Tetrahydroaminoacridine in Alzheimer's disease. Int Y Genatr Psychiaty 36 Brink TL, Yesavage JA, Lum 0, Heersema P, Adey M, Rose TL.
, Rose TL. Screening
Royal Brompton National
Heart and Lung Hospital,
London SW3 6NP
Ann K Sullivan, research
registrar in cardiology
Diana R Holdright, registrar
in cardiology
Christine A Wright, research
sister
Jane L Sparrow, research
technician
David Cunningham, director
of biomedical engineering
Kim M Fox, consultant
cardiologist
Correspondence to:
Dr Diana R Holdright,
London Chest Hospital,
Bonner Road, London
E2 9JX
BMY 1994;308:883-6
BMJ VOLUME 308 2APRIL1994
1990;5:317-21.
22 Forsyth DR, Surman DJ, Morgan RA, Wilcox GK Clinical experience with
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Chest pain in women: clinical, investigative, and prognostic features
Ann K Sullivan, Diana R Holdright, Christine A Wright, Jane L Sparrow, David Cunningham,
Kim M Fox
Abstract
Objective-To characterise clinical, investigative,
and prognostic features of women referred with
chest pain who subsequently underwent coronary
angiography.
Design-Analysis of all women with angina
referred to one consultant during 1987-91 who
subsequently underwent coronary angiography, with
follow up to present day.
Setting-Cardiothoracic centre.
Subjects-Women with normal coronary arteries;
women with coronary artery disease shown on angio-
graphy; men with coronary artery disease matched
for age; men referred with chest pain during the same
period subsequently found to have normal coronary
arteries.
Main outcome measures-Risk factor analysis;
results of exercise testing and coronary angiography;
intervention; morbidity and mortality.
Result.-Women comprised 23% (202/886) of
patients referred with chest pain who subsequently
underwent angiography. 83/202 women had normal
coronary angiograms compared with 55/684 men
(41% v 8%, P<0*001). Diabetes mellitus was the only
risk factor more firequently encountered in women
with coronary artery disease (P-0.001). The specifi-
city and positive predictive value of exercise testing
before angiography were significantly lower in
women than men (71% v 93%, P<0*001 and 76% v
95%, P< 0*001, respectively). Revascularisation pro-
cedures were as common in women with coronary
artery disease as in men (81 (68%) v 70 (59%)),
and there was no difference in event rate during
follow up. Many patients with normal coronary
arteries, irrespective of sex, had symptoms
during follow up (61 (73%) women, 36 (65%) men)
and continued to take antianginal drugs (27 (33%)
women, 14 (28%) men); 14 (17%) women and six
tests for giatric depression. Cinicl Gerontologist 1982;1:37-43.
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Abnormal and Social Psychologo 1941;36:3-33.
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ologicsl Corporation, 1981.
39 Cohen J. Statistical potwer anaysis of the behavioural sciences. Revised edition.
NewYork: Academic Press, 1977.
40 Wurtman RJ, Blusztain JK, Growdon JH, Ulus IH. Cholinesterase inhibitors
increase the brain's need for free choline. In: Giacobini E, Becker R, eds.
Cunent reearch inAlzheimer therapy. New York: Tsylor snd Frsncis, 1988.
41 Beller SA, Oversll JE, Rhoades HM, Swann AC. Long-term outpatient
trestment of senile dementia with oral physostigmine. Y Clin Psychiatry
1988;49:400-4.
42 Peters BH, Levin HS. Effects of physostigmine and lecithin on memory in
Alzheimer's disease.Ann Neurol 1978;6:219-21.
43 Kraemer HC, Peabody CA, Tinklenberg JR, Yesavage JA. Mathematical and
empirical development of a test of memory for clinical and research use.
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44 Applegate WB, Blass JP, Williams TF. Instruments for the functional
assessment of older patients. NEngljMed 1990;322:1207-14.
45 Wilcock GK, Surmon DJ, Scott M, Boyle M, Mulligan K, Neubauer KA, et
aL An evaluation of the efficacy and safety of tetrahydroaminoacridine
(TIHA) without lecithin in the treatment of Alzheimner's disease. Age and
Aging 1993;22:316-24.
46 Gauthier S, Bouchard R, Lamontsgne A, Bailey P, Bergman H, Ratner J, et aL
Tetrahydroaminoacridine-lecithin combination treatment in patients with
intermediate-stage Alzheimer's disease. NEnglJMed 1990;322:1272-6.
47 Summers WK, Tachiki KH, Kling A. Tacrine in the treatment of Alzheimer's
disease. EurNeurol 198929:28-32.
48 Ames DJ, Fraser JRE, Bhathal PS, Gibson PR, Davies BM, Roberts S.
Heterogeneity of adverse hepatic reactions to tetrahydroaminoacridine. Aust
NZjMedicine 1990;20:193-5.
49 Hammel P, Larrey D, Bemuau J, Kalafat M, Freneaux E, Babany G,
et aL Acute hepatitis after tetrahydroaminoacridine administration for
Alzheimer's disease.jClin Gastroenterol 1990;12:329-31.
(Accepted 7February 1994)
(11%) men required hospital readmission for severe
symptoms.
Conclusions-In this series, although women
comprised the minority of patients referred with
chest pain, a diagnosis of normal coronary arteries
was five times more common in women than men.
Risk factor analysis and exercise testing were of
limited value in predicting coronary artery disease in
women. There was no sex bias regarding revascu-
larisation procedures, and outcome was similar. A
diagnosis of non-cardiac chest pain in patients with
normal coronary arteries was of litde benefit to the
patient with regard to morbidity.
Introduction
Chest pain in women is a commonly encountered
condition which accounts for an appreciable number of
referrals to cardiologists for further evaluation.' The
symptom of chest pain has many causes which may or
may not be cardiac in origin, and difficulty arises in
establishing whether or not the patient's symptoms
can be ascribed to reversible myocardial ischaemia.
Coronary angiography is the criterion for establishing a
diagnosis of coronary artery disease.
The reasons for referral for cardiac investigation are
multifactorial and generally take into account the
severity of the symptoms and the perceived likelihood
of coronary artery disease. For example, increasing age
and the presence of several recognised risk factors for
coronary artery disease would tend to lower the
threshold for referral. Patients with positive results on
an exercise test are more likely to be further investi-
gated, but ST segment shift with exercise is a less
specific marker of coronary artery disease in women.>
Many patients referred with chest pain for investi-
gation undergo coronary angiography. However,
coronary angiography carries a small but well docu-
883
 mented risk of complications and consequently should
be reserved for those patients most likely to have chest
pain of cardiac origin.5
Interest is growing in the management and health
care of women with suspected or proved coronary
artery disease. Indeed, in the United States the
National Institutes of Health have made a national
commitment to research on women's health. The
recently established Women's Health Initiative is a
multidisciplinary study that is addressing the main
causes of death and disability in women so that
information can be gathered on the prevention and
treatment of coronary artery disease and other diseases.
For many years research in coronary artery disease has
been focused on men, yet coronary artery disease is also
the major cause of death and an important cause of
disability in women. Available data, most of which
comes from countries other than the United Kingdom,
indicate that women are less likely to be referred for
coronary angiography and revascularisation proce-
dures than men," and referral tends to occur at a later
stage in the disease process."-'
In light of these findings we studied all women
referred to our hospital with chest pain for further
investigation over a five year period. In addition to
comparing the characteristics of women with coronary
artery disease and women with normal coronary
arteries, we compared men similarly referred over the
same period. Follow up data have enabled us to
compare outcome in the different patient groups.
Methods
We identified all women referred to one cardiologist
during 1987-91 with a clinical diagnosis of angina
who subsequently underwent coronary angiography.
Patients were divided into two groups according to the
presence or absence of coronary artery disease identi-
fied by coronary angiography. A diagnosis of coronary
artery disease, based on the combined radiologist's and
cardiologist's report, was made if the diameter stenosis
in any epicardial coronary artery exceeded 30%.
Where necessary the original angiogram was reviewed.
Patients were excluded if they were found to have
cardiac disease other than coronary artery disease.
In addition to comparing women with and without
coronary artery disease, we compared women with
normal coronary arteries with all men referred with
chest pain during the same period who were subse-
quently shown to have normal coronary arteries.
Women with coronary artery disease were compared
with men with coronary artery disease, who were
matched both for age at cardiac catheterisation and
year of catheterisation. The presence of recognised risk
factors for coronary artery disease, which included a
family history (first degree relative with coronary
artery disease), hypercholesterolaemia (random total
cholesterol > 6 5 mmol/l or patient receiving lipid
lowering agent), hypertension requiring specific treat-
ment, history of smoking (current or previous cigarette
TABLE i-Risk factorprofile in patients with chest pain. Values are numbers (percentages) ofsubjects
Family history
of ischaemic
Patient group heart disease Hypercholesterolaemia Hypertension Smoking
Women:
Coronary artery disease
(n-119) 84(71)* 46(39) 60(50)t 72(61)
Normal coronary arteries
(n-83) 50 (60) 28 (34) 32 (39) 38 (46)
Men:
Coronary artery disease
(n- 119) 61 (51) 47 (39) 40 (34) 89 (75)
Normal coronary arteries
(n-55) 32 (58) 19 (35) 11(20) 40 (73)
*P-001 v men with coronary artery disease. *P-0-01 v women with normal coronary arteries.
tP-0-003 v men with coronary artery disease.
884
smoker), and diabetes mellitus requiring treatment by
diet, oral hypoglycaemics, or insulin were recorded.
The original electrocardiograms from the exercise test
at the time of referral were analysed. The test was
considered positive if it showed an ST segment
depression 1 mm from baseline, measured 80 ms
,
after the J point during exercise.
Patients' details were obtained from the clinical
notes, with follow up to present day by telephone
interview and postal questionnaire. The patient's
general practitioner was also contacted. Validation
of events during follow up-including myocardial
infarction, hospital readmission and death-was
sought from other sources such as the admitting
hospital, general practitioner, local cardiologist, and
the coroner's office. Statistical analysis was performed
with the X2 test for categorical data and Student's t test
for continuous data.
Results
A total of 896 patients with chest pain were referred
for coronary angiography from 1987 to 1991 inclusive.
Ten patients were found to have important valvular or
congenital heart disease and were excluded. Of the 886
patients, 202 (23%) were female, of whom 119 (59%)
had coronary artery disease and 83 (41%) had normal
coronary arteries. During the same period, 684 men
were referred with chest pain for cardiac catheterisa-
tion, of whom 629 had coronary artery disease (92%,
P<0-001 v women) and 55 had normal coronary
arteries (80/o, P < 0 001). Women with coronary artery
disease were older than women with normal coronary
arteries (mean (SD) 59 3 (9-1) years v 54-2 (9 3);
P < 0 00 1). Women with normal coronary arteries were
older than men with normal coronary arteries (54-2
(9 3) v 46-6 (9 8) years; P< 0-001).
RISK FACTORS
Only diabetes mellitus was more frequently en-
countered in women with coronary artery disease than
in women with normal coronary arteries (15/119 (13%)
v 2/83 (2%); P-0 01) (table I). Hypertension and a
family history of coronary artery disease were more
frequently encountered in women than men with
coronary artery disease (hypertension 60/119 (50%)
v 40/1 19 (34%), P- 0 003; familyhistory, 84 (71%) v 61
(51%), P-0 01.
EXERCISE TESTING AND DISEASE SEVERITY
The electrocardiographic tracings from the original
exercise testwere available in 79% (298/376) ofpatients;
these results were correlated with the presence or
absence of coronary artery disease. The test was
positive in 18/62 (29%) women with normal coronary
arteries and 56/91 (62%) women with coronary artery
disease, compared with 3/45 (7%/6) men with normal
coronary arteries and 61/100 (61%) men with coronary
artery disease (P < 0 001 for men v women with normal
coronary arteries). The sensitivity of exercise testing
was similar for women and men (62% v 61%) but the
specificity was significantly lower in women (71%
v 93%; P<0 01). The positive predictive value of the
exercise test was lowerinwomen (76% v 95%; P < 0 01)
Diabetes
mellitus whereas the negative predictive value was comparable
(56% v 52%).
In patients with coronary artery disease there was no
15(13)t sex difference in the number of diseased vessels. In
women 43 (36%) had single vessel disease, 32 (27%)
2 (2)
had two vessel disease, and 44 (37%) had triple vessel
disease. In men 31 (26%) had single vessel disease, 35
11 (9)
(29%) had two vessel disease, and 53 (45%) had triple
2 (4) vessel disease. No correlation was found between the
results of the exercise test and number of diseased
vessels.
BMJ VOLUME 308 2 APRIL 1994
 OUTCOME men, continued to have symptoms and seemed to
Follow up details were obtained on 98% of patients. have derived little benefit from cardiac investigation.
Mean (SD) follow up time was 2-4 (1 4) years. Interestingly, once a diagnosis of coronary artery
disease had been established, the rate of referral for
Patients with normal coronary arteries revascularisation was similar in men and women.
Table II shows the outcome in the 83 women and Furthermore, cardiac events were no more frequent in
55 men with normal coronary arteries. Women did women during the follow up period than in men.
not differ significantly from men in the numbers Studies indicate that women are less likely to be
continuing to receive drugs for angina or requiring referred for coronary angiography than men.67 Al-
readmission to hospital for chest pain. One man and though the nature of our study design does not allow us
one woman died from non-cardiac causes, and one to comment on this directly, women represented the
woman died suddenly ofunknown cause. minority of patients referred with a clinical diagnosis of
angina for further investigation. The ratio of men to
TABLE Ia-Outcome in patients referred to hospita with chest pain and women in our series cannot be explained solely by the
found to have normal coronary arteries. Values are numbers (percen- prevalence of angina in men and women,' suggesting
tages) ofpatients that the threshold for referral of women with chest pain
Women Men
is higher than in men, in agreement with earlier
(n-83) (n-55) studies. Even so, 41% of women were subsequently
found to have normal coronary arteries, which is in
Continued chest pain 61(73) 36 (65) keeping with the coronary artery surgery study, in
Further treatment for angina 27 (33) 14 (28)
Readmission to hospital for chest pain 14 (17) 6 (11) which 50% of women referred with chest pain for
Myocardial infarction 1 (1) angiography had normal coronary arteries'2; in men, in
Death from non-cardiac causes 1(1) 1(2)
Sudden death 1 (1) contrast, the suspicion of coronary artery disease was
confirmed in nearly all cases.
Patients with coronary artery disease PRESENCE OF CORONARY ARTERY DISEASE
Table m shows outcome in the 119 women found Regardless of whether or not there is sex bias in
to have coronary artery disease and their matched patient referral, our results suggest that before angio-
controls. Significantly more women than men under- graphy the presence of coronary artery disease can be
went coronary angioplasty (26% v 16%; P-0 03), but predicted more easily in men than in women. Studies
there was no difference in the numbers who had examining the importance of risk factors in the develop-
coronary artery bypass surgery or in the incidence of ment of coronazy artery disease have shown that
myocardial infarction or death from cardiac causes hypertension,"3 smoking,'4"s raised serum concentra-
during follow up. tions of lipids,'6 diabetes mellitus,"7-'9 and a family
history of coronary artery disease2' are all important in
TABLE nI-Outcome in 119 women referred to hospital with chest pain predicting the development of the disease.
andfound to have coronary artery disease and 119 men matchedfor age Other than diabetes mellitus, however, risk factors
at cardiac catheterisation and year of cathetensation. Values are for coronary artery disease in women were poor
numbers (percentages) ofpatients discriminators in our study. The reason(s) why only
diabetes mellitus discriminated between women with
Women Men and without coronary artery disease is uncertain, but
Coronary revascularisadon 81(68) 70 (59) other studies have shown that diabetes imposes a
Coronary artery bypass grafts 50 (42) 51(43) greater risk of heart disease in women than in men.'8 19
Percutaneous transluminal
coronary angioplasty 31(26) 19 (16)* In one study the relative risk of fatal coronary artery
Myocardial infarction 5 (4) 10 (8) disease in diabetic compared with non-diabetic
Death from cardiac causes 3 (3) 8 (7)
patients was 1-9 in men and 3-3 in women after
*P-0*03. adjustment for age, systolic blood pressure, cholesterol,
body mass index, and cigarette smoking.'9
Exercise testing, which is an inexpensive and safe
Discussion technique available in most district general hospitals,
There is growing interest in research into women has been used for many years in evaluating patients
with suspected or documented coronary artery disease with chest pain. The limitations of the technique when
which, until recently, has been little studied. Coronary applied to women have been documented by many
artery disease is the main cause of death in women in investigators.' Our results are in agreement with these
the Western world, yet almost all studies of coronary studies. Whereas the sensitivity and negative predic-
artery disease have been in men. Whether the results tive value were similar in men and women, the
from these studies can be applied to women is un- specificity and positive predictive value were signifi-
known. This imbalance is currently being redressed in cantly lower in women. Positive results on the exercise
the United States with the establishment of the test were found in 29% women subsequently shown on
Women's Health Initiative. The need for similar angiography to have normal coronary arteries, which is
studies in the United Kingdom remains, in view of the comparable with other studies. The reasons for the
social, economic, and racial differences between the so-called false positive sex difference are uncertain;
two countries. Consequently, the aim of our study was some patients may have abnormalities of coronary flow
to characterise women referred with chest pain to reserve which could account for their symptoms.2'
a cardiac centre since they represent an important Regardless of this, many studies indicate that serious
clinical problem. cardiac events are infrequent in patients so defined.22-25
In this series women represented the minority of
patients referred with chest pain for further investiga- OUrCOME
tion, but nearly half were subsequently found to have Our follow up data indicate that the vast majority
normal coronary arteries. Standard risk factors for of patients with normal coronary arteries continue
coronary artery disease and the results of exercise to experience chest pain, irrespective of their sex.
testing were of limited value in distinguishing women Perhaps this is not surprising since the cause of the
with coronary artery disease from those with chest pain patient's symptoms may remain undiagnosed, despite
from non-cardiac causes. Despite a diagnosis of non- further non-cardiological investigation. Alternatively,
cardiac chest pain, many patients, both women and patients may continue to believe that their pain is

BMJ VOLUME 308 2 APRIL1994 885


Clinical implications
* Chest pain in women is common and may or
may not have a cardiac cause
* The clinical, investigative, and prognostic
features in men with chest pain are not neces-
sarily applicable to women
* In this study 41% of women referred with chest
pain who subsequently underwent coronary
angiography were found to have normal
coronary arteries, compared with only 8% of
men similarly referred
* In women with chest pain risk factor analysis
and exercise testing were of limited value in
predicting the outcome of coronary angiography
* Despite a diagnosis of normal coronary
arteries morbidity was considerable; an appreci-
able proportion continued to have chest pain
and to take antianginal drugs.
cardiac in origin, a plausible explanation in some, since
about a third continued antianginal treatment during
follow up. Although these findings are not new,2' 1 5
the implication is that doctors communicate poorly
with patients and reassurance is inadequate. Further-
more, the situation is perpetuated by the continued
prescription of antianginal drugs in the knowledge that
the patient does not have coronary artery disease.
Perhaps cardiologists spend disproportionately little
time counselling patients with normal coronary
arteries compared with patients with coronary artery
disease.
Previous reports have suggested that women are less
likely to be referred for revascularisation than men."
However, in our series men and women with coronary
artery disease were referred for "intervention" in
similar numbers. These findings confirm Healy's
"Yentl syndrome"-she proposed that women were
only treated like men after coronary angiography had
shown the presence of coronary artery disease.26
Indeed, Steingart et al showed that women had angina
before myocardial infarction as commonly as did men,
and yet men were twice as likely to undergo coronary
angiography.'7 When women who had undergone
cardiac catheterisation were examined, however, there
was no difference between the sexes in the likelihood of
coronary bypass surgery. This idea has recently gained
further support from a study of patients discharged
from hospital in the North West Thames and South
West Thames regions with a principal diagnosis of
coronary heart disease-men were significantly more
likely than women to undergo revascularisation; the
authors suggest this provides evidence for a systematic
difference in the treatment received by men and
women.28
CONCLUSIONS
The results of this study indicate that chest pain in
women referred for coronary angiography is often non-
cardiac in origin, and standard criteria used to deter-
mine the likelihood of coronary artery disease in men
are of limited value in women. Current limitations on
health care resources emphasise the need for better
identification of those women most likely to have
coronary artery disease before referral for invasive
886
assessment. Although establishing a diagnosis of
normal coronary arteries may be reassuring for the
patient's physician, such a diagnosis does little to
relieve the symptoms experienced by these patients,
who, in the absence of an alternative diagnosis, con-
tinue to place a considerable drain on health care
resources.
AKS was supported by a Ceizar Memorial Scholarship in
Cardiology, University of Tasmania.
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(Accepted 1IJganuaty 1994)
BMJ VOLUME 308 2 APRIL 1994