Comparative Effectiveness of Exercise Electrocardiography With or Without Myocardial Perfusion Single Photon Emission Computed Tomography in Women With Suspected Coronary Artery Disease: Results From the What Is the Optimal Method for Ischemia Evaluation in Women (WOMEN) Trial

Study Questions:

What is the relative value of standard treadmill exercise testing (ETT) and exercise myocardial perfusion imaging (MPI) for clinical decision making in women suspected of having coronary artery disease (CAD)?

Methods:

This study presents results from the WOMEN trial, which randomized 824 women to ETT or MPI. All patients were symptomatic with suspected CAD, had an interpretable electrocardiogram (ECG), and ≥5 MET capability on the Duke Activity Status Index. Patients were followed for 2 years for major adverse cardiac events (MACE) defined as CAD-related death, or hospitalization for an acute coronary syndrome (ACS) or heart failure. ETTs were performed with a standard or modified Bruce protocol to endpoints of diagnostic ST-segment changes, worsening chest pain, excessive fatigue, or sustained arrhythmias. ETTs were defined as normal in the absence of significant ST changes with adequate exercise tolerance; as indeterminate with 0.5-1.0 mm ST-segment changes, exertional chest pain, and/or submaximal exercise; and abnormal as ≥1 mm ST-segment depression occurring in ≥2 leads. MPIs were graded on a 17-segment model and each segment scored 0 (normal) to 4 (no uptake). Normal, mildly abnormal, and moderately to severely abnormal MPIs were defined as summed stress scores (SSS) of <4, 4 to 8, and >8.

Results:

Subjects were drawn from 43 cardiology practices who identified 2,859 eligible women, of whom 29% agreed to randomization. Median age was 62 years of age and the majority of subjects were postmenopausal. Approximately 60% of subjects had typical angina, 9% atypical angina, and 27% nonspecific chest pain. ETT women exercised to an average of 8.4 METs. ETTs were normal in 64%, indeterminate in 16%, and abnormal in 20%. MPIs were normal in 91%, mildly abnormal in 3%, and moderately to severely abnormal in 6%. Over a 2-year follow-up, 17 MACE occurred including three nonfatal myocardial infarctions, one congestive heart failure hospitalization, 12 ACS, and one sudden cardiac death. Two-year MACE-free survival was 98% for women in both the ETT and MPI arms. Over 2 years, MACE occurred in 1.7% of ETT and 2.3% of MPI subjects. Hospitalization rates for ACS were 3% for the ETT arm and 4% for the MPI arm. MACE-free survival for normal, indeterminate, and abnormal exercise ECGs were 99%, 97%, and 96% (p = 0.016). For normal, mildly abnormal, and moderate to severely abnormal MPI, corresponding MACE-free survival was 99%, 91%, and 88% (p < 0.001). For women with a normal ECG on ETT versus normal MPI, 2-year MACE rates were 0.4% and 1.2% (p = 0.4). For women with abnormal findings, the 2-year MACE rate was 5.1% for ETT and 13.1% for MPI (p = 0.19). Follow-up exercise ECG was performed in only three women, whereas 18% of women undergoing ETT had a subsequent MPI. Rates of referral for coronary angiography in the ETT group were 3%, 7%, and 18% for normal, indeterminate, and abnormal ECG and 4%, 0%, and 29% for the three strata of MPI (both comparisons p < 0.0001). Coronary revascularization was undertaken in 1% and 2.2% of women in the ETT and MPI groups (p = 0.16). For the ETT group, mean cost of the index testing was $154.28 compared to $495.24 for the MPI group. Mean follow-up testing costs for ETT subjects was $179.97 compared to $144.77 for the MPI, and mean total cost was $337.80 vs. $643.24 for ETT and MPI, representing a 48% cost reduction for the ETT strategy.

Conclusions:

In relatively low-risk physically active women, a strategy of ETT, as opposed to empiric use of exercise MPI, results in similar 2-year outcomes and provides significant cost savings.

Perspective:

Conventional wisdom has suggested that because of a perceived high prevalence of false-positive electrocardiographic responses and high-frequency atypical symptoms in female patients, that the diagnostic ability of routine ETT is diminished to the point that routine use of an imaging study such as MPI or stress echocardiography is warranted as a standard practice. This perception is based in large part on studies looking at selected rather than general populations, but has never been validated in a randomized trial such as presented here. It should be emphasized that the women in this subgroup were normally active, may be slightly healthier than those encountered in general practices, had preserved exercise tolerance, and normal resting ECGs. Within the constraints of that specific patient population, this study nicely demonstrates equivalent outcomes over 2 years with respect to adverse events, which presumably is related to an equivalent diagnostic accuracy for routine ETT compared to MPI. The substantial cost savings were apparent with a reduction of overall costs of 48% by employing a strategy of routine exercise testing with ECG as a first test, rather than MPI. It should be emphasized that there are several limitations to this study, including the fact that only 29% of eligible women were actually randomized. The reasons for the low randomization rate are not provided, but suggest that perhaps the patients studied here may not be entirely representative of the general population encountered in practice. An additional limitation is the relatively low number of hard cardiac events. Within the limitations of these considerations, it would appear that a substantial number of female patients presenting with symptoms of CAD may be equally well handled with a strategy of ETT with ECG monitoring alone, as opposed to immediate reliance on MPI or other imaging strategies.

Clinical Topics: Acute Coronary Syndromes, Arrhythmias and Clinical EP, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Atherosclerotic Disease (CAD/PAD), Implantable Devices, Interventions and ACS, Interventions and Coronary Artery Disease, Interventions and Imaging, Angiography, Echocardiography/Ultrasound, Nuclear Imaging

Keywords: Exercise Tolerance, Myocardial Perfusion Imaging, Risk, Coronary Artery Disease, Myocardial Infarction, Myocardial Ischemia, Acute Coronary Syndrome, Follow-Up Studies, Heart Conduction System, Electrocardiography, Prevalence, Death, Coronary Angiography, Ischemia, Chest Pain, Tomography, Cardiology, Echocardiography, Exercise Test


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