Study Suggests FFR Diagnostic ‘Gray Zone’ Complicates Clinical Decision Making

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Due to the intrinsic variability of fractional flow reserve (FFR) measurements, a significant percentage of lesions may fall within a ‘gray zone’ in which revascularization decisions are less than clear, according to a paper published in the March 2013 issue of JACC: Cardiovascular Interventions. The researchers say the problem emphasizes the need for clinicians to make such decisions based on clinical judgment that takes into account a number of factors rather than solely on the basis of a number.

Investigators led by Ricardo Petraco, MD, of Imperial College London (London, United Kingdom) and colleagues analyzed FFR reproducibility data from the DEFER (Deferral Versus Performance of PTCA in Patients Without Documented Ischemia) trial using a cutoff of 0.80. FFR analysis was performed twice, 10 minutes apart in the same lesion, and the standard deviation of the difference was calculated.

Enter the ‘Gray Zone’

At the extremes of the disease spectrum, the diagnostic agreement between the repeated FFR measurements was 100%. However, within the region of physiologically intermediate values (0.75 to 0.85), the agreement declined. Specifically, for lesions in the 0.77 to 0.83 range, measurement certainty was less than 80%, reaching a nadir of approximately 50% around the established clinical cutpoint of 0.80.

“This measurement uncertainty creates a . . . a measurement gray zone—which has several important implications, both to the interpretation of available FFR studies and to its application in clinical practice,” the authors write.

They offer several explanations for the variability of repeat measurements:

  • Variable response of the microcirculation to adenosine
  • Systemic vasodilator effects of adenosine on aortic blood pressure
  • A possible direct effect of adenosine on myocardial function

Dr. Petraco and colleagues say clinicians interpreting the appropriateness criteria for FFR-guided revascularization should be aware of the consequence of natural biological variability of FFR on diagnostic classification of stenoses.

When an FFR measurement is less than 0.75 or more than 0.85, clinicians can use a strict dichotomous approach based solely on the FFR result, confident that a repeat FFR would recommend the same strategy more than 95% of the time, they write, adding that, “For patients with FFR between 0.75 and 0.85, however, a repeat FFR might allocate the patient to the opposite treatment category, with the chance of change in strategy increasing as FFR approximates to 0.80. Between 0.77 and 0.83, the chance of this happening is as high as 1 in every 5 patients (20%).”

Therefore, when measurements fall within this range, clinicians should “use all available information (including other perfusion imaging modalities, considering anatomical features and risk-benefit profile) to deliver safe and suitable care for individual patients,” they write.

In an e-mail communication with TCTMD, Dr. Petraco said the overall message of the study is positive “because it suggests more freedom should be given to interventionalists when judging which stenoses deserve revascularization in cases when FFR values are close to 0.8, at whichever side of the cutoff. In other words, the magic 0.8 number should not be followed so strictly, particularly between 0.77 and 0.83, when the chance of a repeated FFR measurement crossing the cut-off 10 minutes later is about 20%.” He added that “[i]t is only fair that interventionalists are provided with quantifiable information on FFR variability to make appropriate clinical judgement on their patients.”

Confidence in the Current Threshold

But an editorial accompanying the study questions the ‘gray zone’ concept entirely.

William Wijns, MD, PhD, and Stylianos A. Pyxaras, MD, both of Cardiovascular Center Aalst (Aalst, Belgium), write that while no measuring technique is perfect and both biological and measurement variability should be accounted for, the investigators’ argument shows some crucial misunderstandings and is, in effect, playing with numbers. They note that both randomized and observational studies have confirmed the validity of using the 0.80 threshold “as the value below which downstream ischemia becomes highly probable and deserves treatment.”

Nonetheless, the editorial states, given the challenges of accurate FFR measurement, the technique “should not be used as a gatekeeper and is no excuse for go/no-go threshold-driven Pavlovian behavior, replacing angiography by pressure, as a trigger.”

But Dr. Petraco said ample evidence from Dr. Wijns’s own research suggests it is safe to defer revascularization of lesions with an FFR greater than 0.75 as well to treat those with FFR less than 0.8.

Dr. Wijns was the senior author of DEFER, which showed a rate of events of less than 1% per year for lesions with an FFR of at least 0.75, with no benefit of PCI over medical therapy, Dr. Petraco said. “At the same time, we have FAME and FAME II data, which indisputably showed that lesions with FFR < 0.8 should be stented,” Dr. Petraco said. “It is important to remember, however, that the benefits seen in FAME occur on average, across a sample of patients with a wide range of abnormal FFR values.”

He added that FAME II events have been shown to be largely driven by stenoses with severe FFR values (26% were less than 0.5), whereas close to the 0.8 cutoff, events were much less common. This provides further evidence, he suggested, that clinicians should be equally confident in deferring or treating stenoses when FFR values fall very close to the cutoff.

William F. Fearon, MD, of Stanford University Medical Center (Stanford, CA), told TCTMD in an email communication that the paper is not the first to suggest extending the gray zone above 0.80 and agreed that within the range of 0.75 to 0.80, clinical judgment is necessary to decide about revascularization.

“I agree that rigid dichotomy is not ideal and no measurement is perfect,” he said. But Dr. Fearon took issue with the paper as a whole, saying it is “not based on actual data, but incomplete data derived from a graph published in a review article about FFR and not even included in the originally published DEFER manuscript. Moreover, the DEFER data were acquired in the 1990s using inferior and old pressure wire technology.” He said current generation pressure wires have been shown to deliver more reproducible measurements.


1. Petraco R, Sen S, Nijjer S, et al. Fractional flow reserve-guided revascularization: Practical implications of a diagnostic gray zone and measurement variability on clinical decisions. J Am Coll Cardiol Intv. 2013;6:222-225.

2. Wijns W, Pyxaras SA. Chasing numbers: The reinvention of clinical science. J Am Coll Cardiol Intv. 2013;6:226-227.



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  • Drs. Petraco, Wijns, and Pyxaras report no relevant conflicts of interest.
  • Dr. Fearon reports receiving research support from St. Jude Medical.

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