CHICAGO, IL—A strategy of screening asymptomatic patients with diabetes with computed tomography angiography (CTA) and using the results to guide their management does not yield improved long-term outcomes, according to findings from the FACTOR-64 trial presented November 17, 2014, at the American Heart Association Scientific Sessions and simultaneously published in the Journal of the American Medical Association.

Because CTA involves substantial expense and radiation exposure, justification of routine screening requires demonstration of net benefit in an appropriately high-risk population, said lead investigator Joseph B. Muhlestein, MD, of Intermountain Medical Center Heart Institute (Murray, UT), and that was not seen here.

Researchers randomized 900 high-risk asymptomatic patients with long-standing diabetes to screening with 64-slice CTA (Aquilion 64, Toshiba America Medical Systems; n = 452) or guidelines-based optimal diabetes care (n = 448). The groups were well matched in age (about 62 years), sex (slightly more than half men), and diabetes duration (about 10 years). Overall, 12.6% of those assigned to screening did not undergo a scan, mainly due to the inability to reduce heart rate. 

Screening Results Guide Recommendations

CTA screening uncovered a range of CAD severity:

• Severe obstruction (≥ 70% stenosis in at least 1 major proximal or large coronary artery): 11%
• Moderate CAD (50%-59% stenosis or coronary artery calcium score >100): 12%
• Mild stenosis (10%-49% stenosis or coronary artery calcium score > 10-100): 46%
• Normal arteries (< 10% stenosis and coronary artery calcium score ≤ 10): 31%

Diagnostic invasive angiography was recommended for those with severe obstruction while those with moderate CAD were recommended for stress imaging and to proceed to angiography if clinically relevant ischemia were found. Patients with mild stenosis or normal arteries received no further imaging, and revascularization was based on the judgment of the treating physician. 

Medical management of the screening group was also based on scan results. Patients with normal arteries were continued on standard diabetes care, while those with mild-to-severe proximal or distal CAD or a calcium score greater than 10 were recommended to receive aggressive care to reduce risk factors.

Overall, CTA screening resulted in a recommendation for additional diagnostics, more-aggressive risk factor reduction, or both, in more than two-thirds of patients. 

At a mean follow-up of 4 years, intention-to-treat analysis showed similar rates of the composite of death, nonfatal MI, and hospitalization for unstable angina (primary endpoint) between the screened and unscreened groups, as were rates of ischemic MACE and cardiovascular death (table 1). A similar pattern was observed in the as-treated analysis.

In the CTA cohort, 61 (14%) patients received protocol-recommended stress or noninvasive imaging tests and 36 (8%) had protocol-recommended invasive angiography procedures, which together led to 26 revascularizations. Symptom-driven diagnostic angiography tended to be more common in the control group, whereas symptom-driven rates of invasive angiography and revascularization were similar between the groups.

Examination of the impact of medical therapy on various risk factors showed improvements in levels of LDL cholesterol (-2.64 mm/dL; P = .01), HDL cholesterol (1.13 mm/dL; P = .006), and triglycerides (-5.54 mm/dL; P = .06) in screened but not unscreened patients; only HDL exhibited a difference between the groups. In contrast, hemoglobin A_1C values were unchanged in both groups. 

When risk factor changes were assessed at 1 year, improvements were seen in both blood pressure and lipid targets among patients assigned to aggressive medical therapy, but only triglyceride levels demonstrated a difference between the screened and control groups. In general, less than half of screened patients reached the specified aggressive risk factor reduction targets at 1 year.

In post hoc analysis, the primary outcome was proportional to the CAD burden assessed by both CTA and calcium score. 

Explaining the Negative Results

Dr. Muhlestein and colleagues point out that the annual event rate was one-quarter of that predicted, suggesting that the study patients were not really at high risk. They attribute that to the “excellent” medical therapy given all enrollees by the Intermountain Healthcare system. The result was baseline levels of hemoglobin A_1C, LDL cholesterol, and systolic BP near or exceeding target levels, which diminished the odds of finding a difference between screened and unscreened patients. In addition, the impact of revascularization in asymptomatic patients may not have been clinically relevant, they say. 

Pamela S. Douglas, MD, of Duke University (Durham, NC), similarly noted that while 70% of the CTA group upgraded cardiovascular prevention goals, diabetic risk markers were only minimally affected. However, she said, nationally, less than 10% of diabetics are at target goals, underlining a large shortfall in risk reduction outside of clinical trials.

‘An Ounce of Prevention’ 

In an editorial accompanying the JAMA paper, Raymond J. Gibbons, MD, of the Mayo Clinic (Rochester, MN), writes that while the trial may be characterized as “negative,” the issue of CTA screening warrants larger studies focused on a higher-risk population, to enhance the chances of success. Meanwhile, the results suggest that “an ‘ounce of prevention’ with optimal guideline-directed medical therapy in asymptomatic patients with diabetes is more important than cardiac imaging.” The challenge for clinicians is to deliver it more consistently, he adds.

Still, Dr. Douglas suggested that CTA may still have a role in improving outcomes if, for example, seeing a high calcium score motivates diabetics to better adhere to medical therapy or make lifestyle changes. 

She added that because events are not confined to those with obstructive disease, “we need to explore new strategies for better risk prediction in individuals” that go beyond assessing ischemia, perhaps by looking at vulnerable plaque or cellular targets.

Sources:
1. Muhlestein JB, Lappé DL, Lima JAC, et al. Effect of screening for coronary artery disease using CT angiography on mortality and cardiac events in high-risk patients with diabetes: the FACTOR-64 randomized clinical trial. JAMA. 2014;Epub ahead of print.
2. Gibbons RJ. Optimal medical therapy vs CT angiography screening for patients with diabetes [editorial]. JAMA. 2014;Epub ahead of print.

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