February 6th, 2013
FFR vs. iFR: All That Glitters Is Not Gold
Richard A. Lange, MD, MBA and L. David Hillis, MD
The “Gold Standard”: Fractional flow reserve (FFR) is a pressure-derived index of coronary stenosis severity that has been validated for assessing the hemodynamic significance of stenoses that are of “intermediate” angiographic severity. In fact, FFR use during PCI carries a Class 1A recommendation from the European Society of Cardiology and a Class IIA recommendation from the American College of Cardiology, despite the fact that it requires additional instrumentation of the coronary arteries and pharmacologic vasodilation to induce maximal hyperemia.
Easier Money? The instantaneous wave-free ratio (iFR) is an alleged index of coronary stenosis severity that is independent of hyperemia. It is based on the hypothesis that coronary microvascular resistance is minimal during mid and late diastole (when coronary flow is maximal), so the administration of a vasodilator is unnecessary. It is thought that by avoiding the need to administer adenosine, iFR is more likely than FFR to expand the practice of pressure wire-guided decision making.
Convertible Currency? Unfortunately, the results of two new studies suggest that iFR is unlikely to replace FFR.
Using a simulation model to study the relationship between iFR and FFR, then validating their predictions with data from a large, multicenter cohort of humans, Johnson and colleagues found that:
- iFR systematically overestimates FFR, with wide limits of agreement that would often alter management decisions.
- In individual patients, iFR is not interchangeable with FFR.
In VERIFY, a prospective study of 206 consecutive PCI patients compared with a retrospective analysis of 500 archived pressure recordings, Berry and colleagues showed that:
- The diagnostic accuracy of iFR was only 60% compared with the FFR cut-off value of <0.80 (a value that has been validated in randomized trials for clinical management).
Pyrite (Fool’s Gold): The VERIFY authors conclude “…that iFR cannot be recommended for clinical decision making in patients with coronary artery disease.” Too bad, since iFR would be a convenient and quick use of a pressure-wire alone — without a vasodilator — to assess coronary stenosis severity.
With all the concerns of inappropriate PCI, do you feel compelled to use FFR to justify PCI?
In what percentage of patients with “intermediate” coronary stenoses do you use FFR?
Does the hassle associated with administering a vasodilator prevent you from measuring FFR in patients with intermediate stenoses?
2 Responses to “FFR vs. iFR: All That Glitters Is Not Gold”
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The good science of intracoronary physiologic assessment for ischemia- provided one recognizes pitfalls of technique and limitations in certain clinical contexts- utilizing the validated pressure wire from DEFER to FAME-2 has been as important an innovation as PCI in and of itself. Combined with clinical context, it doesn’t necessarily justify, but rather allows for informed decision making and expected outcomes(symptom improvement, rehospitalization or revascularization) to proceed with PCI or treat with medical therapy.
Intermediate stenosis, particularly longer segments of plaque without subjective severe % stenosis, are readily stratifiable as ischemia producing or not. I utilize the technique universally(? = 100%) in this anatomic circumstance if no precedent supportive NIV testing has been obtained precatheteriztion, or if NIV data is ambiguous.
As to “hassle” of vasodilator administration, it is no different than use of other adjunctive pharmacologic therapy(anticoagulation, antiplatelet therapy ) by intravenous route in the cath lab. We interventionalists certainly don’t perceive the use of those necessary agents(?IV antiplalelets-GPI- as necessary) in the lab to prevent complications(in and out of the lab) of PCI as a “hassle”.
It was interesting to see the Berry and Johnson study results in JACC. However, since these results were first presented and disputed at ACC 2012, a multi-centre core lab analysis (the RESOLVE study) has been performed by the CRF core lab in more than 1500 lesions. This study included the VERIFY study data but the conclusions (based on the pre-specified primary endpoints, agreed by all co-investigators) were very different from those presented in VERIFY. In VERIFY the classification match with FFR was found to be as low as 50% whereas, in RESOLVE the agreement was around 80%. The results of RESOLVE are almost identical to the ADVISE-Registry and South Korean study peer reviewed and published and presented last year.
In the Johnson study, the authors were able to show an improved calculation of iFR. However, their algorithm was not sufficiently reliable to show a difference over mean resting Pd/Pa ratio. Again, RESOLVE demonstrated a clear 33% improved performance using iFR when compared to Pd/Pa, and in doing so reduced adenosine use by 60%, whilst maintaining an overall 95% classification match with FFR. These independent, core-lab multi-centre findings are identical to those published in the ADVISE-Hybrid analysis (Eurointervention, December EPub online).
I believe what Berry and Johnson have elegantly demonstrated is that if measurements are made incorrectly, agreement is poor, and if the wrong cut-point is used, results even poorer. However, it is reassuring to see that when measurements are made under rigourous scientific conditions in laboratories skilled at performing such analyses, and when iFR is calculated using the validated iFR algorithm, the results are consistent in blinded studies and in corelab analyses. RESOLVE proved that using the validated iFR algorithm, iFR has a high classification match with FFR, and a dynamic range that is significantly better than resting PdPa ratio alone.
We are really looking forward to ACC 2013 in San Francisco this year. One of the major problems all investigators face when developing a new indices (i.e. Heartflow) is that it is difficult to match FFR. This is in part due to the varied response to adenosine, and in part due to biological factors. It is interesting to note and it may be a surprise to readers to note, that although the authors don’t mention it, that in VERIFY, FFR repeated 2 minutes apart would lead to a FFR classification change in around 6% of patients in the 0.6-0.9 range. In DEFER, in a clinical population, where repeated measurements were made at 10minute intervals, this FFR disagreement is more than doubled to 15%. To put it simply, this means that 15% of cases FFR categorization changes (ie. moving from FFR>0.8 to FFR0.8 to FFR<0.8), when measured only 10 minutes apart. To address this problem we have to turn back to more established measures of ischaemia, and to test FFR, and iFR against other gold standards. We await the breaking data at ACC 2013, to see if when FFR and iFR are compared on a level playing field against a independent measure of ischaemia whether FFR remains significantly better than iFR as prophesied by the VERIFY investigators. If however, the study reveals that FFR and iFR have a similar power to detect ischaemia, it will surely lead to a re-evaluation of the early FFR validation studies. We live in exciting times!
Finally, I would like to ask all inteventionalists a question. When was the last time you assessed a patient with triple vessel disease with physiology? Would it be nice to move those patients from 3VD surgery to 2VD PCI? What's stopping you?
References:
RESOLVE, Jeremias A, TCT 2013
Seoul iFR-FFR study, Park JJ, EuroPCR 2012
ADVISE-Registy: Classification performance of instantaneous wave-free ratio (iFR) and fractional flow reserve in a clinical population of intermediate coronary stenoses: results of the ADVISE registry.
Petraco R, Escaned J, Sen S, Nijjer S, Asrress KN, Echavarria-Pinto M, Lockie T, Khawaja MZ, Cuevas C, Foin N, Broyd C, Foale RA, Hadjiloizou N, Malik IS, Mikhail GW, Sethi A, Kaprielian R, Baker CS, Lefroy D, Bellamy M, Al-Bustami M, Khan MA, Hughes AD, Francis DP, Mayet J, Di Mario C, Redwood S, Davies JE.
EuroIntervention. 2012 Aug 25. doi:pii: 20120413-02. [Epub ahead of print]
Hybrid iFR-FFR decision-making strategy: implications for enhancing universal adoption of physiology-guided coronary revascularisation.
Petraco R, Park JJ, Sen S, Nijjer SS, Malik IS, Echavarría-Pinto M, Asrress KN, Nam CW, Macías E, Foale RA, Sethi A, Mikhail GW, Kaprielian R, Baker CS, Lefroy D, Bellamy M, Al-Bustami M, Khan MA, Gonzalo N, Hughes AD, Francis DP, Mayet J, Di Mario C, Redwood S, Escaned J, Koo BK, Davies JE.
EuroIntervention. 2012 Dec 21. doi:pii: 20121206-02. [Epub ahead of print]