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Chest pain in women: clinical, investigative, and prognostic features

Royal Brompton National Heart and Lung Hospital, London SW3 6NP Correspondence to: Dr Diana R Holdright, London Chest Hospital, Bonner Road, London E2 9JX.

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 angiography; 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.
Results : 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 frequently encountered in women with coronary artery disease (P=0.001). The specificity 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 procedures 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 (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 revascularisation procedures, and outcome was similar. A diagnosis of non-cardiac chest pain in patients with normal coronary arteries was of little 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.¹ 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 investigated, but ST segment shift with exercise is a less specific marker of coronary artery disease in women.*RF 2-4* Many patients referred with chest pain for investigation undergo coronary angiography. However, coronary angiography carries a small but well documented 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 procedures than men,*RF 6-8* and referral tends to occur at a later stage in the disease process.*RF 8-11*

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 identified 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 subsequently 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 treatment, history of smoking (current or previous cigarette 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 catheterisation, of whom 629 had coronary artery disease (92%, P<0.001 v women) and 55 had normal coronary arteries (8%, 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<0.001). 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 encountered 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 40/119 (34%), P=0.003; family history, 84 (71%) v 61 (51%), P=0.01.

TABLE I - Risk factor profile in patients with chest pain. Values are numbers (percentage) of subjects
---------------------------------------------------------------------------------------------------------------------------------------------
                                     Family histor
                                     of ischaemic                                                                 Diabetes
Patient group                        heart disease      Hypercholesterolaemia      Hypertension      Smoking      mellitus
---------------------------------------------------------------------------------------------------------------------------------------------
Women:
 Coronary artery disease
   (n=119)                             84 (71)*                46 (39)             60 (50)(dagger)    72 (61)      15 (13)(double dagger)
 Normal coronary arteries
   (n=83)                              50 (60)                 28 (34)             32 (39)            38 (46)       2 (2)
Men:
 Coronary artery disease
   (n=119)                             61 (51)                 47 (39)             40 (34)            89 (75)      11 (9)
 Normal coronary arteries
   (n=55)                              32 (58)                 19 (35)             11 (20)            40 (73)       2 (4)
---------------------------------------------------------------------------------------------------------------------------------------------
 *P=0.01 v men with coronary artery disease.
 (double dagger) P=0.01 v women with normal coronary arteries.
 (dagger)P=0.003 v men with coronary artery disease.

Exercise testing and disease severity

The electrocardiographic tracings from the original exercise test were available in 79% (298/376) of patients; 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%) 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 lower in women (76% v 95%; P<0.01) whereas the negative predictive value was comparable (56% v 52%).

In patients with coronary artery disease there was no sex difference in the number of diseased vessels. In women 43 (36%) had single vessel disease, 32 (27%) had two vessel disease, and 44 (37%) had triple vessel disease. In men 31 (26%) had single vessel disease, 35 (29%) had two vessel disease, and 53 (45%) had triple vessel disease. No correlation was found between the results of the exercise test and number of diseased vessels.

Outcome

Follow up details were obtained on 98% of patients. Mean (SD) follow up time was 2.4 (1.4) years.

Patients with normal coronary arteries

Table II shows the outcome in the 83 women and 55 men with normal coronary arteries. Women did not differ significantly from men in the numbers continuing to receive drugs for angina or requiring readmission to hospital for chest pain. One man and one woman died from non- cardiac causes, and one woman died suddenly of unknown cause.

TABLE II - Outcome in patients referred to hospital with chest pain and
found to have normal coronary arteries. Values are numbers (percentages)
of patients
------------------------------------------------------------------------
                                                 Women         Men
                                                 (n=83)       (n=55)
------------------------------------------------------------------------
Continued chest pain                             61 (73)      36 (65)
Further treatment for angina                     27 (33)      14 (28)
Readmission to hospital for chest pain           14 (17)       6 (11)
Myocardial infarction                             1 (1)
Death from non-cardiac causes                     1 (1)        1 (2)
Sudden death                                      1 (1)
------------------------------------------------------------------------
 Patients with coronary artery disease

Table III shows outcome in the 119 women found to have coronary artery disease and their matched controls. Significantly more women than men underwent coronary angioplasty (26% v 16%; P=0.03), but there was no difference in the numbers who had coronary artery bypass surgery or in the incidence of myocardial infarction or death from cardiac causes during follow up.

TABLE III - Outcome in 119 women referred to hospital with chest pain
and found to have coronary artery disease and 119 men matched for age
at cardiac catheterisation and year of catheterisation. Values are
numbers (percentages) of patients
-----------------------------------------------------------
                                    Women        Men
-----------------------------------------------------------
Coronary revascularisation         81 (68)      70 (59)
 Coronary artery bypass grafts     50 (42)      51 (43)
 Percutaneous transluminal
   coronary angioplasty            31 (26)      19 (16)*
Myocardial infarction               5 (4)       10 (8)
Death from cardiac causes           3 (3)        8 (7)
-----------------------------------------------------------
 *P=0.03.

Discussion

There is growing interest in research into women with suspected or documented coronary artery disease which, until recently, has been little studied. Coronary artery disease is the main cause of death in women in the Western world, yet almost all studies of coronary artery disease have been in men. Whether the results from these studies can be applied to women is unknown. This imbalance is currently being redressed in the United States with the establishment of the Women's Health Initiative. The need for similar studies in the United Kingdom remains, in view of the social, economic, and racial differences between the two countries. Consequently, the aim of our study was to characterise women referred with chest pain to a cardiac centre since they represent an important clinical problem.

In this series women represented the minority of patients referred with chest pain for further investigation, but nearly half were subsequently found to have normal coronary arteries. Standard risk factors for coronary artery disease and the results of exercise testing were of limited value in distinguishing women with coronary artery disease from those with chest pain from non-cardiac causes. Despite a diagnosis of non- cardiac chest pain, many patients, both women and men, continued to have symptoms and seemed to have derived little benefit from cardiac investigation. Interestingly, once a diagnosis of coronary artery disease had been established, the rate of referral for revascularisation was similar in men and women. Furthermore, cardiac events were no more frequent in women during the follow up period than in men.

Studies indicate that women are less likely to be referred for coronary angiography than men.^6,7 Although the nature of our study design does not allow us to comment on this directly, women represented the minority of patients referred with a clinical diagnosis of angina for further investigation. The ratio of men to women in our series cannot be explained solely by the prevalence of angina in men and women,¹ suggesting that the threshold for referral of women with chest pain is higher than in men, in agreement with earlier studies. Even so, 41% of women were subsequently found to have normal coronary arteries, which is in keeping with the coronary artery surgery study, in which 50% of women referred with chest pain for angiography had normal coronary arteries¹²; in men, in contrast, the suspicion of coronary artery disease was confirmed in nearly all cases.

Presence of coronary artery disease

Regardless of whether or not there is sex bias in patient referral, our results suggest that before angiography the presence of coronary artery disease can be predicted more easily in men than in women. Studies examining the importance of risk factors in the development of coronary artery disease have shown that hypertension,¹³ smoking,^14,15 raised serum concentrations of lipids,¹⁶ diabetes mellitus,*RF 17-19* and a family history of coronary artery disease²⁰ are all important in predicting the development of the disease.

Other than diabetes mellitus, however, risk factors for coronary artery disease in women were poor discriminators in our study. The reason(s) why only diabetes mellitus discriminated between women with and without coronary artery disease is uncertain, but other studies have shown that diabetes imposes a greater risk of heart disease in women than in men.*RF 18-19* In one study the relative risk of fatal coronary artery disease in diabetic compared with non-diabetic patients was 1.9 in men and 3.3 in women after adjustment for age, systolic blood pressure, cholesterol, body mass index, and cigarette smoking.¹⁹

Exercise testing, which is an inexpensive and safe technique available in most district general hospitals, has been used for many years in evaluating patients with chest pain. The limitations of the technique when applied to women have been documented by many investigators.*RF 2-4* Our results are in agreement with these studies. Whereas the sensitivity and negative predictive value were similar in men and women, the specificity and positive predictive value were significantly lower in women. Positive results on the exercise test were found in 29% women subsequently shown on angiography to have normal coronary arteries, which is comparable with other studies. The reasons for the so-called false positive sex difference are uncertain; some patients may have abnormalities of coronary flow reserve which could account for their symptoms.²¹ Regardless of this, many studies indicate that serious cardiac events are infrequent in patients so defined.*RF 22-25*

Outcome

Our follow up data indicate that the vast majority of patients with normal coronary arteries continue to experience chest pain, irrespective of their sex. Perhaps this is not surprising since the cause of the patient's symptoms may remain undiagnosed, despite further non-cardiological investigation. Alternatively, patients may continue to believe that their pain is cardiac in origin, a plausible explanation in some, since about a third continued antianginal treatment during follow up. Although these findings are not new,^22,24,25 the implication is that doctors communicate poorly with patients and reassurance is inadequate. Furthermore, 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.*RF 6-8* 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.²⁷ 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

Conclusion

s

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 determine 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 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, continue 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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