Noninvasive Technologies for Diagnosing Coronary Artery Disease in

Noninvasive Technologies for Diagnosing Coronary Artery Disease in Women Prepared for: Agency for Healthcare Research and Quality (AHRQ) www. ahrq. gov

Outline of Material Introduction to the noninvasive technologies currently available for diagnosing coronary artery disease (CAD) in women Systematic review methods The clinical questions addressed by the comparative effectiveness review Results of studies and evidence-based conclusions about the relative accuracy and safety of the noninvasive technologies currently available for diagnosing CAD in women Gaps in knowledge and future research needs What to discuss with patients and their caregivers Dolor RJ, Patel MR, Melloni C, et al. AHRQ Comparative Effectiveness Review No. 58. Available at www. effectivehealthcare. ahrq. gov/diagnosecad. cfm.

Background: Prevalence and Burden of Coronary Artery Disease Cardiovascular disease is the leading cause of mortality in women in the United States. Coronary heart disease (including coronary artery disease, angina, myocardial infarction, and acute coronary syndromes) accounts for the majority of deaths. According to a 2005 report from the American Heart Association (AHA), over 240, 000 women versus 250, 000 men die from coronary heart disease annually. It is estimated that in the United States: 8. 1 million women have a history of myocardial infarction or angina or both. More women (5. 5 million) than men (4. 3 million) have angina. Coronary heart disease is also a significant cause for morbidity and disability in women in the United States. The 2005 AHA report estimated that coronary heart disease is prevalent in 5. 9 million women (5. 6 percent of the total population). Dolor RJ, Patel MR, Melloni C, et al. AHRQ Comparative Effectiveness Review No. 58. Available at www. effectivehealthcare. ahrq. gov/diagnosecad. cfm. American Heart Association. Heart and Stroke Statistics. 2005 Update. Available at www. americanheart. org. Lloyd-Jones D, Adams RJ, Brown TM, et al. Circulation 2010; 121(7): e 46 -e 215. PMID: 20019324. Mieres JH, Shaw LJ, Arai A, et al. Circulation 2005; 111(5): 682 -96. PMID: 15687114.

Background: The Importance of Diagnosing Coronary Artery Disease in Women An effective diagnosis of coronary artery disease (CAD) is critical in women, as up to or as many as 40 percent of initial cardiac events are fatal. The 2005 American Heart Association update on heart disease and stroke estimated new and recurrent myocardial infarctions (MIs) to occur in 520, 000 men versus 345, 000 women. Women who have had an acute MI have a worse prognosis than men. The goals of diagnostic workup for women with symptoms suspicious for CAD are to identify CAD with optimal accuracy and to establish the basis for instituting preventive and therapeutic interventions. Dolor RJ, Patel MR, Melloni C, et al. AHRQ Comparative Effectiveness Review No. 58. Available at www. effectivehealthcare. ahrq. gov/diagnosecad. cfm. American Heart Association. Heart and Stroke Statistics. 2005 Update. Available at www. americanheart. org. Lloyd-Jones D, Adams RJ, Brown TM, et al. Circulation 2010; 121(7): e 46 -e 215. PMID: 20019324. Mieres JH, Shaw LJ, Arai A, et al. Circulation 2005; 111(5): 682 -96. PMID: 15687114.

Background: Using Coronary Angiography To Diagnose Coronary Artery Disease Coronary angiography is considered the gold standard for coronary artery disease (CAD) diagnosis and is indicated in patients with chest pain and a high risk of CAD. The benefits of this procedure include the ability to: Visualize arteries anatomically Combine diagnosis and treatment in one step Disadvantages of this procedure include: Its invasive nature The inability to perform functional assessment of coronary disease The possibility of bleeding at the access site The rare risk of injury to the coronary artery due to coronary dissection The risk of anaphylaxis or renal impairment due to contrast agent use The risk of radiation exposure from imaging Dolor RJ, Patel MR, Melloni C, et al. AHRQ Comparative Effectiveness Review No. 58. Available at www. effectivehealthcare. ahrq. gov/diagnosecad. cfm. Matchar DB, Mark DB, Patel MR, et al. AHRQ Technology Assessment. Available at www. cms. gov/determinationprocess/downloads/id 34 TA. pdf.

Background: Using Noninvasive Technologies To Diagnose Coronary Artery Disease (1 of 2) For patients with intermediate risk of coronary artery disease (CAD) or with contraindications to coronary angiography, noninvasive technologies (NITs) are an important diagnostic option. The consensus statement on the role of NITs in diagnosing CAD in women developed by the American Heart Association in 2005 recommends that: Women who are asymptomatic and at low risk of CAD should not undergo cardiac imaging studies. NITs are suggested for women with atypical chest pain and low risk of CAD who might need reassurance about their symptoms. NITs are indicated for symptomatic women with intermediate pretest probability of CAD. Dolor RJ, Patel MR, Melloni C, et al. AHRQ Comparative Effectiveness Review No. 58. Available at www. effectivehealthcare. ahrq. gov/diagnosecad. cfm. Mieres JH, Shaw LJ, Arai A, et al. Circulation 2005; 111(5): 682 -96. PMID: 15687114.

Background: Using Noninvasive Technologies To Diagnose Coronary Artery Disease (2 of 2) For patients with intermediate risk of coronary artery disease (CAD) or with contraindications to coronary angiography, NITs are an important diagnostic option. NITs used to diagnose CAD may be categorized as “functional” or “anatomic” tests. Functional NITs for CAD diagnosis include: Exercise/stress electrocardiography (ECG) Exercise/stress echocardiography (ECHO) Exercise/stress radionuclide myocardial perfusion imaging (single photon emission computed tomography [SPECT]) Exercise/stress cardiac magnetic resonance imaging (CMR) Anatomic NITs for CAD diagnosis include: Coronary computed tomography angiography (CTA) Cardiac magnetic resonance imaging (CMR)* *Cardiac magnetic resonance imaging can be used as an anatomic or a functional modality. Dolor RJ, Patel MR, Melloni C, et al. AHRQ Comparative Effectiveness Review No. 58. Available at www. effectivehealthcare. ahrq. gov/diagnosecad. cfm. Matchar DB, Mark DB, Patel MR, et al. AHRQ Technology Assessment. Available at www. cms. gov/determinationprocess/downloads/id 34 TA. pdf. Mieres JH, Shaw LJ, Arai A, et al. Circulation 2005; 111(5): 682 -96. PMID: 15687114. Stangl V, Witzel V, Baumann G, et al. Eur Heart J 2008; 29(6): 707 -17. PMID: 18272503.

Background: Factors Affecting the Accuracy of NITs in Diagnosing CAD in Women Several factors affect the accuracy of the noninvasive technologies (NITs) used to diagnose coronary artery disease (CAD) in women, including: Symptoms of CAD being less predictive and more often atypical when compared with men Lower prevalence of obstructive epicardial CAD than in men Higher prevalence of single-vessel disease Smaller coronary artery size and left ventricular chamber size Limited exercise tolerance because of older age, obesity, and diabetes at initial diagnosis Suboptimal response of the left ventricle to stress Hormonal influences of estrogens mimicking a digitalis-like electrocardiographic response Female breast attenuation artifacts Poor left ventricular opacification on echocardiography Dolor RJ, Patel MR, Melloni C, et al. AHRQ Comparative Effectiveness Review No. 58. Available at www. effectivehealthcare. ahrq. gov/diagnosecad. cfm. Stangl V, Witzel V, Baumann G, et al. Eur Heart J 2008; 29(6): 707 -17. PMID: 18272503.

Background: Uncertainties Surrounding the Use of NITs in Diagnosing CAD in Women While the 2005 American Heart Association consensus statement was a thorough synopsis of the literature, it did not include a comparative effectiveness review of the accuracy of the various noninvasive technologies (NITs). An understanding of the relative specificity, sensitivity, and harms of the various NITs in diagnosing coronary artery disease in women could support physicians in clinical decisionmaking. Dolor RJ, Patel MR, Melloni C, et al. AHRQ Comparative Effectiveness Review No. 58. Available at www. effectivehealthcare. ahrq. gov/diagnosecad. cfm. Mieres JH, Shaw LJ, Arai A, et al. Circulation 2005; 111(5): 682 -96. PMID: 15687114.

Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review (CER) Development Topics are nominated through a public process, which includes submissions from health care professionals, professional organizations, the private sector, policymakers, members of the public, and others. A systematic review of all relevant clinical studies is conducted by independent researchers, funded by AHRQ, to synthesize the evidence in a report summarizing what is known and not known about the select clinical issue. The research questions and the results of the report are subject to expert input, peer review, and public comment. The results of these reviews are summarized into Clinician Research Summaries and Consumer Research Summaries for use in decisionmaking and in discussions with patients. The Research Summaries and the full report, with references for included and excluded studies, are available at www. effectivehealthcare. ahrq. gov/diagnosecad. cfm. Dolor RJ, Patel MR, Melloni C, et al. AHRQ Comparative Effectiveness Review No. 58. Available at www. effectivehealthcare. ahrq. gov/diagnosecad. cfm.

Clinical Questions Addressed by the Comparative Effectiveness Review (1 of 2) Key Question 1: What is the accuracy of one noninvasive technology (NIT) in diagnosing obstructive and nonobstructive coronary artery disease (CAD) when compared with another NIT or with coronary angiography in women with symptoms suspicious for CAD? Exercise ECG stress test, including resting ECG (e. g. , multifunctional cardiogram) Exercise/stress ECHO with or without a contrast agent Exercise/stress radionuclide myocardial perfusion imaging, including SPECT and PET CMR imaging Coronary CTA Key Question 2: What are the predictors of diagnostic accuracy (e. g. , age, race/ethnicity, body size, heart size, menopausal status, functional status, stress modality) of different NITs in women? Dolor RJ, Patel MR, Melloni C, et al. AHRQ Comparative Effectiveness Review No. 58. Available at www. effectivehealthcare. ahrq. gov/diagnosecad. cfm.

Clinical Questions Addressed by the Comparative Effectiveness Review (2 of 2) Key Question 3: Is there evidence that the use of noninvasive technologies (NITs), when compared with other NITs or coronary angiography, improves: a. Risk stratification/prognostic information? b. Decisionmaking regarding treatment options (revascularization, optimal medical therapy)? c. Clinical outcomes (death, myocardial infarction, unstable angina, hospitalization, revascularization, angina relief, quality of life)? Key Question 4: Are there significant safety concerns/risks (i. e. , radiation exposure, access site complications, contrast agentinduced nephropathy, nephrogenic systemic fibrosis, anaphylaxis, arrhythmias) associated with the use of different NITs to diagnose coronary artery disease (CAD) in women with symptoms suspicious of CAD? Dolor RJ, Patel MR, Melloni C, et al. AHRQ Comparative Effectiveness Review No. 58. Available at www. effectivehealthcare. ahrq. gov/diagnosecad. cfm.

Rating the Strength of Evidence From the Comparative Effectiveness Review The strength of evidence was classified into four broad categories: High confidence that the evidence reflects the true effect. Further research is very unlikely to change the confidence in the estimate of effect. Moderate confidence that the evidence reflects the true effect. Further research may change the confidence in the estimate of effect and may change the estimate. Low confidence that the evidence reflects the true effect. Further research is likely to change the confidence in the estimate of effect and is likely to change the estimate. Insufficient Evidence either is unavailable or does not permit estimation of an effect. Dolor RJ, Patel MR, Melloni C, et al. AHRQ Comparative Effectiveness Review No. 58. Available at www. effectivehealthcare. ahrq. gov/diagnosecad. cfm.

Accuracy of NITs in Diagnosing CAD in Symptomatic Women Without a Known Diagnosis of CAD (1 of 2) Exercise/stress ECG: High strength of evidence The summary sensitivity and specificity of exercise/stress ECG in symptomatic women with no known coronary artery disease (CAD) were 62 percent and 68 percent respectively. Exercise/stress ECHO: High strength of evidence The summary sensitivity and specificity of exercise/stress ECHO were 79 percent and 83 percent, respectively. Exercise/stress radionuclide myocardial perfusion imaging with SPECT: High strength of evidence The summary sensitivity and specificity of exercise/stress myocardial perfusion imaging with SPECT were 81 percent and 78 percent, respectively. Dolor RJ, Patel MR, Melloni C, et al. AHRQ Comparative Effectiveness Review No. 58. Available at www. effectivehealthcare. ahrq. gov/diagnosecad. cfm.

Accuracy of NITs in Diagnosing CAD in Symptomatic Women Without a Known Diagnosis of CAD (2 of 2) CMR imaging: Low strength of evidence The summary sensitivity and specificity of CMR imaging in symptomatic women with no known CAD were 72 percent and 84 percent, respectively. Multidetector cardiac CTA: Low strength of evidence The summary sensitivity and specificity of multidetector cardiac CTA were 93 percent and 77 percent, respectively. Analysis for a statistical difference between the accuracies of NITs for diagnosing CAD in women with no known CAD revealed that: For women with no previously known CAD, the sensitivities of ECHO and SPECT were statistically significantly higher than that of ECG (p < 0. 001). In the subset of good-quality studies, the specificities of CMR and ECHO were significantly higher than that of ECG (p = 0. 006). Dolor RJ, Patel MR, Melloni C, et al. AHRQ Comparative Effectiveness Review No. 58. Available at www. effectivehealthcare. ahrq. gov/diagnosecad. cfm.

Summary: Accuracy of NITs Versus Coronary Angiography in Diagnosing CAD in Women With No Known CAD Modality ECG ECHO SPECT CMR Coronary CTA Quality of Studies Number of Studies All Number of Patients Total Women Summary Sensitivity, % (95% CI) Summary Specificity, % (95% CI) 29 8, 825 3, 392 62 (55 – 68) 68 (63 – 73) Good 10 3, 821 1, 410 70 (58 – 79) 62 (53 – 69) All 14 2, 538 1, 286 79 (74 – 83) 83 (74 – 89) Good 5 1, 227 561 79 (69 – 87) 85 (68 – 94) All 14 1, 340 1, 000 81 (76 – 86) 78 (69 – 84) Good 4 484 394 83 (52 – 95) 72 (37 – 92) All 5 580 501 72 (55 – 85) 84 (69 – 93) Good 5 580 501 72 (55 – 85) 84 (69 – 93) All 5 1, 298 474 93 (69 – 99) 77 (54 – 91) Good 3 312 124 85 (26 – 99) 73 (17 – 97) 95% CI = 95 -percent confidence interval; CMR = cardiac magnetic resonance imaging; CTA = computed tomography angiography; ECG = electrocardiography; ECHO = exercise/stress echocardiography; SPECT = single photon emission computed tomography Dolor RJ, Patel MR, Melloni C, et al. AHRQ Comparative Effectiveness Review No. 58. Available at www. effectivehealthcare. ahrq. gov/diagnosecad. cfm.

Noninvasive Technologies for Diagnosing Coronary Artery Disease in Women: Other Findings Within a given modality, the summary sensitivities and specificities were similar for both types of populations (unknown coronary artery disease [CAD] and mixed known and unknown CAD). The diagnostic accuracy of the noninvasive technologies (NITs) appeared to be consistent over time. Studies evaluating CMR and coronary CTA in women are limited (low level of evidence) with wider confidence intervals and would benefit from additional investigations. Evidence from comparative studies was insufficient to permit meaningful conclusions about: Predictors of the diagnostic accuracy of the NITs Safety of the various NITs Ability of the NITs to impact risk stratification, prognostic information, treatment decisions and harms. Dolor RJ, Patel MR, Melloni C, et al. AHRQ Comparative Effectiveness Review No. 58. Available at www. effectivehealthcare. ahrq. gov/diagnosecad. cfm.

Conclusions (1 of 2) Overall, within a given modality, the summary sensitivities and specificities were similar for all studies when compared with good-quality studies alone. When considering only the good-quality studies, the diagnostic accuracy of detecting coronary artery disease (CAD) in women with anginal chest pain but with no known CAD appeared to be better (in descending order) for coronary CTA, SPECT, ECHO, CMR, and ECG. However, the confidence intervals were wide, especially for CTA and CMR. Dolor RJ, Patel MR, Melloni C, et al. AHRQ Comparative Effectiveness Review No. 58. Available at www. effectivehealthcare. ahrq. gov/diagnosecad. cfm.

Conclusions (2 of 2) Analyses for statistical differences between the diagnostic accuracies of NITs in women revealed that: The sensitivities of ECHO and SPECT were statistically significantly greater than that of ECG. The specificities of CMR and of ECHO were statistically significantly higher than that of ECG (when considering only goodquality studies). There was insufficient evidence concerning the influence of clinical and demographic factors on the diagnostic accuracy of NITs, risk stratification, prognostic information, treatment decisions, clinical outcomes, and harms. Dolor RJ, Patel MR, Melloni C, et al. AHRQ Comparative Effectiveness Review No. 58. Available at www. effectivehealthcare. ahrq. gov/diagnosecad. cfm.

Gaps in Knowledge and Future Research Needs (1 of 2) It is hoped that future randomized controlled trials will provide more information on how the choice of a diagnostic modality impacts coronary artery disease prognosis, treatment, clinical outcomes, and costs. In the studies evaluated in this review that included both sexes, women were poorly represented; this affected the ability to assess the influence of sex differences on the diagnostic accuracy of the various noninvasive technologies (NITs). Few studies assessed the impact of factors such as weight, functional status, race/ethnicity, sex, age, microvascular disease, menopausal status, and heart size on the diagnostic accuracy of the various NITs. Dolor RJ, Patel MR, Melloni C, et al. AHRQ Comparative Effectiveness Review No. 58. Available at www. effectivehealthcare. ahrq. gov/diagnosecad. cfm.

Gaps in Knowledge and Future Research Needs (2 of 2) This review did not identify studies that discussed the order in which different noninvasive technologies (NITs) were used to evaluate coronary artery disease (CAD). Multiple tests or layered-testing strategies areas where significant research is needed. Reporting of adverse effects associated with the NITs was very limited in the studies included in this review. Future studies should address this important knowledge gap. The accuracy of the NITs assessed may be location or operator dependent. It is unclear if the results of studies conducted at highly specialized centers apply to routine clinical practice. Dolor RJ, Patel MR, Melloni C, et al. AHRQ Comparative Effectiveness Review No. 58. Available at www. effectivehealthcare. ahrq. gov/diagnosecad. cfm.

What To Discuss With Your Patients (1 of 2) Their risk for developing coronary artery disease (CAD) and factors that might increase their risk, such as smoking, obesity, and a sedentary lifestyle The importance of early detection and management of CAD Coexisting conditions such as diabetes and the metabolic syndrome that impact the risk of CAD Dolor RJ, Patel MR, Melloni C, et al. AHRQ Comparative Effectiveness Review No. 58. Available at www. effectivehealthcare. ahrq. gov/diagnosecad. cfm.

What To Discuss With Your Patients (2 of 2) The relative accuracy of the noninvasive technologies (NITs) available for diagnosing coronary artery disease (CAD) Their physical status, health conditions, or medication use that might preclude the use of a certain diagnostic procedure The relative safety of the NITs available for diagnosing CAD, particularly the risk of radiation exposure in younger women The possible consequences of an abnormal test result Dolor RJ, Patel MR, Melloni C, et al. AHRQ Comparative Effectiveness Review No. 58. Available at www. effectivehealthcare. ahrq. gov/diagnosecad. cfm.