Diagnostic Testing to Evaluate Ischemic Symptoms in Women

“Women with stable angina report more physical limitations and lower quality of life…”

Chest pain is a common problem in women. There are many diagnostic strategies available to evaluate patients with chest pain for suspected ischemic heart disease (IHD), each with special considerations for sex differences in presentation and test characteristics. Stable angina is the most frequent manifestation of IHD in women, affecting approximately 4,200,000 (3.2%) women in the USA, and the age-adjusted prevalence of angina is greater in women than men [1–4]. Women with stable angina report more physical limitations and lower quality of life, and suffer from a greater number of nonfatal myocardial infarctions (MIs) and deaths compared with men after 1–2 years [5–7]. This underscores the importance of identifying IHD in women initially presenting with chest pain and other related ischemic symptoms.

For patients with suspected IHD noninvasive stress testing is recommended as the first study to confirm diagnosis and risk stratify patients as per current guidelines from the American College of Cardiology (ACC) and American Heart Association (AHA) [8]. Computed tomography (CT) angiography is another choice for patients with symptoms and suspected ischemia. Symptomatic women are less likely than men to undergo stress testing [6–9].

This editorial addresses the challenges in selecting an initial diagnostic test for a woman with possible ischemic symptoms and proposes strategies for choosing the most appropriate first test to diagnose and risk-stratify women with suspected IHD.

Challenges to making the diagnosis of ischemic heart disease in women

Variability in presentation among women

The evaluation of symptoms that may be due to IHD in women is inherently problematic because the ‘typical’ description of angina so familiar to clinicians derives from studies with predominantly male cohorts [10,11]. Even when present, the ‘typical angina’ description is less likely to be associated with significant coronary artery disease (CAD) at angiography among women than men [11]. While women have a higher frequency of presentation for evaluation of chest pain than men, women are more likely to report a discomfort in other locations such as the throat, jaw or neck as well as additional symptoms such as shortness of breath, fatigue, palpitations, mid-back pain, indigestion, nausea and numbness in hands [12–14]. Symptoms are often triggered by mental stress rather than exercise [10,15]. The presence of typical symptoms is associated with obstructive CAD in women but obstructive CAD certainly cannot be excluded based on atypical symptom presentation [16–18].

Lower prevalence of obstructive CAD among women & stress test accuracy

According to Bayes' theorem, the well-known lower prevalence of obstructive CAD among women affects diagnostic accuracy of stress testing [10,17,19,20]. Over one-half of women referred for angiography with symptoms or suspected myocardial ischemia have normal arteries or nonobstructive CAD on angiography (defined as <50% or 70% stenosis, depending on the study) [17,21,22]. For example, among 375,886 patients referred for angiography from the ACC National Cardiovascular Data Registry^®, the prevalence of obstructive disease was lower in women of all age groups (<50 to ≥80 years old), ranging from 27 to 64% compared with 45–87% of men (p < 0.0001) [17]. The lower prevalence of obstructive disease should also be considered in the context of a lower number of referrals for angiography among women [6,7,23].

“The goal of testing is usually to identify ischemia as the cause of symptoms and several tests are available for this purpose.”

In addition, there are inherent sex differences in sensitivity and specificity of stress testing, such that exercise ECG has lower diagnostic accuracy in women than men [24,25]. It has been hypothesized that false-positive ECG changes may be due to estrogenic effects, which can induce ECG changes that mimic ischemia [26–28]. Because stress imaging using echocardiography or perfusion imaging is more accurate in women than the exercise ECG, a team of investigators conducted a randomized trial of exercise ECG testing versus exercise nuclear imaging, with a focus on outcomes. The results showed no difference in events between the two randomized testing arms with higher cost in the nuclear testing arm [29]. Low risk of the women included likely influenced results. An AHA consensus statement does suggest the exercise ECG for women with a normal ECG who are able to exercise based on ability to carry out activities of daily living [30].

Microvascular disease is an important consideration in women with ischemic symptoms

Ultimately with the reference standard of 50% angiographic stenosis, many women with positive-stress tests are labeled as having ‘false-positive’ tests. However, some women with ischemic symptoms and normal or nonobstructive coronary arteries have disease of the microvasculature. Microvascular coronary disease may lead to symptoms and an abnormal stress test; that is, some women with ‘false-positive’ test results actually do have ischemia and are at increased risk, but the reference standard of angiographically evident atherosclerosis does not reflect the true cause of ischemia [31]. Approximately, half of women with chest pain without angiographically obstructive CAD were found to have abnormal coronary flow reserve in the WISE study [32] and 65% an abnormal vasomotor response to adenosine in a different consecutive series [33]. Abnormal coronary flow reserve is important, as it is a significant predictor of adverse outcomes (MI, congestive heart failure, stroke, and death) regardless of CAD severity [34].

Stress testing or CT angiography?

Stress testing provides information about ischemia and angiography provides information about coronary atherosclerosis. Both stress testing and coronary CT angiography provide prognostic information. The two approaches have been evaluated head to head in a large randomized trial, the PROMISE trial. The results showed that an initial diagnostic strategy of CT coronary angiography did not improve clinical outcomes (including death, nonfatal MI, unstable angina) as compared with non-invasive stress testing, over 2-year follow-up in over 10,000 patients with stable symptoms suggesting CAD. This result did not differ by sex. More patients in the CT angiography group underwent invasive coronary angiography in follow-up but fewer of them had nonobstructive CAD. Radiation exposure was higher in the CT group [35].

Goals of testing

When choosing a test for a female patient, clinicians should keep in mind the goals of testing in that patient. Some goals may be to determine the cause of chest pain, to identify risk of cardiovascular events and to tailor preventive medication use. Many tests are available, ranging from the relatively simple and low cost exercise ECG through stress imaging and anatomic evaluation with CT or conventional coronary angiography. Each offers prognostic information.

We agree with the AHA Consensus Statement that the exercise ECG is the best first test for women who are able to exercise, to determine if chest discomfort is due to ischemia, understanding its limitations in terms of diagnostic accuracy [30]. Exercise time and whether the presenting complaint was elicited during the test in addition to ECG findings of ischemia are considered when interpreting results and deciding on next steps.

If the ECG is abnormal in a premenopausal woman who can exercise, or if the woman cannot exercise, stress echocardiography is preferred based on its excellent sensitivity and specificity and lack of radiation exposure [30].

A positive-stress test is followed up with antianginal and antiatherosclerotic treatment with consideration of angiography depending on post-test risk assessment. The ISCHEMIA trial is currently testing the role of routine angiography and revascularization in patients with moderately-severely abnormal stress test results (clinicaltrials.gov: NCT01471522).

A negative exercise ECG with reproduction of symptoms leads to additional diagnostic testing, either stress echocardiography stress nuclear imaging or coronary CT angiography as appropriate. Coronary CT imaging may also be helpful when there is intermediate likelihood of cardiovascular events, to aid decision making regarding lipid lowering therapy [36]. In general, however, prevention efforts are centered on risk factor assessment and modification and imaging is rarely needed for this purpose.

Conclusion

Chest pain and other ischemic symptoms are frequently reported in women. The diagnosis of ischemic heart disease may be difficult to make because women are more likely to have ‘atypical’ symptoms, less likely to have obstructive CAD and more likely to have microvascular coronary disease as the cause of symptoms. The goal of testing is usually to identify ischemia as the cause of symptoms and several tests are available for this purpose. Current recommendations favor the exercise ECG as the first test when the ECG is normal and the woman can exercise. Risk factor evaluation and modification remain important regardless of diagnostic test results.