New Technologies

Clinical and Economic Advantages of the iFR Modality for Physiologic Assessment

Bruce A. Samuels, MD, Division of Cardiology, Cedars-Sinai Medical Center; Assistant Professor of Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, California

Bruce A. Samuels, MD, Division of Cardiology, Cedars-Sinai Medical Center; Assistant Professor of Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, California

Disclosure: Dr. Samuels reports he has served as a consultant to Volcano Corporation. Dr. Bruce Samuels can be contacted at

The cath lab at Cedars-Sinai Hospital is one of the busiest on the west coast, performing approximately 1,500 percutaneous coronary interventions (PCIs) each year. Like all cath labs, we struggle to ensure that we are providing the appropriate treatment for each patient from a variety of options, which include medical therapy, stenting, or referral to bypass surgery. Critical to guiding these treatment decisions is not only the determination of coronary stenosis, but also the documentation of ischemia. Over the years, we have relied on coronary angiography, then fractional flow reserve (FFR), and most recently, the Instant wave-Free Ratio (iFR) software modality (Volcano Corporation) to guide treatments. In this article, I describe the clinical and economic benefits of migrating to a more iFR-focused approach to ischemia diagnosis.  

Unlike the traditional angiogram that relies on a static, visual interpretation, FFR and iFR are physiology-based diagnostics. Data have conclusively shown that physiologic assessment of intermediate lesions is far more reliable in guiding intervention and leads to better outcomes than a simple angiographic assessment alone. Both the FAME and the DEFER trials showed an improvement in treatment outcomes when FFR is used to guide PCI decisions, and FAME II showed a significant improvement in economic outcomes using physiologic-guided PCI.  

Though different clinicians use physiologic assessment to differing degrees in our lab, FFR has become standard practice for the evaluation of either angiographically intermediate lesions or lesions that are discordant with pre-cath stress testing. FFR helps avoid unnecessary surgery by ensuring that patients referred for coronary artery bypass graft surgery truly have multivessel, ischemic lesions requiring revascularization. There are, however, a number of disadvantages to FFR, including increased procedural times, the cost of the adenosine, and occasional patient intolerance of the vasodilator.  

Approved by the FDA in March 2014, iFR is a diagnostic tool used to assess whether a stenosis is causing a limitation of blood flow in coronary arteries with subsequent ischemia. This tool preserves the advantages of physiology-based assessments while, in our cath lab’s experience, it reduces both procedure time and costs. 

iFR: a new diagnostic modality in the cath lab

With multiple studies completed on its clinical utility, iFR has proven to have a similar predictive accuracy to FFR in the determination of a lesion’s physiological significance. The VERIFY and RESOLVE studies confirmed that iFR and resting Pd/Pa (distal coronary pressure to aortic pressure ratio) have a diagnostic accuracy similar to FFR of around 80%.1,2 ADVISE II study investigators reported that a hybrid iFR-FFR strategy correctly diagnosed over 90% of cases when compared to a strategy of measuring FFR in all lesions, and avoided the need to administer adenosine in two-thirds of patients.3

The obvious advantage of using just iFR is that the use of adenosine is eliminated. iFR is performed using the same high-fidelity pressure wires used in FFR that are passed distal to the coronary stenosis. iFR also measures the ratio of distal coronary pressure (Pd) to the aortic pressure (Pa), but only during an isolated period during diastole, called the “wave-free period.” The competing forces (waves) that affect coronary flow are quiescent, which makes downstream resistance fixed. This in turn creates a more linear relationship between pressure and flow, which is not the case through the entirety of the cardiac cycle. An iFR value of <0.9 is correlated with reduction in flow similar to an FFR value of <0.8. 

iFR can be calculated and displayed using the existing FFR Volcano console with a simple software upgrade. We currently use an average of five heartbeats, but future iterations of the software may allow the procedure to be performed based on a single heartbeat. iFR is measured at rest, without the need for pharmacological vasodilator or stressors, and compares favorably to other invasive and non-invasive markers of ischemic or flow limitations.

The hybrid approach

The hybrid iFR-FFR approach has been proposed as a method of minimizing patient exposure to adenosine or other vasodilators. In this approach, an iFR is measured, and a stenosis with an iFR >0.93 may be deferred, while those with an iFR <0.86 should be treated by revascularization. Stenoses with an iFR between 0.86-0.93 are considered to be in the “grey zone”, requiring adenosine administration and an FFR assessment to guide therapy. Utilizing this hybrid strategy, we are able to eliminate using adenosine in approximately two-thirds of our patients, similar to what was reported in the ADVISE II study.  

Appropriate stenting for overall cost reduction

We have been using iFR at Cedars-Sinai since April 2014 and have found it very useful to help decide if we should proceed with PCI. Being able to accurately identify lesions that require treatment can have a significant financial impact on the hospital.  Appropriate treatment results in better outcomes and reduced costly readmissions.  The real sweet spot for physiologic assessments is in lesions that are intermediate in their angiographic appearance or are in areas that are discordant with previous stress test data. With FFR, and now iFR, I have stopped making visual assessments on intermediate lesions, because I know from experience and from the literature how inaccurate visual assessments can be. If a stenosis is not flow limiting, then it can be safely deferred without stenting or surgery, reducing patient exposure to unnecessary procedures and potential complications.

The literature also has shown instances where the clinician may have decided to use medical therapy for an intermediate lesion based on angiographic assessment when in fact, that lesion was physiologically significant and should have had PCI. I think physiologic assessment works both ways. It allows us to identify patients that are appropriate for PCI and identify lesions that are inappropriate for PCI. To be clear, physiologic assessment is not necessary in a clinical situation where a patient has a very severe lesion in an area already predicted by prior stress testing. However, physiologic assessment definitely has a role to play in the patient with serial stenoses of a coronary artery. In this case, performing a pullback of the pressure wire is necessary to determine the site of the most ischemic lesions requiring intervention. This is something that we have done for years using FFR and adenosine administration. Again, because there is no adenosine administration with iFR, the time that will be required to get your initial assessment and then do a slow pullback over the blockages is much more attractive using iFR than with FFR, where adenosine must be flowing the entire time.

Reduced procedure time 

In my opinion, one of the most significant savings resulting from iFR is that it can speed up the diagnostic procedure and reduce case time in the cath lab. The iFR procedure is simple. It requires inserting the wire, pressing the record button, and waiting five heartbeats to get the iFR result. Because it is so quick, we will often take two or three assessments to ensure reproducibility of the iFR value, in a fraction of the time it takes to perform adenosine administration for FFR.

Reduce adenosine costs and improve patient experience

A tangible cost savings of iFR is the reduced need for adenosine in the procedure.  Depending on the volume of the cath lab, it could be a significant cost savings. 

Another benefit of an adenosine-free diagnostic procedure is improving the patient experience, since some patients experience increased risk and/or discomfort due to adenosine, especially those with bronchospasm or conduction abnormalities. Patient satisfaction is an increasingly important measurement in assessing quality of care and a key determinant in pay-for-performance metrics. Under the CMS Hospital Inpatient Value-Based Purchasing (HIVBP) program, Medicare reimbursements are linked to patient satisfaction and surveys completed by patients. It is reasonable to assume that patient satisfaction will increase as iFR use grows. They will not experience some of the adenosine side effects associated with FFR such as tightening of the chest, sensation of dyspnea, anxiety, or flushing. Routine clinical application of a vasodilator-free index would expand the use and the benefits of physiology-guided revascularization to potentially more patients with coronary disease, as the need for vasodilator use is often cited as one of the reasons for the low adoption of FFR. 

Flow evaluation post stent placement

iFR has also been compared to FFR and the resting Pd/Pa ratio in the post coronary intervention setting. Similar to FFR, iFR can be used to measure the hemodynamic change induced by stent placement and detect any residual stenosis. I routinely deploy devices over the pressure wire, as it is very easy to hook the wire back up and do a repeat measurement following PCI. Though not commonly used for this purpose, many of us find iFR a fast and easy means to check if the pressure loss was successfully treated, without the need to give adenosine.  


As of August 2014, the last impediment to reimbursement of iFR was removed. The American College of Cardiology and Society for Cardiovascular Angiography and Interventions are now recommending iFR measurements be coded using the FFR CPT codes with a -52 modifier. With reimbursement, physicians will be more inclined to use the procedure. My prediction is that adoption will increase rapidly when operators experience how easy it is to use iFR, how much better the patient experience is, and how costs can be reduced as a result of its use.  

Challenges to adoption

Several clinical trials have demonstrated a very high degree of correlation between an iFR cutoff value of 0.9 and an FFR cutoff value of 0.8. Over 4000 patients have been studied with iFR across a broad range of patient populations, and numerous prospective studies have been published. The strength of this data led to FDA approval in the United States. Multicenter prospective outcome studies are currently enrolling. DEFINE-FLAIR is the most important of these studies. It is designed to answer the question of whether iFR-guided PCI is as accurate in affecting outcomes as FFR. It should also permit analysis of those instances where there may be disagreement around the cut point and settle which value is more accurate. DEFINE-FLAIR will compare strategies of revascularization guided by iFR and FFR in 2500 patients requiring physiological interrogation in clinical practice. The trial will use a binary iFR cut-off value of <0.9 and an FFR cut-off of <0.80 to define a functionally significant stenosis. As evidence supporting iFR as an index of stenosis severity accumulates and large-scale clinical outcome data confirming a single measure for iFR in decision-making is completed, the global adoption of iFR as a single measure will likely accelerate.  

Advice for colleagues

The important hurdle to get over for most interventionalists is to work physiologic assessment of coronary stenosis into their routine practice. Right now, physiologic assessment is still utilized in <20% of coronary interventions, a dramatic underuse for a measurement that has significant clinical support, patient benefits, and economic impact. In October 2014, the International Survey on Interventional Strategy4 revealed that even when all potential external constraints (reimbursement, availability of technology) were eliminated, visual assessment continued to dominate the treatment decisions for intermediate stenosis, with 71% based solely on angiographic appearance. Of those treatment decisions, 47% were discordant with the known FFR. The amount of available clinical trial evidence is overwhelming in asserting that visual assessment is a poor indication, not only of the severity of the stenosis, but more importantly, of the clinical significance of that stenosis. The bottom line is that we need to be doing more physiologic assessment. Once that psychological hurdle has been overcome and physicians understand the value of physiologic assessment of lesions, I believe clinicians will naturally gravitate toward using iFR as often as possible, because of both its ease of use and the reduced costs.   

Future of iFR

If DEFINE-FLAIR shows that iFR is comparable or superior to FFR in the predictive accuracy of intermediate lesions, then iFR is likely going to replace FFR. There will be no reason for people to persist with utilizing hyperemic agents, which add time and cost to each procedure. With iFR, physiologic measurement will be faster, easier, less expensive, and available to a wider range of patients. In Europe, even in the absence of randomized control trial data, many clinicians have already stopped giving adenosine, because they find iFR to be more straightforward and simple to use. n


  1. Berry C, van ‘t Veer M, Witt N, Kala P, Bocek O, Pyxaras SA, 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 Apr 2; 61(13): 1421-1427. doi: 10.1016/j.jacc.2012.09.065.
  2. Jeremias A, Maehara A, Généreux P, Asrress KN, Berry C, De Bruyne B, et al. Multicenter core laboratory comparison of the instantaneous wave-free ratio and resting Pd/Pa with fractional flow reserve: the RESOLVE study. J Am Coll Cardiol. 2014 Apr 8; 63(13): 1253-1261. doi: 10.1016/j.jacc.2013.09.060.
  3. Sen S, Escaned J, Malik IS, Mikhail GW, Foale RA, Mila R, et al. Development and validation of a new adenosine-independent index of stenosis severity from coronary wave-intensity analysis: results of the ADVISE (ADenosine Vasodilator Independent Stenosis Evaluation) study. J Am Coll Cardiol. 2012 Apr 10; 59(15): 1392-1402. doi: 10.1016/j.jacc.2011.11.003.
  4. Toth GG, Toth B, Johnson NP, De Vroey F, Di Serafino L, Pyxaras S, et al. Revascularization decisions in patients with stable angina and intermediate lesions: results of the International Survey on Interventional Strategy. Circ Cardiovasc Interv. 2014 Oct 21. pii: CIRCINTERVENTIONS.114.001608.