Studies Question Accuracy of Adenosine-Free Gauge of Stenosis Severity

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An alternative drug-free index of stenosis severity once thought to rival fractional flow reserve (FFR) does not provide equivalent results in 2 separate studies published online February 6, 2013, ahead of print in the Journal of the American College of Cardiology. According to the findings, instantaneous wave-free ratio (iFR) correlates weakly with FFR and is not independent of hyperemia.

iFR is a new pressure-based index designed by the authors of the ADVISE (ADenosine Vasodilation Independent Stenosis Evaluation) study presented at the annual Transcatheter Cardiovascular Therapeutics scientific symposium in November 2011 in San Francisco, CA. It is based on the diastolic ‘wave-free period’ when intracoronary resistance is naturally constant and minimized. Unlike FFR, iFR calculation does not require the administration of adenosine or any other vasodilating drug. ADVISE found iFR to have diagnostic accuracy similar to that of FFR.

Verifying a Method

For the international VERIFY (Verification of Instantaneous Wave-Free Ratio and Fractional Flow Reserve for the Assessment of Coronary Artery Stenosis Severity in Everyday Practice) trial, Colin Berry, MBChB, PhD, of the University of Glasgow (Glasgow, United Kingdom), and colleagues prospectively looked at 206 consecutive patients referred for angiography and conducted a retrospective analysis of 500 archived pressure wire recordings obtained under both resting conditions and during intravenous adenosine infusion. Results were previously presented at EuroPCR 2012 in Paris, France.

Using an iFR cut-off for significant stenosis of either ≤ 0.80 or ≤ 0.83, there was a moderate overall correlation between FFR and iFR, but only weak correlation in the clinically important range for decision making of 0.60 to 0.90 (table 1).

Table 1. Overall Diagnostic Accuracy of iFR vs. FFR

 

All Vessels (95% CI)

FFR 0.60-0.90 (95% CI)

iFR ≤ 0.80

60% (53% to 67%)

51% (43% to 59%)

iFR ≤ 0.83

68% (61% to 75%)

60% (52% to 68%)


In addition, iFR was influenced by the induction of hyperemia (0.82 ± 0.16 at rest vs. 0.64 ± 0.18 with hyperemia; 95% CI for difference 0.17-0.20; P < 0.0001).

Both iFR and FFR showed excellent reproducibility. However, FFR had better reproducibility with the iFR differences having between 2.5 and 4.4 times larger variance than FFR differences.

Results from the retrospective analysis were consistent with the prospective study.

“The hypothesis underlying iFR depends on accepting that mean resting myocardial resistance during the [wave-free period] of diastole is minimal and equivalent to mean resistance during maximal hyperemia over the complete cardiac cycle. However, this is clearly not the case,” Dr. Berry and colleagues write. “The concept of iFR also depends on accepting that adenosine exerts its predominant effect on coronary flow during systole and does not influence mean resistance during the [wave-free period] in diastole. This is also incorrect.”

Additional Issues Arise

For the second study, K. Lance Gould, MD, of the University of Texas Medical School at Houston (Houston, TX), and colleagues retrospectively analyzed information from 1,129 patients, including 120 with combined pressure-flow and clinical data. A model was used to simulate the effects of varying several physiological parameters.

Clinical data showed that iFR was 0.09 higher than FFR on average, with ± 0.17 limits of agreement. There was a trade-off regarding the frequency of adenosine administration necessary to obtain FFR when iFR was discordant. For example, if a 99% level of diagnostic accuracy were desired, then the iFR range requiring adenosine would be 0.74 to 0.98 and 76% of cases would need vasodilation. On the other hand, if only a 96% level of diagnostic accuracy were desired, then the iFR range requiring adenosine would shrink to 0.82 to 0.96, but 54% of cases would still need vasodilation.

Diastolic resting resistance was 2.46 ± 1.03 times higher than mean hyperemic resistance in patients.

Dr. Gould and colleagues argue that iFR “provides a biased estimate [of] FFR on average with significant and unpredictable discordance that limits its widespread application, especially when considering the clinical consequences. Such discordance is fundamental to the physiologic basis for iFR itself.”

The End of iFR?

In an e-mail communication with TCTMD, William F. Fearon, MD, of Stanford University Medical Center (Stanford, CA), said that iFR is yet another resting pressure parameter introduced to rival FFR and “subject to the same limitations as previously tested ones.”

Dr. Fearon, who coauthored both papers, said that “resting [distal pressure/aortic pressure (Pd/Pa)] and iFR are equivalent in their diagnostic accuracy, now shown in multiple studies to be roughly 80%. This means that 1 in 5 patients will be incorrectly diagnosed based on iFR or resting Pd/Pa. We have known this limitation of resting Pd/Pa for years, and that is why it has never been adopted as a viable index.”

He gave 2 reasons why iFR should not be a viable option moving forward. “First, iFR is not accurate enough to replace FFR,” he commented. “Second, administering a hyperemic agent, such as intracoronary adenosine, is inexpensive, extremely safe with few if any side effects, no known contraindications, and easy to do.”

Dr. Fearon referenced several reasons why interventionalists might opt to not measure FFR, including “unfamiliarity with the technique, unhappiness with the pressure wire characteristics, financial disincentive, and the perception that it will unduly prolong the procedure.”

Regarding adenosine, Dr. Berry and colleagues noted that “[a]ny adverse reactions that do occur are short lived and harmless, with severe asthma being the only absolute contraindication.”

iFR Measurement Method Crucial

ADVISE coauthor Justin E. Davies, MD, PhD, of Imperial College (London, United Kingdom), told TCDMD in an e-mail communication that although VERIFY data were included in both of the above papers, “the authors conclude very different findings. This is curious. If the same data [are] analyzed in 2 different studies, why do the results vary from as low as 50% agreement in VERIFY to 80% agreement in [the second] paper?”

The exact method of iFR measurement is “key,” he continued, noting that both the RESOLVE and ADVISE trials calculated iFR with specific algorithms not used in the VERIFY trial.

Dr. Davies and his team have been conducting “our first cases on the real-time iFR console, which is hugely exciting, and it has now been deployed in a number of sites in Europe,” he said. “Real-time iFR assessment hugely simplifies multivessel assessment, and periprocedural PCI assessment, making it really easy, as the measurement doesn’t require adenosine and takes only 5 seconds.”

He added that the multicenter, international ADVISE 2 study, currently enrolling patients, will report further data on iFR and FFR agreement later this year.

Study Details

In the VERIFY trial, pressure measurements were obtained using the RadiAnalyzer Xpress instrument (St. Jude Medical, Uppsala, Sweden) and a Certus pressure wire (also St. Jude Medical).

 


Sources:
1. Berry C, van’t Veer M, Witt N, et al. VERIFY (VERification of Instantaneous wave-free ratio and Fractional flow reserve for the assessment of coronary artery stenosis severity in everydaY Practice): A multicenter study in consecutive patients. J Am Coll Cardiol. 2013;Epub ahead of print.

2. Johnson NP, Kirkeeide RL, Asrress KN, et al. Does the instantaneous wave-free ratio approximate the fractional flow reserve? J Am Coll Cardiol. 2013;Epub ahead of print.

 

 

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Disclosures
  • St. Jude Medical provided the coronary pressure wires as an unrestricted research grant for the VERIFY trial.
  • Drs. Berry and Fearon report receiving research support from St. Jude Medical.
  • Dr. Gould reports receiving internal funding from the Weatherhead PET Center for Preventing and Reversing Atherosclerosis, University of Texas Medical School.
  • Dr. Davies reports receiving research contracts from Medtronic and serving as a consultant for Medtronic and Volcano.

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