; data not shown).
Smoking and Hypertension
Because of the strong influence that smoking has on both FEV1 and risk of stroke and because the level of FEV1 has been proposed for use in the management of hypertension,10 we examined the relationship between FEV1 and stroke in hypertensive subjects stratified by current smoking status. Because men in the lower two thirds of the FEV1 distribution showed similar increased risk in hypertensive men (Table 2⇑), these men were combined and compared with the highest third of the FEV1 distribution (Table 4⇓). Lower FEV1 is associated with higher rates of stroke in hypertensive men irrespective of smoking status. The difference in age-adjusted absolute rates of stroke between high and lower FEV1 amounted to 1.4/1000 person-years in currently nonsmoking hypertensive subjects (1.6 versus 3.0/1000 person-years) and to 2.5/1000 person-years in smoking hypertensive subjects (3.9 versus 7.4/1000 person-years).
We determined the RR of stroke in hypertensive men adjusting for age and other potential confounders (as in Table 2⇑), using nonsmoking hypertensive men in the highest third of the FEV1 distribution as the reference group (Table 4⇑). In nonsmokers, hypertension accompanied by low FEV1 was associated with a twofold increase in risk of stroke (RR, 2.1; 95% CI, 1.0 to 4.0). In smokers, hypertensive men with high FEV1 showed more than a twofold increase in risk, and this increased to more than fourfold in hypertensive men with lower FEV1. The higher rates of stroke seen in men with lower FEV1 who were hypertensive were seen even when men with evidence of IHD (group 2) were excluded.
Risk Score for Stroke
A scoring system derived from logistic regression in this cohort using age, smoking, systolic blood pressure, and evidence of anginal chest pain (on WHO [Rose] questionnaire) has been produced to identify men at high risk of stroke.24 We used a model based on these factors and examined the stroke rate per 1000 person-years and the percent yield of strokes occurring in the top 20% of the risk score distribution, with and without FEV1 in the model (Table 5⇓). In the whole cohort, inclusion of FEV1 in the model provided only a small increase in yield and stroke rate per 1000 person-years. If the model is confined to hypertensive subjects (ie, men with systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥90 mm Hg or those on treatment for hypertension), the yield and stroke rate per 1000 person-years was also only slightly increased. Thus, even restricting the method to hypertensive subjects would only increase the rate of strokes in the high-risk fifth by 1/1000 person-years.
In this study of middle-aged British men, lower FEV1 was associated with an increased risk of stroke that in multivariate analysis was independent of age, smoking, physical activity, preexisting IHD, diabetes, antihypertensive treatment, and systolic blood pressure. The inverse association was apparent only in older men, current nonsmokers, hypertensive men, and those with preexisting IHD. The inverse association in nonsmokers, largely due to the increased risk in ex-smokers, persisted even when the degree of past smoking and secondary pipe or cigar smoking was taken into account. This suggests that lower FEV1 in this situation does not merely reflect the effects of smoking on lung function but may be an indication of an underlying ischemic myocardium. This possibility is supported by the fact that the inverse association between FEV1 and stroke is seen only in men with preexisting IHD (groups 2 and 3 separately) and not in men without preexisting IHD.
Another possibility as to why the relationship is only seen in ex-smokers may be due to the problem of residual confounding as a result of inaccurate measurements of past smoking habits. However, blood cadmium levels, which are considered to be a strong biological marker of smoking, have been shown in this cohort to relate strongly to smoking levels and to converge to the levels of never-smokers after 10 years of smoking cessation.16 17 It is recognized that cessation of smoking is associated with a reduction in risk of stroke, and ex-smokers in this study were shown to experience a reduction of risk in stroke.17 On the basis of recall of past smoking habits, we demonstrated that the benefit was dependent on quantity of cigarettes smoked in the past and not the number of years smoked. Ex–heavier smokers retained some increased risk compared with those who had never smoked, while ex–light smokers reverted to the level of never-smokers.17 However, the inverse association in ex-smokers persisted even when the degree of past smoking was taken into account, suggesting that the relationship seen in ex-smokers was not due to residual confounding. Residual confounding is also an unlikely explanation of the findings in hypertensive men, in whom a relationship between FEV1 and stroke was found in both current smokers and nonsmokers, and it is also unlikely to explain the findings in those with prevalent IHD. Furthermore, adjustment for smoking in the crude comparisons made only a modest difference in the relationships (Table 1⇑), suggesting that any residual confounding would be small and unlikely to explain the large differences observed in hypertensive and older subjects and those with prevalent IHD.
In the Whitehall Study of male civil servants aged 40 to 64 years at entry, there were 262 deaths due to stroke in 18 403 men during an average follow-up of 16.6 years. Men with FEV1 levels lower than 3.0 L were almost twice as likely to die of stroke as those with FEV1 levels of 3.5 L or greater, irrespective of blood pressure and apparently independent of smoking status and other risk factors, including IHD. We have identified five other cohort studies that examined the specific relationship between respiratory function and risk of stroke.6 7 8 9 11 In three of these—the Framingham Study (United States), the Gothenburg study (Sweden), and the Italian cohort of the Seven Countries Study—the relationship between lung function and stroke, although inverse, was not statistically significant at the 5% level after adjustment for the presence of confounding risk factors. The Framingham Study did not find FVC to be significantly related to stroke in either men or women in the multivariate analysis. In the present study FVC is strongly correlated with FEV1 (r=.83) and showed similar significant inverse relationships with stroke. In the Gothenburg study the relationship between FEV1 and stroke was of marginal significance (P=.08) after adjustment for smoking and other confounders. The lack of significance in both the male Gothenburg and the Italian cohorts may be due in part to the small number of stroke cases involved (57 and 68 cases, respectively). Indeed, in a recent report based on the same Italian cohort but with longer follow-up, FEV1 was shown to be significantly and independently (inversely) associated with stroke.11 Lung function expressed as peak expiratory flow has also been shown to be independently associated (inversely) with stroke in a Swedish cohort of women.7 Although FEV1 has been shown to be independently associated with stroke in multivariate analyses, the relationship has not been examined by levels of risk factors and, in particular, separately for normotensive and hypertensive subjects or separately for men with and without preexisting IHD. The Whitehall Study showed an inverse relationship between FEV1 and stroke in both smokers and nonsmokers at different levels of blood pressure. However, the Whitehall Study used the mean value of the two highest measures of these FEV1 estimations and did not use height-standardized FEV1 for individuals. This makes direct comparison with the present study difficult.
Other Potential Confounders
Reduced lung function may be a marker of physiological abnormalities such as polycythemia, which may predispose individuals to stroke.10 Although FEV1 was significantly associated with hematocrit in the present study (r=−.10), risk of stroke was only elevated in men with hematocrit levels of 51% or greater,25 constituting 2% of the cohort, and adjustment for elevated hematocrit made little difference to the significant inverse association seen between FEV1 and stroke. It has also been suggested that the increased risk may be associated with alcohol intake, which has been shown to influence both lung function26 and risk of stroke.23 However, the findings in this study were independent of alcohol intake.
Both FEV1 and FVC were significantly and inversely related to the risk of stroke, suggesting effects on both airway function and lung volume. Reduced lung volume may reflect impaired cardiac function due to occult coronary disease,1 and it has been shown that cardiac impairment is associated with an increased risk of stroke.27 28 The strong association seen in ex-smokers, hypertensive subjects, and men with preexisting IHD suggests that low FEV1 may be an early marker of ischemic myocardial disease, resulting in greater susceptibility to stroke, particularly in older men. This concept of FEV1 as a measure of physiological reserve capacity to withstand pathological insults to the cerebrovascular circulation seems tenable, particularly in view of the stronger inverse association between FEV1 and stroke in older and hypertensive subjects and in those with preexisting IHD. The pathophysiological mechanism(s) by which lower FEV1 may be associated with stroke is not clear. Myocardial ischemia may be associated with bronchial wall edema, which can lead to bronchial hyperresponsiveness and airway obstruction.29 30 Impaired lung function is associated with the development of hypertension,31 suggesting that the observed association between stroke incidence and lower FEV1 and FVC measured at baseline in our study might be due to strokes occurring in those who developed hypertension during the course of follow-up.
Risk Assessment in Hypertensive Subjects
In the study of Whitehall male civil servants, increased risk of stroke was associated with low FEV1 (<3.0 L) in each third of the systolic blood pressure distribution (<126, 126 to 142, and ≥143 mm Hg). It was suggested that the measurement of ventilatory function might be more useful than many conventional cardiovascular risk factors in guiding decisions about the management of mild hypertension (undefined). At present, it is widely recommended that the decision to treat subjects with elevated blood pressure with drugs should depend not only on the levels of blood pressure but on the estimated absolute risk of developing cardiovascular disease, taking other risk factors into account.32 33 34 35 Such recommendations do not always carry with them clear methods for estimating this risk, but they are available and could readily be used in both clinical practice and clinical trials, although they are not used for this purpose at present.24 36 37 When FEV1 is added as an additional factor to the scoring system already available for estimating risk of major stroke events based on smoking, systolic blood pressure, and presence of angina,24 there is only a small increase in absolute risk or yield of total events in the follow-up period. Despite the role that diminished lung function apparently plays in the risk of stroke, there would appear to be little value in adding it to the major risk factors already used in the various systems of risk assessment.
Since a higher FEV1 appears to be associated with lower risk of stroke in high-risk subjects, eg, those with preexisting IHD or hypertension, it would seem advantageous to maintain higher levels of FEV1. However, there seems a limited amount that one can do to prevent the progressive decline of FEV1 with increasing age, although the rate of decline of FEV1 will be less in those who never smoke or give up smoking early in life. Although lower levels of FEV1 are associated with increased risk of stroke, there is no indication that measurement of FEV1 is a useful adjunct in deciding whether to use drug treatment in a hypertensive subject, as proposed.
Selected Abbreviations and Acronyms
|FEV1||=||forced expiratory volume in 1 second|
|FVC||=||forced vital capacity|
|IHD||=||ischemic heart disease|
|WHO||=||World Health Organization|
The British Regional Heart Study is a British Heart Foundation Research Group and receives support from The Stroke Association.
- Received June 13, 1995.
- Revision received August 2, 1995.
- Accepted August 16, 1995.
- Copyright © 1995 by American Heart Association
Krzyzanowski M, Wysocki M. The relation of thirteen-year mortality to ventilatory impairment and other respiratory symptoms: the Cracow Study. Int J Epidemiol. 1986;15:56-64.
Cook DG, Shaper AG. Breathlessness, lung function and the risk of heart attack. Eur Heart J. 1988;9:1215-1222.
Ebi-Kryston KL, Hawthorne VM, Rose G, Shipley MJ, Gillis CR, Hole DJ, Carmen W, Eshleman S, Higgins MW. Breathlessness, chronic bronchitis and reduced pulmonary function as predictors of cardiovascular disease mortality among men in England, Scotland and the United States. Int J Epidemiol. 1989;18:84-88.
Persson C, Bengtsson C, Lapidus L, Rybo E, Thiringer G, Wedel H. Peak expiratory flow rate and risk of cardiovascular disease and death: a 12 year follow-up of participants in the population study of women in Gothenburg, Sweden. Am J Epidemiol. 1986;124:942-948.
Farchi G, Menotti A, Conti S. Coronary risk factors and survival probability from coronary and other causes of death. Am J Epidemiol. 1987;126:400-408.
Strachan D. Ventilatory function as a predictor of fatal stroke. BMJ.. 1991;302:84-87.
Menotti A, Lanti M, Seccarecia F, Gianpaoli S, Dima F. Multivariate prediction of the first major cerebrovascular event in an Italian population sample of middle-aged men followed up for 25 years. Stroke. 1993;24:42-48.
Shaper AG, Pocock SJ, Walker M, Cohen NM, Wale CJ, Thomson AG. British Regional Heart Study: cardiovascular risk factors in middle-aged men in 24 towns. Br Med J. 1981;283:179-186.
Shaper AG, Wannamethee G, Walker M. Alcohol and mortality in British men: explaining the U-shaped curve. Lancet. 1988;2:1266-1273.
Shaper AG, Wannamethee G. Physical activity and ischaemic heart disease in middle-aged British men. Br Heart J. 1991;66:384-394.
Cook DG, Shaper AG, Macfarlane PW. Using the WHO (Rose) angina questionnaire in cardiovascular epidemiological studies. Int J Epidemiol. 1989;18:607-613.5.
Macfarlane PW, Watts MP, Peden J, Lennox G, Lawrie TDV. Computer assisted ECG interpretation. Br J Clin Equip. 1976;1:61-70.
Cox DR. Regression models and life tables. J R Stat Soc B. 1972;34:187-220.
Shaper AG, Pocock SJ, Phillips AN, Walker M. Risk factors for stroke in middle-aged British men. BMJ. 1991;302:1111-1115.
Coppola WGT, Whincup PH, Papacosta O, Walker M, Ebrahim S. Scoring system to identify men at high risk of stroke: a strategy for general practice. Br J Gen Pract. 1995;45:185-189.
Lange P, Groth S, Mortensen J, Applegard M, Nyboe I, Jensen G, Schnohr P. Pulmonary function is influenced by heavy alcohol consumption. Am Rev Respir Dis. 1987;137:1119-1123.
Hermann B, Leyten ACM, Van Luijk, Frenken CWGM, Op de Coul AAW, Schulte BPM. An evaluation of risk factors for stroke in a Dutch community. Stroke. 1982;13:334-339.
Sparrow D, Weiss ST, Vokonas PS, Cupples LA, Ekerdt DJ, Colton T. Forced vital capacity and the risk of hypertension: the Normative Aging Study. Am J Epidemiol. 1988;127:734-741.
Sever P, Beevers G, Bulpitt C, Lever A, Ramsay L, Reid J, Swales J. Management guidelines in essential hypertension: report of the second working party of the British Hypertension Society. BMJ. 1993;306:983-987.
Jackson R, Barham P, Bills J, McLenan L, MacMahon S, Maling T. Management of raised blood pressure in New Zealand: a discussion document. BMJ. 1993;307:107-110.
Subcommittee of WHO/ISH Mild Hypertension Liaison Committee. Summary of 1993 World Health Organisation–International Society of Hypertension guidelines for the management of mild hypertension. BMJ. 1993;07:1541-1546.
Shaper AG, Pocock SJ, Phillips AN, Walker M. Identifying men at high risk of heart attacks: a strategy for use in general practice. BMJ. 1986;293:474-479.