FACTOR-64: No Outcomes Gains from Treatment Based on CT Screening in Asymptomatic Diabetics

December 08, 2014

CHICAGO, IL — Screening asymptomatic persons with diabetes using coronary computed tomographic angiography (CTA) may improve their cardiovascular risk profile by steering many of them toward more aggressive therapy, but the strategy has little effect on mortality or nonfatal CV events over 4 years, concluded researchers based on a randomized 900-patient trial[1].

The burden of coronary artery disease by coronary CTA screening varied widely among the patients; many went on to PCI when obstructions were severe enough, and the cohort as a whole showed trends toward better control of blood pressure and lipids, according to Dr Joseph B Muhlestein (Intermountain Medical Center Heart Institute, Murray, UT).

"But in the end, these findings do not support coronary CTA screening in this population," Muhlestein said when presenting the study, called FACTOR-64, at the American Heart Association (AHA) 2014 Scientific Sessions. He is also lead author of the article published in the Journal of the American Medical Association in tandem with the trial's presentation.

Great Medical Therapy vs Useful Risk Stratification

It's been hoped that coronary CTA might identify diabetics without cardiovascular symptoms for whom more aggressive intervention, including PCI, might provide solid clinical benefits, but "at the present time I don't know if [such screening should have] a significant role in asymptomatic patients," Muhlestein said.

"We have to figure out how to identify the higher-risk populations, especially when they're already well medically managed. It appears that aggressive, excellent medical management is the most important thing in asymptomatic patients."

Noninvasive testing, whether functionally with stress testing or anatomically, as with coronary angiography, can indeed identify a high-cardiovascular-risk group among asymptomatic diabetics, but the effect may be limited to the population level, according to Muhlestein's assigned discussant, Dr Pamela Douglas (Duke University School of Medicine).

"Diabetes is a cardiovascular risk equivalent, and they should [already] be receiving aggressive secondary-prevention management, [which] will make it difficult to change care with a risk-stratification strategy."

Also, she continued, "there's no established role for revascularization in asymptomatic coronary artery disease, especially in individuals without ischemia." And even in those with symptoms, "such as those in the COURAGE trial, we now know that revascularization does not reduce events. It's unlikely that revascularization will have greater benefit in an asymptomatic group such as was studied here."

There's one situation in which such coronary CTA may have a role, she observed. "I think if somebody's on the fence about how aggressively to treat and doesn't want to be confined to medication, it's possible that imaging can provide additional evidence that may tip the balance."

Cohort Included Types 1 and 2 Diabetes

The 900 FACTOR-64 patients, with type 1 or type 2 diabetes of at least 3 years' (mean 12 years') duration, recruited from 45 centers and practices within a single regional healthcare system, were randomized to coronary CTA screening (452 patients, using the same 64-slice scanner at one location) or standard management (448 patients).

Standard management consisted of medical therapy consistent with "standard national-guidelines–based optimal diabetes care," with targets to <7.0% for HbA1c, <100 mg/dL for LDL cholesterol, and <130 mm Hg for systolic blood pressure.

The screened patients were classified by CAD severity or coronary artery calcium (CAC) score as having disease that was severe (>70% stenosis in at least one major proximal or large coronary artery), moderate (50%–69% stenosis or CAC score >100), or mild (10%–49% stenosis in any coronary artery or CAC score >10–100) or having normal coronaries (<10% stenosis and minimal or no evidence of plaque, and CAC score <10).

Patients with severe disease were referred for diagnostic angiography; those with moderate disease were referred to stress perfusion imaging and then, if appropriate, diagnostic angiography. The decision whether to revascularize was left to the treating physicians. Patients with mild disease or normal coronaries were not referred for imaging.

Medical therapy in the coronary-CTA group consisted of standard management in those with normal coronaries (30% of screened patients) and aggressive management (70% of screened patients) in those with mild to severe proximal disease or distal CAD by imaging or a CAC score >10. Targets for aggressive medical therapy included:

  • HbA1c to <6.0%.

  • LDL cholesterol to <70 mg/dL.

  • HDL to >50 mg/dL for women or >40 mg/dL for men.

  • Triglycerides to <150 mg/dL.

  • Systolic blood pressure to <120 mm Hg.

After a mean 4-year follow-up, the primary end point (all-cause mortality, nonfatal MI, or unstable angina requiring hospitalization) was met by 6.2% of screened patients and 7.6% of standard-care patients by intention to treat, for a hazard ratio (HR) of 0.80 (95% CI 0.49–1.32), P=0.38. There were no significant differences for any of the components of the composite primary end point.

Nor was there a significant difference for the secondary end point of ischemic major adverse cardiovascular events, 4.4% and 3.8%, respectively (HR 1.15, 95% CI 0.60–2.19; P=0.68), nor for stroke or heart-failure hospitalization.

Unlike patients in the control group, patients randomized to screening showed significant improvements in mean levels of diastolic blood pressure, LDL cholesterol, and HDL cholesterol, and a trend toward improved triglycerides. Neither group showed improved HbA1c.

"The negative results of this trial will be disappointing to those who have advocated cardiac imaging for screening but are consistent with the prior negative results of the DIAD study," writes Dr Raymond J Gibbons (Mayo Clinic, Rochester, MN) in an editorial accompanying the FACTOR-64 paper[2].

That randomized trial with >1000 asymptomatic diabetics without CAD symptoms also concluded that screening, in that case with adenosine stress perfusion imaging, didn't make a difference to clinical outcomes.

According to Gibbons, a main message from FACTOR-64 is that "guideline-directed medical therapy for hypertension and hyperlipidemia is effective in asymptomatic patients with diabetes and should be implemented more consistently."

The regional system that conducted FACTOR-64 "has set a new published standard for what is achievable in patients with diabetes with respect to blood-pressure control and lipid-lowering therapy and, when therapy is applied this effectively, patients with diabetes are no longer at high risk for major cardiovascular events."

FACTOR-64 was supported by Toshiba and Bracco Diagnostics. Muhlestein and coauthors and Douglas reported they had no relevant financial relationships. Gibbons discloses serving as a consultant for Lantheus Medical Imaging.

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