Efeito de Triagem para doença arterial coronariana Usando CT Angiografia de Mortalidade e de eventos cardíacos em alto risco pacientes com diabetes

Joseph B. Muhlestein, MD; Donald L. Lappé, MD; Joao A. C. Lima, MD; Boaz D. Rosen, MD; Heidi T. May, PhD; Stacey Knight, PhD; David A. Bluemke, MD, PhD; Steven R. Towner, MD; Viet Le, PA1; Tami L. Bair, BS1; Andrea L. Vavere, MS; Jeffrey L. Anderson, MD
JAMA. 2014;312(20):2146-2155. doi:10.1001/jama.2014.10705

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Importance  Coronary artery disease (CAD) is a major cause of cardiovascular morbidity and mortality in patients with diabetes mellitus, yet CAD often is asymptomatic prior to myocardial infarction (MI) and coronary death.

Objective  To assess whether routine screening for CAD by coronary computed tomography angiography (CCTA) in patients with type 1 or type 2 diabetes deemed to be at high cardiac risk followed by CCTA-directed therapy would reduce the risk of death and nonfatal coronary outcomes.

Design, Setting, and Participants  The FACTOR-64 study was a randomized clinical trial in which 900 patients with type 1 or type 2 diabetes of at least 3 to 5 years’ duration and without symptoms of CAD were recruited from 45 clinics and practices of a single health system (Intermountain Healthcare, Utah), enrolled at a single-site coordinating center, and randomly assigned to CAD screening with CCTA (n = 452) or to standard national guidelines–based optimal diabetes care (n = 448) (targets: glycated hemoglobin level <7.0%, low-density lipoprotein cholesterol level <100 mg/dL, systolic blood pressure <130 mm Hg). All CCTA imaging was performed at the coordinating center. Standard therapy or aggressive therapy (targets: glycated hemoglobin level <6.0%, low-density lipoprotein cholesterol level <70 mg/dL, high-density lipoprotein cholesterol level >50 mg/dL [women] or >40 mg/dL [men], triglycerides level <150 mg/dL, systolic blood pressure <120 mm Hg), or aggressive therapy with invasive coronary angiography, was recommended based on CCTA findings. Enrollment occurred between July 2007 and May 2013, and follow-up extended to August 2014.

Main Outcomes and Measures  The primary outcome was a composite of all-cause mortality, nonfatal MI, or unstable angina requiring hospitalization; the secondary outcome was ischemic major adverse cardiovascular events (composite of CAD death, nonfatal MI, or unstable angina).

Results  At a mean follow-up time of 4.0 (SD, 1.7) years, the primary outcome event rates were not significantly different between the CCTA and the control groups (6.2% [28 events] vs 7.6% [34 events]; hazard ratio, 0.80 [95% CI, 0.49-1.32]; P = .38). The incidence of the composite secondary end point of ischemic major adverse cardiovascular events also did not differ between groups (4.4% [20 events] vs 3.8% [17 events]; hazard ratio, 1.15 [95% CI, 0.60-2.19]; P = .68).

Conclusions and Relevance  Among asymptomatic patients with type 1 or type 2 diabetes, use of CCTA to screen for CAD did not reduce the composite rate of all-cause mortality, nonfatal MI, or unstable angina requiring hospitalization at 4 years. These findings do not support CCTA screening in this population.


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Coronary artery disease (CAD) with associated myocardial infarction (MI) is the most common cause of morbidity and mortality in the United States.1 Often MI is the first symptom of CAD, suggesting the need for more effective screening of high-risk, asymptomatic patients.1,2

Diabetes mellitus is the most important CAD risk factor.3,4 Diabetes mellitus and its precursor, the metabolic syndrome, have become epidemic in the United States.5 Additionally, patients with diabetes often develop severe but asymptomatic CAD.6 The combination of aggressive CAD and asymptomatic presentation has made CAD the most common cause of death among patients with diabetes.5

In the past, screening for asymptomatic CAD has been limited to noninvasive tests with variable sensitivity and specificity and capable of identifying only obstructive CAD causing myocardial ischemia.7 The development of high-resolution multidetector coronary computed tomography angiography (CCTA) now provides the opportunity to evaluate the actual coronary anatomy noninvasively and ascertain the overall extent and severity of coronary atheroscleosis.8 Studies such as CORE 64 (Coronary Artery Evaluation Using 64-Row Multidetector Computed Tomographic Angiography) have demonstrated a high correlation between CCTA and invasive coronary angiography in the determination of CAD extent and severity,9 resulting in increased clinical utilization of CCTA. However, whether routine CCTA screening in high-risk populations can effect changes in treatment (such as preemptive coronary revascularization or more aggressive medical therapy), leading to a reduction in cardiac events, remains unproven.2,10- 14

The FACTOR-64 study was a randomized clinical trial that assigned high-risk, asymptomatic patients with diabetes to receive either systematic screening with 64-slice CCTA or standard treatment. The study was performed completely within the Intermountain Healthcare network of hospitals and clinics in the United States. The aim of FACTOR-64 was to test the hypothesis that screening patients with diabetes deemed to be at high risk for the presence of asymptomatic CAD through the use of 64-slice CCTA would result in a significant long-term reduction in death, MI, or hospitalization for unstable angina.


After approval of the study by the Intermountain Urban Central Region institutional review board, patients with a history of either type 1 or type 2 diabetes mellitus, with no clinical evidence of CAD, who met other eligibility criteria, and who provided personally signed informed consent were enrolled. Inclusion criteria consisted of men 50 years or older or women 55 years or older with diabetes (ie, with documentation of fasting glucose ≥126 mg/dL [6.99 mmol/L] or glycated hemoglobin [HbA1c] level >6.5%) documented for at least 3 years or men 40 years or older or women 45 years or older with diabetes for at least 5 years, with use of antidiabetic medication for at least 1 year prior to enrollment (study protocol available in Supplement 1).

Exclusions included any documented atherosclerotic cardiovascular disease (known CAD [coronary stenosis ≥70%], history of MI, or angina; history of stroke, transient ischemic attack, or carotid or cerebral artery revascularization; or history of claudication, amputation, or peripheral [including renal artery] arterial revascularization); treatment with an investigational drug within 30 days; therapy or condition posing a risk for adherence to study requirements; pregnancy, lactation, or childbearing potential without effective contraception; or limited life expectancy or comorbidity making primary screening and treatment inappropriate.

Baseline clinical and laboratory characteristics were obtained for each participating patient at enrollment. Patient characteristics noted included age; sex; type of diabetes; years diagnosed as having diabetes; race/ethnicity (as self-reported in the medical record); height; weight; blood pressure; smoking history; levels of HbA1c, creatinine, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides; hypertension; hyperlipidemia; all patient-reported medications; family history of diabetes or cardiovascular disease; and comorbidities (based on clinical International Classification of Diseases, Ninth Revision diagnosis). Any further laboratory tests were performed only as clinically indicated.
Patients were randomized 1:1 to the screening or no screening groups using a permuted-block randomization scheme.

Patient Management

Patients randomized to the screening group underwent CCTA screening as detailed in Figure 1. Imaging was performed on a single 64-slice coronary computed tomography (CT) scanner (Aquilion 64, Toshiba America Medical Systems) at Intermountain Medical Center using a standardized protocol.15 Coronary artery calcium (CAC) levels were obtained from non–contrast-enhanced scans using 3 mm of collimation at a 3-mm slice increment and were scored by the Agatston method. Coronary computed tomography angiography was performed with retrospective gating at 120kV and 350 to 600 mA, with a gantry rotation time of 400 milliseconds. Heart rate was controlled to less than 60/min with oral and, if necessary, intravenous metoprolol. Vasodilation was achieved with sublingual nitroglycerin (0.4 mg). Iopamidol 370 contrast (Isovue, Bracco Diagnostics) was injected into the right antecubital vein with automated bolus tracking at 180 Hounsfield units. Reconstruction using phaseXact software was performed using the FC43 “regular” kernel at 75% of the R-R interval. If phase was not optimal for image analysis, subsequent data sets were reconstructed based on an operator-determined phase of the R-R interval. Mean effective dose was 12 (SD, 2) mSv for CCTA.


All 14 208 patients enrolled in the 45 clinics and practices of Intermountain Healthcare’s Urban Central and North regions along the Wasatch Front of Northern Utah who were identified with diabetes in the Intermountain Healthcare electronic medical records were screened, and 4613 who qualified for inclusion by medical record review were approached for enrollment by research coordinators from Intermountain Medical Center, Salt Lake City, Utah. Of these, 3713 were excluded for reasons detailed in Figure 1. The remaining 900 patients from 45 clinics and practices provided informed consent, and 448 patients were randomized to the control group and 452 to the CCTA screening group.

Baseline Characteristics

Baseline characteristics of the study cohort, stratified by randomization group, are shown in Table 1. Randomization resulted in well-matched groups. The mean age was 62 years; the study population was approximately equally divided between men and women. Enrolled patients had a diagnosis of diabetes for an average of more than 12 years and had well-managed care, with baseline blood pressures, HbA1C levels, and lipid measurements close to or exceeding Intermountain targets.


The FACTOR-64 randomized trial evaluated whether routine CCTA screening of asymptomatic patients with diabetes (average disease duration >12 years) could beneficially influence clinical outcomes and risk factor control. Overall, annual event rates in both control and intervention groups were low (<2%), and outcomes (death, MI, or unstable angina) did not differ significantly between the CCTA and no CCTA groups after a mean of 4 years of follow-up.

Coronary computed tomography angiography involves significant expense and radiation exposure, so that justification of routine screening requires demonstration of net benefit in an appropriately high-risk population. We tested whether patients with long-standing diabetes represent such a group. Although CCTA screening demonstrated a marked diversity of CAD burden that was related to cardiovascular risk and led to more aggressive treatment recommendations for lipids, blood pressure, and glucose control in 70% of patients, which resulted in significant improvements in statin use and intensity, lipid fractions, and blood pressure levels, there was no advantage in reducing death and coronary heart disease outcomes. With the restrictions the protocol placed on contrast use according to baseline serum creatinine levels, no long-term adverse effects on renal function were observed in patients who received CCTA.

In a previous study, the DIAD (Detection of Ischemia in Asymptomatic Diabetics) Investigators10randomized 1123 asymptomatic patients with type 2 diabetes to undergo adenosine-stress myocardial perfusion imaging or no screening. Similar to our study, these authors noted a low cardiac event rate (2.9% in 4.8 years) and found no difference in the primary end point of cardiac death or nonfatal MI (HR, 0.88; P = .73). However, as with our study, evidence of CAD in the screened group predicted higher event rates. Unlike our study, DIAD was not designed as a treatment trial and did not provide a specific treatment plan based on myocardial perfusion imaging results.

There are several possible explanations for our results. First, despite specifically targeting enrollment of high-risk patients with diabetes (based on age and diabetes duration), the annual event rate was one-fourth of predicted, so the patients in this study were not actually at high risk. At study planning in 2006, a higher anticipated event rate was justified by our internal analysis within Intermountain Healthcare and further supported by published registries.18 We attribute the lower event rate we observed within the FACTOR-64 study to the excellent medical management received by all enrollees, with baseline levels near or exceeding system targets for HbA1c, LDL-C, and systolic blood pressure (Table 1). This high-quality care may be ascribed to the initiation in 1997 of the Intermountain Healthcare Diabetes Prevention and Management Development Team, which was charged with providing system-wide standards and therapeutic guidance and was fully functioning by 2005, thus making the differences in medical management between FACTOR-64 patients randomized to CCTA screening vs control less than might otherwise be expected.

Second, any effect of coronary revascularization for severe CAD on outcomes was limited by its much lower than anticipated incremental rate of application (5.8%). On the other hand, the benefit of revascularization applied as in FACTOR-64 may not be clinically relevant. Although our recommendations regarding coronary revascularization were similar to recently published national guidelines for improving survival in patients with severe CAD,19 results from the BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes)14 and COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation)20 studies raise the question of whether revascularization can provide important incremental benefit over optimal medical therapy alone.

Strengths of our study include the relatively large size, the randomized study design, and the 4-year follow-up. Also, CCTA results were used to inform medical and procedural management using a standardized algorithm. The major limitation of our study was the unexpected low overall incidence of adverse events, limiting power to exclude a clinically important difference between the 2 study groups. This limitation arises from at least 3 sources: (1) the lower than expected annual event rates, (2) the overly optimistic assessment of risk reduction, and (3) the variable implementation of treatment recommendations by the broad spectrum of clinicians caring for these patients. Other potential limitations include that the study was performed in a single health system, some patients were lost to telephone follow-up, some patients were randomized to receive CCTA scanning but ultimately did not undergo the procedure, and information on functional status and cost was not available.


Among asymptomatic patients with type 1 or type 2 diabetes, use of CCTA to screen for CAD did not reduce the composite rate of all-cause mortality, nonfatal MI, or unstable angina requiring hospitalization at 4 years. These findings do not support CCTA screening in this population.[/tab]


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