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DeFACTO Propels CT Fractional Flow Reserve Closer to Clinical Practice

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DeFACTO Advances Quest for Imaging 'Holy Grail'

"Technologies that provide both a highly sensitive anatomic evaluation for obstructive disease and a highly specific physiologic evaluation for ischemia represent the ‘Holy Grail’ for noninvasive imaging for CAD," Dr. Manesh R. Patel wrote in an accompanying editorial (JAMA 2012 Aug. 26 [doi: 10.1001/2012.jama.11383]).

One possible investigational approach is the combination of anatomic analysis using CT and functional analysis using fractional flow reserve based on CT data (FFR-CT).

The DeFACTO investigators "raise the bar by comparing this diagnostic technology with a reference standard of both invasive angiography and invasive FFR. This change in reference standard may in part explain some of the accuracy findings. So how should these findings be considered with regard to current clinical evaluation for chest pain?" asked Dr. Patel.

It’s important to put the findings on the performance of CT angiography into context, he wrote. "Several recent multicenter studies have reported diagnostic performance of CT angiography to have high sensitivity (i.e., between 85%-95%) compared with conventional invasive angiography for stenoses of 50% or greater." The high sensitivity of CTA has been used to triage low-risk patients in acute settings.

"However, in stable intermediate-risk patients, for whom a higher degree of specificity (low rate of false positive results) may be desirable to reduce referrals for invasive angiography, concerns exist about the specificity of CT angiography," Dr. Patel noted. In the present study, CT angiography had a sensitivity of 84% but a specificity of only 42% with the more rigorous reference standard.

"It is in this context that FFR-CT represents a novel and important innovation, with the possibility not only to diagnose but also to help direct invasive treatment. The current ... multicenter report by Min et al. confirms a high sensitivity (90%) but demonstrates modest specificity (54%), albeit better than CTA alone," he wrote.

"At first glance, readers of the study may consider FFR-CT technology to be limited based on the results presented. However, this would be a naive conclusion, likely based on the published diagnostic performance of noninvasive tests compared only with invasive angiography," Dr. Patel warned. By comparing existing noninvasive imaging technologies with invasive angiography plus FFR, it is highly likely that the published diagnostic performance would be reduced. "In fact, in clinical practice, the sole use of invasive angiography for lesion evaluation has decreased. Additionally, in real-world practice, the current noninvasive technologies used for diagnosis and risk stratification in stable elective patients prior to invasive angiography do not perform at the published diagnostic levels, as evidenced by the low rates of obstructive CAD at elective catheterization. Hence, the current report describes an important noninvasive technology that may improve existing care and has the potential to outperform established noninvasive technologies," according to Dr. Patel.

DR. PATEL is the cardiology section leader in the peripheral vascular program at Duke University in Durham, N.C., and is assistant director of the cardiac catheterization laboratory. Dr. Patel reports consultancy for Bayer, Jansen, Baxter, and Otsuka, and grants from Johnson & Johnson and AstraZeneca.



The addition of CT-based fractional flow reserve information to CT alone improved the diagnostic accuracy of stenoses, allowing noninvasive assessment of the physiologic consequences of lesions, according to the long-awaited results of the Determination of Fractional Flow Reserve by Anatomic Computed Tomographic Angiography (DeFACTO) study.

However, CT fractional flow reserve (FFR-CT) plus CT narrowly failed to meet the trial’s primary end point – diagnostic accuracy greater than 70% for the lower bound of the 95% confidence interval. Per-patient performance diagnostic accuracy of FFR-CT plus CT was 73% with a 95% CI of 67%-78%.

Nevertheless, the addition of FFR-CT "demonstrated superior diagnostic performance characteristics, as compared with CT stenosis alone, in all patients, in all vessels, and also in vessels of intermediate stenosis severity," lead author Dr. James K. Min said during a press conference.

The results of the study were released in JAMA on Aug. 26th to coincide with the presentation of the study at the European Society of Cardiology meeting (JAMA 2012;308 [doi: 10.1001/2012.jama.11274]).

Fractional flow reserve (FFR) is currently assessed during invasive coronary angiography (ICA) to determine whether a coronary stenosis results in ischemia, and is the currently accepted reference standard for determining lesion-specific ischemia. FFR is the ratio of the mean coronary pressure distal to a coronary stenosis to the mean aortic pressure during maximal coronary blood flow. This value describes coronary flow still attainable despite the presence of a stenotic lesion.

While CT angiography has long been used to accurately and noninvasively assess the anatomic severity of stenoses, the technique has been criticized because it does not yield functional information about the hemodynamic effect of lesions.

Noninvasive calculation of FFR from CT "is a novel method that applies computational fluid dynamics to determine the physiologic significance of CAD [coronary artery disease]. Fractional flow reserve from CT enables calculation of rest and hyperemic pressure fields in coronary arteries without additional imaging, modification of CT acquisition protocols, or administration of medications," the investigators wrote.

"Taken together, these study results suggest the potential of FFR-CT as a promising noninvasive method for identification of individuals with ischemia. The present study findings can be considered proof of concept of the feasibility of this novel technology."

A total of 252 patients were included in the final analysis of the DeFACTO study. These patients had CAD and underwent clinically indicated ICA after CT with no intervening coronary event. Patients were not eligible if they had a history of coronary artery bypass graft (CABG) surgery or percutaneous coronary intervention. About 77% of patients had experienced angina within the past month.

Among 615 study vessels, 271 had less than 30% stenosis and 101 had at least 90% stenosis. In all, 407 vessels were directly assessed by both FFR and FFR-CT.

Computed tomographic angiography was performed on 64- or greater detector scanners with prospective or retrospective electrocardiographic gating.

The investigators evaluated CTs for maximal patient-, vessel-, and segment-based diameter stenosis (characterized as 0%, 1%-29%, 30%-49%, or 50% or larger).

Per-patient and per-vessel CAD stenosis were the maximal stenoses identified in all segments or in all segments within a vessel distribution, respectively. Vessel distributions were categorized for the left anterior descending, left circumflex, and right coronary artery. Computed tomographic angiograms (CTAs) were judged as excellent, good, adequate, or nondiagnostic.

Selective ICA was performed by standard protocol, and FFR was performed at the time of ICA. Fractional flow reserve was considered diagnostic of ischemia at a threshold of 0.80 or less. Computation of FFR-CT was performed in blinded fashion by the FFR-CT core laboratory at HeartFlow, the study’s sponsor.

Per-patient diagnostic accuracy for FFR-CT plus CT was 73%. By comparison, diagnostic accuracy of CT alone was 64%.

FFR-CT also demonstrated greater discriminatory power than CT alone for vessels directly assessed by invasive FFR. For these vessels, the diagnostic sensitivity and specificity of FFR-CT alone were 80% and 61%, respectively.

Importantly, the researchers performed a secondary analysis of patients with an intermediate stenosis ranging from 30% to 70%, "wherein the clinical utility of FFR-CT would be most commonly expected for use." Diagnostic accuracy (73% for FFR-CT and 57% for CT), sensitivity (82% and 37%, respectively), positive predictive value (54% and 34%) and negative predictive value (88% and 68%) were greater for FFR-CT than for CT, though specificity was similar at 66%.

This intermediate group is an important patient population. "We know that patients with 30%-70% stenosis – even though they don’t look high-risk anatomically – actually, some of them experience ischemia and physiologic consequences of their coronary artery disease," said Dr. Min, director of cardiac imaging research and co-director of cardiac imaging at the Cedars-Sinai Heart Institute in Los Angeles.


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