(Stroke. 1996;27:2020-2025.)
© 1996 American Heart Association, Inc.
Articles |
Risk Factors for Cerebral Hemorrhage in the Era of Well-Controlled Hypertension
the Department of Epidemiology and Preventive Medicine, Monash Medical School, Alfred Hospital (A.G.T., J.J.M., A.F.), Prahran; and the Department of Neurology, Austin and Repatriation Hospitals, Heidelberg (G.A.D.), Victoria, Australia.
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Abstract |
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Background and Purpose Given that hypertension is now relatively well controlled and use of antiplatelet agents has increased, our primary aims were to investigate the risk of intracerebral hemorrhage (ICH) associated with hypertension and use of antiplatelet agents.
Methods In this city-wide case-control study, 370 consecutive cases of primary ICH, verified by CT or autopsy, were identified from one of 13 Melbourne hospitals. Ten subjects (or their next of kin) could not be located and 29 refused to participate, resulting in 331 eventual cases. Patients were aged between 18 and 80 years and had no prior stroke. Population-based control subjects were individually age- (±5 years), sex-, and geographically matched to subject cases. A questionnaire administered to participants (or next of kin) elicited information about prior exposure to various potential risk factors.
Results Hypertension approximately doubled the risk of ICH (odds ratio, 2.55; 95% confidence interval, 1.72 to 3.79). The use of aspirinlike drugs, in doses used for secondary prevention of ischemic stroke or cardiac disease, was not associated with an increased risk of ICH (odds ratio, 0.66; 95% confidence interval, 0.20 to 2.21). Factors associated with a reduced risk of ICH were a history of cardiovascular disease, arthritis, or high cholesterol level; being moderately overweight or using hormone replacement therapy; and drinking coffee.
Conclusions Hypertension was the most important risk factor for ICH but not as high as previously reported, nor was it higher than that reported for ischemic stroke. There was no evidence for any association between the use of aspirinlike drugs and ICH.
Key Words: Australia • case-control studies • cerebellar hemorrhage • intracerebral hemorrhage • risk factors
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Introduction |
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Intracerebral hemorrhage accounts for 10% to 15% of all strokes and is characterized by a high mortality rate (30% to 50% within the first month),1 2 3 4 with a high proportion (30%) of survivors being functionally incapacitated.2 Unfortunately, information about risk factors for ICH is limited,5 largely because of its relative infrequency and the clinical imprecision in diagnosis that preceded the introduction of CT.
The epidemiological studies conducted in the 1960s and early 1970s in which risk factors for ICH were examined relied on clinical criteria or autopsy findings to establish the diagnosis.6 7 8 This probably resulted in the selection of the more severe cases, which may have a different risk profile.9 More recent studies using a more reliable CT-based diagnosis have been limited by low statistical power10 11 12 13 14 15 16 17 18 19 and/or the inclusion among the cases of secondary causes of ICH,12 15 17 recurrent hemorrhages,19 20 and other pathological entities such as subarachnoid hemorrhage.14 18
Two important changes in medical practice highlight the need for a reexamination of risk factors for ICH. First, recent advances in antihypertensive medications and the consequent improved control of hypertension may have led to a reduced impact of hypertension on the risk of ICH. Second, the findings of a number of clinical trials in which aspirin was used as a form of prevention against vascular events have provided evidence that aspirin may predispose to ICH.21 22 Even if the contribution of these drugs to the risk of ICH is relatively small, their impact on public health could still be quite high given their widespread use in the community, particularly in the stroke-prone age groups.23
The primary aims of the present study were to determine whether the risk of ICH altered with smoking, hypertension, or the use of aspirinlike drugs in a case series including only first episodes of CT-proven primary ICH. This study provides the largest sample of ICH patients accrued for risk-factor analysis, involving 331 matched case-control pairs.
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Subjects and Methods |
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Case Subjects
Cases of ICH in Melbourne, Australia, occurring between 1990 and 1992 were identified by discharge record surveillance of 13 major city hospitals and regular inspection of the Coroner's Office reports. Melbourne has a population of approximately 3.5 million, and these hospitals manage most ICH cases occurring in the metropolitan area, with the exception of those occurring among already disabled nursing home residents.
An ICH was defined as a sudden onset of an acute focal neurological event with confirmation of intraparenchymal ICH, including brain stem and cerebellar hemorrhage, determined by CT (94.9% of cases), autopsy (4.8%), or MRI (0.3%). Case subjects included those patients from 18 to 80 years of age experiencing a first-episode primary ICH. Children with ICH were excluded because of the likely differing etiologies. Individuals over 80 years of age were excluded because of the difficulty in obtaining matched control subjects among this age group. Patients with hemorrhagic infarction (transformation) were not included; nor were those in whom the event was secondary to an arteriovenous malformation, tumor, or bleeding diathesis or followed the ingestion of sympathomimetic drugs; nor were those residing in nursing homes at the time of their stroke.
Control Subjects
Control subjects were identified from among those individuals living in the same neighborhood as the case subject because this allows for some degree of matching by socioeconomic status. Controls were recruited and interviewed by the nurse who interviewed the corresponding patient.
Neighborhood selection involved a nurse interviewer going to the same street address from which the case originated, starting with neighbors sequentially to the left, and attempting to identify the first individual of the same sex and age (±5 years) as the case subject. Repeated visits (up to three times) were made during evenings and weekends when there was no one at home during the day. To avoid the possibility of biasing toward the unemployed or those who were immobile for health reasons, it was always established that no potential control existed in a given dwelling before moving on to the next one. Weekly quality control meetings were conducted to monitor all procedures and response rates.
Ascertainment of Exposure to Risk Factors
A structured questionnaire, administered in person by trained research nurses, elicited information about exposures of interest. All questions related to the time period immediately preceding the stroke (cases) or interview (controls). On average, case subjects were interviewed at 6 to 7 months after their stroke, and control subjects were interviewed within 2 months of the case interview. Because case subjects were first seen after the occurrence of their ICH, information on previous medical illness could only be determined by history. Hypertension, previous cardiovascular disease, high cholesterol, arthritis, and diabetes were considered present when patients reported that their medical practitioner had advised them of their having the condition. Peripheral vascular disease was judged to be present if there was history of walking-induced calf pain that was relieved by rest.
A detailed history of medication use was also recorded. Use of oral contraceptives or hormone replacement therapy was considered present when the subject had used these medications at any time in their life. Aspirin and other NSAID use was deemed to be present when the subject had taken these drugs at any time in the 2-week period preceding their stroke (cases) or interview (controls). Care was taken to avoid accessing other information sources that might have led to ascertainment bias.
Self-reported height and weight data were used to calculate body mass index (kilograms per meter squared). We defined a current smoker as a person smoking at least one cigarette, cigar, or pipe per day for the previous 3 months and an ex-smoker as a person who had smoked this amount at one time in their life but did not smoke currently. Individuals were judged to be current drinkers when they self-reported drinking any amount of alcohol at the time of the stroke or interview and previous drinkers if they reported drinking alcohol in the past but were not current drinkers. Subjects were considered to have exercised if they had ever undertaken regular physical activity that caused breathlessness for a minimum of once a week at any time in their lives. All subjects were asked about their frequency of adding salt to food and drinking tea or coffee, whether they removed fat from meat or skin from chicken before eating, and whether they ever followed a vegetarian diet. Subjects were also asked whether they considered themselves to be "always busy doing things," have an "average approach to life," or were "very relaxed and easygoing" individuals, and also whether they considered themselves to have had a major crisis in their lives in the 12 months preceding the stroke (cases) or interview (controls).
The questionnaire had previously been validated with information from patients' medical records.24 An excellent level of agreement for the exposures under study has been reported (
=0.98).
Because of the nature of the disease, interviewers could not be blinded to the case-control status of the interviewee. However, subjects were not told of the specific hypotheses involved but were informed that this was a study of lifestyle factors and stroke.
Interviews for index cases were usually conducted in the presence of a spouse or other close relative. When an eligible patient had died (107 cases), was mentally impaired, or was dysphasic, information was obtained from the closest available relative or informant. Such proxy interviews were required in 43% of cases. To minimize information bias, matched control subjects for cases with proxy interviews were asked to nominate a relative (of a relationship similar to the case's proxy to the case), when available. This procedure was used in 31% of control interviews.
Scrutiny of all procedures for recent interviews occurred at weekly quality control meetings.
Statistical Analysis
Conditional logistic regression (using the EGRET25 software package) was used to compute ORs approximating the relative risks of ICH for various exposures. When information on a particular variable under investigation was missing, both the individual and the matched pair were excluded from the analysis.26 Initially univariate ORs were calculated for exposure variables of interest and potentially confounding variables. Confounding variables with a value of P
.10 were retained for use in multivariate analyses. Smoking and alcohol consumption were also controlled for in these analyses because of their association with other vascular diseases. CIs for ORs were based on large sample theory for conditional maximum likelihood estimators. Two-sided significance levels were used throughout.
The coefficient27 was used to test agreement between self-reported and medical history data on past illness.
Ethics
This study was approved by ethics committees at Monash University and each of the participating hospitals. Informed consent was obtained from each participant after explanation of the study purpose and methods by a nurse interviewer.
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Results |
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A total of 370 consecutive patients with ICH were identified from the participating hospitals. Ten cases had either moved and could not be located or, if deceased, had no known living relatives, and 29 refused to participate. This resulted in an eventual case series of 331 case subjects (89% participation). To obtain the same number of control subjects, 342 potential age- and sex-matched controls were identified, of whom 11 refused to participate (97% participation). The mean age was 63.4±12.4 years for both cases and controls. Over 90% of subjects were white, and 60% were men (Table 1
). Despite matching for socioeconomic status, there were more control subjects who had completed high school and more case subjects who had not attended high school. However, these differences were not statistically significant. Similar numbers of case and control subjects reported having a parent with a history of stroke, although a large number (79 cases and 46 controls) did not know their parents' medical histories.
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Table 2 summarizes the crude and adjusted ORs of ICH for all exposure variables maintained in the multivariate analysis. A history of hypertension was a significant predictor of ICH, with an OR of 2.55 (95% CI, 1.72 to 3.79). Comparison of self-reported hypertensive status of case subjects with information from their medical records produced a of 0.75 (95% CI, 0.68 to 0.82), indicating good agreement. Reports of a high cholesterol level, a history of cardiovascular disease, and being moderately overweight (a body mass index between 25 and 30 kg/m2) were associated with reduced risks of ICH, but regular exercise, smoking, and current alcohol consumption did not influence the risk of ICH.
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It is possible that self-reported height and weight data are not accurate; however, exclusion of body mass index from the multivariate model did not alter the results, and it has been retained in the model. Inclusion of age or level of education did not alter the outcome or interpretation of the results. Neither did the results alter according to the respondent status of the person interviewed (ie, index or proxy). Further categorization of proxies resulted in small numbers of respondents in some cells (Table 1
); further evaluation of this was not possible. Respondent-proxy agreement has been shown to be greatest when the proxy lives in the same house as the respondent.28 In the present study, 82% (3% unknown) of cases and 91% (6% unknown) of controls lived in the same house as the index, thus reducing the potential for bias introduced by proxy interviews.
Crude and adjusted ORs of ICH for previous illness and medication use are provided in Table 3. Individuals with diabetes or peripheral vascular disease had no added risk of ICH. Interestingly, having a history of arthritis appeared to be associated with a reduction in the risk of ICH (OR, 0.61; 95% CI, 0.42 to 0.90). Investigation of past medication use in women provided no evidence for an added risk of ICH with use of oral contraceptives, whereas hormone replacement therapy appeared to be associated with a reduced risk of ICH, although this was of only borderline significance (OR, 0.36; 95% CI, 0.14 to 0.95).
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Importantly, recent use of aspirin (at least 150 mg in the last 5 days) or NSAIDs (an equivalent dose in the last 2 days) was not associated with ICH (OR, 1.19; 95% CI, 0.71 to 1.97). Neither was any use of aspirin or other nonsteroidal anti-inflammatory drugs in the preceding 2 weeks associated with ICH. However, when regular doses totaling at least 750 mg aspirin (or equivalent in NSAIDs) were considered, a borderline increase in risk of ICH was observed (OR, 1.67; 95% CI, 0.97 to 2.88), while irregular use appeared to be associated with a reduced risk (OR, 0.48; 95% CI, 0.25 to 0.92).
Investigation of the subjects' culinary habits (Table 3) provided support for the notion that adding salt to food increases the risk of ICH (OR, 1.53; 95% CI, 1.05 to 2.22), while drinking coffee was associated with a reduced risk (OR, 0.64; 95% CI, 0.44 to 0.93). Other culinary habits such as removing fat from meat or skin from chicken before eating showed no association with ICH.
The outcome of the results of the primary hypotheses (ie, aspirinlike drugs, hypertension, and smoking) did not alter when taking into account the overall number of comparisons undertaken and when using the Bonferroni correction.29
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Discussion |
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The degree of risk of ICH imparted by hypertension has not been well studied in the post-antihypertensive era.5 Many studies were performed before CT diagnosis was available6 7 8 or involved relatively small numbers of cases.10 11 12 13 14 15 16 17 18 19 Among participants in the present study, a history of hypertension diagnosed by a physician was associated with a 2.55-fold increase in risk of primary ICH. This is less than that reported in many previous investigations8 13 17 20 but is of the same order as in some other recent studies.15 16 19 The ORs reported by earlier investigators might be unduly inflated because of the bias toward greater evaluation and diagnosis of hypertension among cases than controls. A further explanation might be that blood pressure control among hypertensive persons has improved since the time of the earlier studies. In support of this notion, 37% of control subjects in the present study reported a past history of hypertension compared with between 9.5% and 35% in previous studies.13 15 16 20 The possibility that this indicates both greater ascertainment and treatment of hypertension is supported by evidence from recent Australian surveys.30 An alternative reason for this higher proportion of hypertensives among control subjects may be that the definition of hypertension used in this study (ie, "ever told by a doctor" that they were hypertensive) has led to the inclusion of substantial numbers of mild or transient blood pressure elevations.
Although ICH is believed to be caused by hypertension-induced lipohyalinotic changes in penetrating blood vessels,31 the cause of ICH in the large group of cases reporting no prior history of hypertension (46%) remains unknown and deserves further study. It is possible that a proportion of these individuals were hypertensive but had not had their blood pressure checked. Scrutiny of case subjects' medical records showed that 32 of these "nonhypertensive" cases (21%) were diagnosed as hypertensive after their stroke and required ongoing treatment.
The observation that high dietary salt increases the risk of ICH may need to be viewed carefully given that investigation of dietary factors was not the primary aim of the study. However, there is biological plausibility in the results, since high salt intake may act to increase the risk of ICH through a hypertensive mechanism. The relative risk of ICH associated with high salt intake was higher in a previously reported study19 (OR, 3.14; 95% CI, 1.52 to 6.48) than in the present study (OR, 1.53), although the 95% CI in the previous study covers this OR. This difference in OR might result from a different definition of high salt intake or might be explained by the larger sample size in the present study.
It is reassuring that there was no evidence that accepted doses of aspirin, used for secondary prevention of ischemic stroke or cardiac disease, created any additional risk of ICH. There were, however, indications that aspirin and other NSAIDs may increase the risk of ICH at higher doses, although this finding was not statistically significant. These results are largely in keeping with those of several large-scale cohort studies and clinical trials21 22 32 33 34 35 36 37 that found a small increase in hemorrhagic stroke associated with aspirin use. In the US Physicians' Health Study22 the OR of "probable" hemorrhagic strokes associated with aspirin use was 2.14 (95% CI, 0.96 to 4.77), which is similar to that obtained in the present study. In studies using lower doses of aspirin, a small excess of hemorrhagic strokes in the treated group has been observed,36 37 but the small numbers of subjects involved did not allow for useful interpretation.
This study is the first to report that hormone replacement therapy is associated with a reduced risk of ICH in menopausal and postmenopausal women. It is possible that the decision to use hormone therapy may have been influenced by the presence or absence of important cardiovascular risk factors38 ; however, controlling for these possible confounding factors resulted in an OR similar to that obtained using univariate analysis. Although a number of studies have shown a protective effect of hormone replacement therapy on the risk of cardiovascular disease, contradictory evidence still exists for an effect of such therapy on the risk of ischemic stroke.39 40 Further support of this finding from other studies is eagerly awaited.
Interestingly, individuals who had ever been told that their cholesterol was high appeared to have approximately half the risk of ICH of those whose cholesterol level had either not been measured or had been measured and was known to be low. Although a self-reported history of high cholesterol is a relatively crude measure of plasma cholesterol, the validity of the result is assisted by the relatively high level of screening for hyperlipidemia undertaken by general practitioners in Australia since the early 1980s.41 A previous study42 has shown that low plasma cholesterol levels confer an increased risk of ICH, but this is the first study, using CT-verified cases of ICH, to provide evidence that high plasma lipid levels may be associated with a reduced risk of ICH. If so, it would appear that cholesterol bears a relation to a hemorrhagic tendency that exists throughout the normal range. This is supported by experimental findings that cholesterol may protect against medial necrosis in rats43 44 ; however, this suggestion is entirely speculative. Alternatively, either case or control subjects may have responded positively because of a previously elevated triglyceride level, and this may have influenced the results.
Unlike ischemic strokes, for which smoking is a well-established risk factor,45 there was no observed association between smoking and ICH in the present study. Previous studies vary in support of this finding, with some studies reporting no association between smoking and ICH,6 8 11 13 16 46 one reporting a decreased risk,47 and two studies reporting increased risks.48 49 The large numbers of unspecified hemorrhages in the latter two positive studies48 49 are likely to include many subarachnoid hemorrhages. Because smoking is reported to increase the risk of this type of stroke,50 51 52 the inclusion of subarachnoid hemorrhage may explain the positive results observed. The present study confirms the finding of no association between smoking and ICH reported in some previous studies, although it was previously unclear whether this lack of association was due to low statistical power. Even though a recent meta-analysis reported a protective association between smoking and ICH,53 the analysis was largely influenced by one study with a similar association. The criteria for inclusion of studies in this meta-analysis are unclear and may not be limited to studies using CT for in vivo diagnosis.
Individuals with arthritis and previous cardiovascular disease were apparently protected from ICH. An explanation for this observation may be that patients with a diagnosed illness requiring regular medical intervention are more intensively investigated and managed. It is possible that these findings may also be due to ascertainment bias because of the time delay in interviewing case subjects. However, questions were carefully limited to include objective rather than subjective questions so that the potential for this type of bias was minimized.
There are a number of potential biases that may have influenced the results of this study. Many of these have already been mentioned; however, one further potential bias may have occurred if exposure variables were misclassified. This type of bias has the potential to alter the OR in either direction.
It was of interest that several lifestyle factors that may potentially affect blood pressure levels were associated with an increased risk of ICH. Specifically, this included having a busy disposition and self-reporting a recent crisis. Although these associations appear to be biologically plausible, potential biases associated with focused recall among affected case compared with control subjects should be considered for any study of this type.26
In summary, a large number of potential risk factors for ICH have been quantified in the present study using 331 first-episode primary ICH cases and the same number of age- and sex-matched controls. A Bonferroni correction29 does not alter the outcome or the interpretation of the results for the primary hypotheses (aspirinlike drugs, hypertension, and smoking), although the number of overall comparisons should be considered carefully when attempting to interpret the results of the other factors. Most importantly, however, this study has provided evidence that the risk factor profile for ICH appears to be different in many ways from that of ischemic stroke, thus emphasizing the different underlying mechanisms between these two stroke subtypes.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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The study was made possible by financial support from the Victorian Health Promotion Foundation, the Alfred Hospital Research Fund, and the Australian Stroke and Neuroscience Institute. We would also like to acknowledge the assistance of research nurses Judy Snaddon, Belinda Muir, Fiona Ellery, and Annie Crowe, as well as the computer assistance of Lichun Quang.
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Footnotes |
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Reprint requests Dr A. Thrift, Department of Neurology, Austin and Repatriation Medical Centre, Studley Rd, Heidelberg, Victoria 3084, Australia. E-mail thrift@austin.unimelb.edu.au.
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Appendix |
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Participating Individuals and Centers
Dr Judith Frayne (Alfred Hospital), Prof Geoffrey Donnan (Austin Hospital), Alan Davis (Boxhill Hospital), R. Evans (Dandenong Hospital), Prof Stephen Cordner (Coroner's Offices), Denis Hogg (Epworth Hospital), Dr Brian Chambers (Heidelberg Repatriation Hospital), Dr Malcolm Horne (Monash Medical Centre, Prince Henry's Hospital), Dr Alan Sandford (Preston and Northcote Hospital), Prof Stephen Davis (Royal Melbourne Hospital), J. Clarebrough (St Vincent's Private Hospital), Prof Edward Byrne (St Vincent's Hospital), and Dr Mary Stannard (Western Hospital).
Received May 17, 1996; revision received July 29, 1996; accepted August 9, 1996.
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