Historical Risk Factors for Stroke: A Case Control Study

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1 Historical Risk Factors for Stroke: A Case Control Study DAVID A. SPRIGGS, JOYCE M. FRENCH, JUDITH M. MURDY, DAVID BATES, OLIVER F. W. JAMES Summary The aim of this study was to determine the risk factors for admission to hospital with stroke by means of a case-control study recruiting age- and sex-matched controls from the local community. Four hundred pairs of patients and controls were recruited. Of historical factors, preceding cerebrovascular disease contributed the greatest odds of stroke (odds ratio 9.8). Taking prescribed medicines (odds ratio 2.6), regular snoring (odds ratio 3.2), smoking (odds ratio.7) and some factors in the family history were also significant risk factors. Introduction The burden of stroke is enormous in personal terms and because of the financial resources devoted to the care of the stroke victim [-2]. In 969 it was suggested that since the incidence of strokes at various ages mirrored so closely the overall mortality at those ages the disease could be considered a direct effect of ageing and was therefore not susceptible to preventive measures [3]. Since then this view has been contradicted by the apparent decline in mortality from stroke and in its incidence reported in the USA [4, 5]. Unfortunately, other studies and projections from USA and Europe have been less sanguine about current morbidity and mortality of stroke and about future projections [6]. Notwithstanding this uncertainty, it is clearly important to examine risk factors for stroke in the hope not only of identifying those at greatest risk, but of indicating which risk factors may be amenable to change thus preventing stroke [7]. The identification of risk factors associated with a disease such as stroke can be achieved either by a longitudinal or a case-control study [8]. The advantages of the case-control method are the avoidance of prolonged follow-up of subjects and the relatively small numbers of subjects required for the study. The aim of this study was to examine, in a case-control manner, the major risk factors contributing to stroke in an unselected group of patients admitted to hospital with an acute stroke by comparing these individuals with age- and sex-matched controls from the local community. Methods The definition of stroke was that used by the WHO [9] 'rapidly developing clinical signs of focal (or global) disturbance of cerebral function, lasting for more than 24 hours or leading to death, with no apparent cause other than of vascular origin'. Subjects la) Stroke patients: All patients admitted between April 987 and May 988 (inclusive) to the three Age and Ageing 990,9:

2 HISTORICAL RISK FACTORS FOR STROKE 28 acute general hospitals in Newcastle upon Tyne within 7 days of the onset of symptoms attributable to stroke and who lived within the city of Newcastle and the adjacent counties of Tyne and Wear and Northumberland were entered. The patients were assessed and interviewed by one investigator (D.A.S.)- Where necessary and possible, a relative or carer was interviewed. Family doctor records were not examined. The following patients were excluded: patients admitted while the interviewer (D.A.S.) was on leave; patients with subarachnoid haemorrhage; subjects on whom insufficient data were available; non-caucasians. (b) Control subjects: The controls were selected from the register of patients of the family doctor for each stroke propositus. Each patient was matched for sex and for date of birth (+ 2 years) with a control. Controls were the next, unrelated, matching individual to the propositus in the register. If this individual was subsequently excluded, the next eligible individual in the register was selected. Each control was initially contacted by letter and interviewed usually at home. Data were obtained from relatives where possible and applicable. The family doctor records were not examined. The study received the approval of the Newcastle District Joint Ethical Committee. Data collection All subjects were personally interviewed using identical questionnaires, the results being recorded on a specially designed pro forma. A history of cerebrovascular disease was taken as a history of either stroke or transient ischaemic attack (TIA), a history of ischaemic heart disease (IHD) was a positive history of either myocardial infarction or angina. The family history was taken by asking the subject or his relatives whether they knew of any first-degree relative with the examined conditions. Electrocardiographic examination was performed only on the patients and is therefore not discussed in this paper. As a measure of obesity we used the Body Mass (Quetelet's) Index (BMI) (weight/height 2 ), obesity being defined as BMI > 30 kg/m [2, 0]. To assess snoring habits our subjects (patients and controls) or their co-habiters or relatives were asked the question: 'How often do you snore?'. Their responses were recorded as: 'never', 'occasionally', 'often' or 'almost always'. Those responding either 'often' or 'almost always' were considered to be 'regular snorers'. Where possible, information was confirmed with a regular sleeping partner. Expression of results and statistics The risk factors studied were divided into four main groups previous medical history, treatment, lifestyle and family history. In order to express the possible risk for the various factors we have used the odds ratio []. The odds in any group are the probability of the event happening compared with the probability of that event not happening. The ratio of the odds in exposed to unexposed risk groups is the odds ratio. The amount of disease attributable to a particular risk factor in the community at large bearing in mind the size of the odds ratio and the prevalence of that risk factor in the community studied is the 'population-attributable risk percent' [2]. This is equivalent to the 'population-attributable fraction' used by the Framingham group [3]. All recorded data were transferred to the Northumbria Universities Multiple Access Computer (NUMAC). Analysis of the data used SPSS X (SPSS X Batch System, SPSS Inc., Chicago, Illinois, USA). Discrete variables were analysed using the % 2 test with Yates' correction where appropriate. Paired testing with McNemar's test gave very similar results to the '/} test and so will not be considered further. The non-parametric Wilcoxon matched-pairs signed-ranks test was used for the paired comparison of age. A local programme for the calculation of odds ratios and attributable risk was written by J.M.F. As the increase in odds ratios follows an exponential pattern they are graphically represented on a logarithmic scale. Results Four hundred stroke patients (75 men, 225 women) and their controls were recruited. The mean age of patients was 72.5 years (median 74, range 33-97), and of controls 72.9 years (median 74, range 34-98). Table I shows the numbers exposed to each risk factor studied in the patient group and the controls and the y 2 p value for each variable. Figure shows the odds ratios for each variable and the population attributable risk o is displayed in Figure 2. The mean difference between the age of the patient and the paired control = 0.40 years (range 2 to + 3) (p, Wilcoxon). Median difference =0 years. This difference is entirely attributable to the delay between the recruitment of patients and of their community controls.

3 282 D. A. SPRIGGS ET AL. Table I. Numbers of patients and controls (with percentages) exposed to each variable Patient Control Variable n No. with risk factor (%) n No. with risk factor (%) P Previous medical history Ischaemic heart disease Atrial fibrillation Treatment On tablets On antihypertensives Lifestyle Regular snoring Ever smoked Current smoking Drinking alcohol BMI 3s3O Family history Ischaemic heart disease p value by /} test The reasons for exclusion from the sample population are given in Table II; 32 stroke victims were excluded but 92.6% of strokes initially assessed were included. We attempted to approach 567 controls; 67 were not included (7.% inclusion rate). In 34 other cases the family doctor register was incorrect (7 were subsequently found to have died, 5 had moved, one wrong sex and one wrong date of birth). Details of snoring habits were obtained for 326 patients and 345 controls, we obtained information from sources other than the patients or controls from relatives/cohabiters of 55 (38.8) 70(42.6) 77(9.3) 70(42.6) 43 (0.8) 22(5.5) 66(6.5) 37(79.8) 87(47.0) 88(57.7) 265 (67.) 46(37.0) 2 (53.7) 23 (5.2) 24(37.9) 56(47.7) 2(3.7) 32(9.8) 30(9.2) 0(3.) (6.0) 70(9.5) 24 (6.0) 3 (28.4) 7(4.3) 5(.2) 3 (7.8) 242 (60.5) 37(34.2) 04(30.) 255 (63.8) 0 (25.3) 305 (76.3) 52(3.6) 90 (22.7) 8(29.7) 9(2.3) 23 (5.8) 26(6.5) 9(2.3) < patients and 78 controls. This information corroborated that of patients or controls in almost every case. Figure 3 shows the odds ratio for stroke in those who always snore, those who regularly snore and all who snore versus nonsnorers. The prevalence of regular snoring in the control population was 3 % giving a population attributable risk of stroke for regular snoring of 8.8%. Discussion The three major types of stroke, infarcts,

4 HISTORICAL RISK FACTORS FOR STROKE 283 Previous medical histor) Ischaemic heart disease Peripheral vascular diseav Atrialflbnllatkxi Treatment On tablets On antihvpertensives Lifestyle Regular snonng Ever smoked Current smoking Drinking alcohol I [ BM230 Family hislory Ischacmic heart disease I H I I Log scale -» Increasing odds of stroke Figure I. The odds ratio of the patients to the controls. The horizontal bars show 95 O confidence intervals. haemorrhages and lacunar strokes may have different risk factors, but it is not possible to distinguish these clinically. The Guy's Hospital score [4] does not allow an accurate distinction to be made between infarcts and haemorrhages, the only reliable way to make the distinction being by computerized tomography (CT). This technique was not available to us. It is most important, when considering risk factors, to distinguish between a marker of risk and a causative factor. The present study allows us to claim an association between the variables concerned and admission to hospital with a stroke. Some of the factors we believe have a causal role, for instance hypertension, while others, for example peripheral vascular disease are presumably not causally related to stroke but share a common aetiology and are therefore merely markers of risk. It is for this reason that we have not attempted a multivariate analysis of the results. Some epidemiological studies of stroke have concentrated on the first stroke [ 5] rather than including those with second or subsequent strokes. It is suggested that this allows the recruitment of a purer group of stroke victims and the confounding influence of the survival from previous stroke can be avoided [6]. This claim depends on the accurate identification of the first stroke retrospectively which even with CT scanning may be difficult [7]. We have included subjects with a previous history of cerebrovascular disease as they are a significant group of stroke victims (38 O patients have previously suffered a stroke or TI A) and, as the incidence of further stroke is about 8 o -ll o per year [8] for those with a previous stroke and about 4 0 per year for TIA [9], these subjects represent an important group for the secondary prevention of stroke. Whilst it may be argued that those patients admitted to hospital with stroke are not representative of stroke patients as a whole, Wandless [20] demonstrated that 68 O individuals over age 65 sustaining a stroke in a defined local

5 28 4 D. A. SPRIGGS ET AL. Previous medical history Ischaemic heart disease Atnal fibrillation Treatment On tablets Onantihvpertcnsives Lifestyle Regular snoring Ever smoked Current smoking BMIS30 r amily history Ischacmic heart disease ZH 3 ] j nfl i i i Drinking alcohol : ] u D Population attributable nsk % Figure 2. The population attributable risk % admission to hospital with stroke. Tyneside population were admitted to hospital. There was no suggestion that patients remaining at home following stroke were 'different' from those admitted to hospital except as regards severity of stroke (more patients with impaired consciousness admitted to hospital), and age and social circumstances (mean age of hospital admissions older, more lived alone). for n=33alwavsi> none n=560 Regular v. none n=67 Any v. none L » Log(lncreasingoddsofstrokemsnorers) Figure 3. The odds ratio of regular to non-regular snorers in patient and control groups by variables. A previous history of cerebrovascular disease greatly increased the odds of suffering a stroke as did IHD and peripheral vascular disease (PVD). These factors were found to have a similar prevalence in our patients to that recently reported from Oxford IHD in 38% and PVD in 25% of the Oxfordshire community stroke project subjects [2], versus 38.8% and 9.3%, respectively, in the present study. These conditions are related to hypertension which conferred a relatively modest odds of stroke. However, when the prevalence of a history of hypertension was considered, the risk of stroke attributable to hypertension was considerable. This is much less than the risk seen in some other studies [22] which may be explained by the older age group of our subjects (Grimley Evans has shown that hypertension does not confer an increased risk of stroke in the elderly women in a local population [23]) and also by the fact that, because of the nature of the study, we sought a retrospective history of hypertension from the subjects rather than a measurement of blood pressure. However, the preval- Table II. Reasons for exclusion from the patient and control groups Patients Controls I h Diagnosis changed 3 Lack of information Lived too far away 4 Xon-Caucasian Refused 88 Could not be traced 36 GP advised against approach 9 Unable to answer questions 4 Carer refused 4 Non-Caucasian 3 pairs excluded owing to failure to match ages adequately

6 HISTORICAL RISK FACTORS FOR STROKE 285 ence of a history of hypertension in our subjects was comparable to that in Oxfordshire where family doctor records were used. Other prospective studies from America have shown that diabetes [24] and atrial fibrillation [25] increase the risk of stroke. The present data suggest that the risk is not as great in our population as in those studies. Furthermore, as the prevalence of atrial fibrillation and diabetes in the local community was apparently low, these factors only conferred a relatively small population-attributable risk percentage. Interestingly, epilepsy greatly increased the odds of stroke, this has been previously reported [26] and is being investigated further. Again the low prevalence of epilepsy in our control population accounts for the very small attributable risk per cent. The fact of being prescribed medicine increased the odds of being admitted to hospital with a stroke and thus conferred an enormous attributable risk due to high prevalence of prescribed medicine in the elderly. This supports the contention of Ostfeld [27] that it is the sick elderly who suffer stroke rather than the fit elderly and it is to be hoped that the therapy is a marker of risk rather than a cause of stroke. The prescription of antihypertensive medication conferred a similar risk of stroke as the history of hypertension despite the fact that 50 patients and 25 controls who had a history of past hypertension were not being treated at the time of stroke or interview presumably because the blood pressure had settled. This supports the hypothesis that stroke in the elderly reflects not so much present causes of vascular disease as causes which occurred in the past [28]. It has been suggested that starting or changing antihypertensive medication increases the immediate risk of stroke by precipitating a sudden fall in blood pressure [29], only four ( 0 ) patients and two (0.5 o ) controls had their antihypertensive medication changed within 3 days of stroke or interview (XS). We have shown that snoring contributed greatly both to the individual's odds of stroke but also to the community risk. This has been seen in some other studies which have recently been reviewed [30], but the present study has recruited many more patients than previous studies. Our definition of snoring was based on the responses to a simple question as to whether or not the respondent snored. This is the only pragmatic definition that can be applied to large community studies, and we accept that there was no independent validation of the responses. This may be one explanation for the higher prevalence of regular snoring in the population studied (3 ' o of control population) than in some other studies [30]. However, our population is different in some other respects particularly the high median age range of the subjects. Previous epidemiological studies on snoring have shown an increased incidence of snoring in the older age groups [3]. It is strange that no clear consensus has appeared as to the risk of stroke in smokers [32], our data suggest an increased odds of stroke in current smokers but not in ex-smokers. These results are in keeping with a recent metaanalysis on the relationship between smoking and stroke [33]. Alcohol consumption seemed to protect from stroke. There is a lack of agreement in recently published data on the relationship between alcohol and stroke [34, 35]. As none of the stroke victims in this study claimed to be a heavy drinker and none had a history of a 'binge' before the stroke this would be in keeping with the recognized U-shaped mortality curve in drinkers. This apparent protective effecfmay be artefactual [36], either because heavy drinkers did not reach the strokeprone age group or because previous heavy drinkers entered the non-drinking group and conferred on that group the risks associated with their past drinking habits. Obesity did not seem to be related to stroke although the collection of data, particularly from the patients is incomplete due to the difficulties in obtaining height and weight measurements in the severely ill and disabled. We must stress the possibility of reporting bias with regard to family history, but notwithstanding this a family history of cerebrovascular disease, IHD and hypertension all conferred a significantly increased odds of stroke and in the first two of these a substantial attributable risk. A family history of stroke has been shown to increase the risk of cerebral haemorrhage in Japan [37] but this does not, of course, necessarily imply a genetically linked aetiology [38]. In conclusion, although there are unavoid-

7 286 D. A. SPRIGGS ET AL. able methodological flaws in our study, notably the lack of validation of some data independently from subjects and their relatives we believe that this is the first major European case-control study of risk factors in stroke. References. Drumond MF, Ward GH. The financial burden of stroke. In: Stroke: epidemiological, therapeutic and socio-economic aspects. International Congress and Symposium Series Number 99. London: Royal Society of Medicine, Dombovy ML, Bashford JR, Whisnant JP, Bergstrahl EK. Disability and use of rehabilitation services following stroke in Rochester Minnesota, Stroke 987;8: Kurtzke JF. Epidemiology of cerebrovascular disease. Berlin: Springer Verlag, Garraway W, Whisnant J, Drury I. The continuing decline in the incidence of stroke. Mayo ClinProc 983;58: Klag MJ, Whelton PK, Seidler AJ. Decline in US stroke mortality. Stroke 989;20: Malmgren R, Bamford J, Warlow C, Sandercock P, Slattery J. Projecting the number of patients with first ever strokes and patients newly handicapped by stroke in England and Wales. Br Med J989;298: Evans J Grimley. The decline of stroke. In: Stroke: epidemiological, therapeutic and socioeconomic aspects. International Congress and Symposium Series Number 99. London: Royal Society of Medicine, Kramer MS. Clinical epidemiology and biostatistics. Berlin: Springer Verlag, Aho K, Harmsen P, Marquardsen J, et al. in the community: results of WHO collaborative study. Bull WHO 980;58:l Truswell AS. Obesity: diagnosis and risks. In: Truswell AS. ABC of nutrition. Br Med J 98S;29: Armitage P. Statistical methods in medical research. Oxford: Blackwell Scientific Publications, Cole P, MacMahon B. Attributable risk percent in case-controlled studies. Br J Prev Soc Med 97;25: Wolf PA, Kannell WB, McGee DL. Prevention of ischaemic stroke. In: Barnett HJM, Stein BM, Mohr JP, Yatsu FM, eds. Stroke; pathophysiology, diagnosis and management. New York: Churchill Livingstone, Sandercock PAG, Allen CMC, et al. Clinical diagnosis of intracerebral haemorrhage using Guy's Hospital Score. Br Merf7985;29: Bamford J, Sandercock PAG, Dennis M, et al. A prospective study of acute cerebrovascular disease in the community: the Oxford Community Stroke Project : I. Methodology, demography, and incident cases of first ever stroke. J Neurol Neurosurg Psychiatry 988;5: Sackett DL, Haynes RB, Tugwell P. Clinical epidemiology: a basic science for clinical medicine. Toronto: Little Brown, Harrison MJG, Marshall J. Evidence of silent cerebral embolism in patients with amaurosis fugax. J Neurol Neurosurg Psychiatry 977;4O: Marquardsen J. Natural history and prognosis of cerebrovascular disease In: Ross Russell RW, ed. Vascular disease in the central nervous system. 2nd edn. Edinburgh: Churchill Livingstone, UK-TIA Study Group. United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: interim results. Br MedJ 988;296: Wandless I. Hospital referral in acute stroke. Public Health 983;97: Sandercock PAG, Warlow CP, Jones LN, Starkey IR. Predisposing factors for cerebral infarction: the Oxford Community Stroke Project. Br Med J\989;289: Davis PH, Dambrosia JM, Schoenberg BS, et al. Risk Factors for ischaemic stroke: a prospective study in Rochester, Minnesota. Ann Neurol 987;22: Evans JG. Blood pressure and stroke in an elderly English population. J Epidemiol Community Health 987;4: Abbott RD, Donahue RP, MacMahon SW, et al. and risk of stroke. JAMA 987,257: Wolf PA, Abbott RD, Kannell WB. Atrial fibrillation: a major contributor to stroke in the elderly. Arch Intern Med 987;47: 56^. 26. Shinton RA, Gill JS, Zezulka AV, Beevers DG. The frequency of epilepsy preceding stroke. Lancet 987;i:l Ostfeld AM, Shekelle RB, Klawans H, Tufo HM. Epidemiology of stroke in elderly welfare population. Am J Public Health 974;64: Evans JG, Prudham D, Wandless I. Risk factors for stroke in the elderly. In: Barbagallo-Sangiorgi G, Exton-Smith AX, eds. The ageing brain: neurological and mental disturbances. New York: Plenum Press, Jansen PAF, Schulte BPM, Meyboom RHB, Gribnau FWJ. Antihypertensive treatment as a

8 HISTORICAL RISK FACTORS FOR STROKE 287 possible cause of stroke in the elderly. Age Ageing 986;5: Waller PC, Bhopal RS. Is snoring a cause of vascular disease. Lancet 989;i: Mondini S, Zucconi M, Cirignotta F, et al. Snoring as a risk factor for cardiac and circulatory problems: an epidemiological study. In: Guilleminault C, Lugaresu E, eds. Sleepjwake disorders: natural history, epidemiology and longterm evolution. New York: Raven Press;983; Wolf PA. Cigarettes, alcohol and stroke. N Engl JM«^986;35: Shinton R, Beevers G. Meta-analysis of relation between cigarette smoking and stroke. Br MedJ 989;298: Gill JS, Zezulka AV, Shipley MJ, et al. Stroke and alcohol consumption. N Engl J Med 986;35: Gorelick PB, Rodin MB, Langenberg P, et al. Is acute alcohol ingestion a risk factor for ischaemic stroke. Stroke 987;8: Anonymous. Alcohol and mortality: the myth of the U-shaped curve. Lancet 988;ii: Okada H, Horibe H, Ohno Y. et al. A prospective study of cerebrovascular disease in Japanese rural communities, Akabane and Asahi. Stroke 976;7: Narowicz M, Kelley RI. Mendelian etiologies of stroke. Ann Neurol 987;22: Authors' addresses D. A. Spriggs, J. M. Murdy, O. F. W. James* Department of Medicine (Geriatrics), J. M. French, D. Bates Department of Neurology, University of Newcastle upon Tyne, Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH * Address correspondence to Professor O. F. W. James Received in revised form 2 March 990