J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S V O L . 8 , N O . 6 , 2 0 1 5

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P U B L I S H E D B Y E L S E V I E R I N C . h t t p : / / d x . d o i . o r g / 1 0 . 1 0 1 6 / j . j c i n . 2 0 1 5 . 0 1 . 0 2 9

Prospective Assessment of theDiagnostic Accuracy of InstantaneousWave-Free Ratio to AssessCoronary Stenosis RelevanceResults of ADVISE II International, Multicenter Study(ADenosine Vasodilator Independent Stenosis Evaluation II)

Javier Escaned, MD, PHD,*y Mauro Echavarría-Pinto, MD,*z Hector M. Garcia-Garcia, MD, PHD,zTim P. van de Hoef, MD,x Ton de Vries, MA,k Prashant Kaul, MD,{ Ganesh Raveendran, MD,# John D. Altman, MD,**Howard I. Kurz, MD,yy Johannes Brechtken, MD,zz Mark Tulli, MD,xx Clemens Von Birgelen, MD, PHD,kkJoel E. Schneider, MD,{{ Ahmed A. Khashaba, MD,## Allen Jeremias, MD,*** Jim Baucum, MD,yyyRaul Moreno, MD,zzz Martijn Meuwissen, MD, PHD,xxx Gregory Mishkel, MD,kkk Robert-Jan van Geuns, MD, PHD,zHoward Levite, MD,{{{ Ramon Lopez-Palop, MD,### Marc Mayhew, MD,**** Patrick W. Serruys, MD, PHD,zHabib Samady, MD,yyyy Jan J. Piek, MD, PHD,x Amir Lerman, MD,zzzz on behalf of the ADVISE II Study Group

ABSTRACT

Fro

(CN

Ro

Ne

oli

Ce

OBJECTIVES The purpose of this study was to assess the diagnostic accuracy of the instantaneous wave-free ratio (iFR)

to characterize, outside of a pre-specified range of values, stenosis severity, as defined by fractional flow reserve

(FFR) #0.80, in a prospective, independent, controlled, core laboratory–based environment.

BACKGROUND Studies with methodological heterogeneity have reported some discrepancies in the classification

agreement between iFR and FFR. The ADVISE II (ADenosine Vasodilator Independent Stenosis Evaluation II) study was

designed to overcome limitations of previous iFR versus FFR comparisons.

METHODS A total of 919 intermediate coronary stenoses were investigated during baseline and hyperemia. From these,

690 pressure recordings (n ¼ 598 patients) met core laboratory physiology criteria and are included in this report.

RESULTS The pre-specified iFR cut-off of 0.89 was optimal for the study and correctly classified 82.5% of the stenoses,

with a sensitivity of 73.0% and specificity of 87.8% (C statistic: 0.90 [95% confidence interval (CI): 0.88 to 0.92,

p < 0.001]). The proportion of stenoses properly classified by iFR outside of the pre-specified treatment (#0.85) and

deferral ($0.94) values was 91.6% (95% CI: 88.8% to 93.9%). When combined with FFR use within these cut-offs, the

percent of stenoses properly classified by such a pre-specified hybrid iFR-FFR approach was 94.2% (95% CI: 92.2% to

95.8%). The hybrid iFR-FFR approach obviated vasodilators from 65.1% (95% CI: 61.1% to 68.9%) of patients and

69.1% (95% CI: 65.5% to 72.6%) of stenoses.

CONCLUSIONS The ADVISE II study supports, on the basis rigorous methodology, the diagnostic value of iFR in

establishing the functional significance of coronary stenoses, and highlights its complementariness with FFR when used

in a hybrid iFR-FFR approach. (ADenosine Vasodilator Independent Stenosis Evaluation II–ADVISE II; NCT01740895)

(J Am Coll Cardiol Intv 2015;8:824–33) © 2015 by the American College of Cardiology Foundation.

m the *Cardiovascular Institute, Hospital Clinico San Carlos and Centro Nacional de Investigaciónes Cardiovasculares Carlos III

IC), Madrid, Spain; yFaculty of Medicine, Complutense University of Madrid, Spain; zErasmus MC, Department of Cardiology,

tterdam, the Netherlands; xAMC Heart Center, Academic Medical Center, University of Amsterdam, Amsterdam, the

therlands; kCardialysis BV, Rotterdam, the Netherlands; {University of North Carolina at Chapel Hill, Chapel Hill, North Car-

na; #Cardiovascular Division of the University of Minnesota, Minneapolis, Minnesota; **St. Anthony’s Heart and Vascular

nter and Colorado Heart and Vascular PC, Denver, Colorado; yyDivision of Cardiology, Department of Medicine, Washington

SEE PAGE 834

AB BR E V I A T I O N S

AND ACRONYM S

ECG = electrocardiogram

FFR = fractional flow reserve

iFR = instantaneous wave-free

ratio

Pa = aortic pressure

PCI = percutaneous coronary

intervention

Pd = distal pressure

Pd/Pa = baseline distal-to-

aortic pressure ratio

ROC = receiver-operating

characteristic

J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S V O L . 8 , N O . 6 , 2 0 1 5 Escaned et al.M A Y 2 0 1 5 : 8 2 4 – 3 3 Prospective Assessment of iFR Diagnostic Accuracy

825

T he instantaneous wave-free ratio (iFR)is a recently-introduced pressure-derived,hyperemia-free index for the functional

assessment of coronary stenoses (1). Previousstudies have investigated the classification agree-ment between iFR and fractional flow reserve(FFR), used as a reference standard, which in gen-eral has been good (1–8). However, some discrep-ancies in their agreement have been observed,potentially related to methodological heterogeneity.Although the possible benefits and limitations ofnonhyperemic indexes to guide coronary revascular-ization still need to be determined (9), a prospectivestudy with rigorous methodology was deemedrequired to accurately establish the diagnostic valueof iFR.

Since the introduction of iFR, a hybrid iFR-FFR diagnostic strategy has been proposed, whereupper and lower iFR cut-offs are used to restrictdecisions on the basis of iFR to those regions inwhich its agreement with FFR is very high, andFFR use is limited to the intermediate iFR rangeof values called the “adenosine zone” (3). Hence,the ADVISE II (ADenosine Vasodilator Indepen-dent Stenosis Evaluation II) study was designedto investigate, in a prospective, controlled, corelaboratory–based environment, the diagnostic accu-racy of iFR to characterize coronary stenosisseverity as determined by FFR, exploring also theusefulness and convenience of the hybrid iFR-FFRapproach.

University School of Medicine, St. Louis, Missouri; zzRegions Hospital, Saint

Florida, Gainesville Florida; kkThoraxcentrum Twente, Department of C

Technology and Services Research, MIRA, University of Twente, Enschede, th

Raleigh, North Carolina; ##Al Dorrah Heart Care Hospital, Ain Shams Univers

Center, Stony Brook, New York; yyyGreenville Memorial Hospital, Grenvill

Madrid, Spain; xxxDepartment of Cardiology, Amphia Hospital, Breda, the

Hospital, Springfield, Illinois; {{{AtlantiCare Regional Medical Center, Eg

versitario de San Juan de Alicante, Alicante, Spain; ****Wellmont Hols

yyyyDivision of Cardiology, Department of Medicine, Andreas Gruentzig C

Medicine, Atlanta, Georgia; and the zzzzCenter for Coronary Physiology and

Department of Internal Medicine, Mayo Clinic and Mayo Foundation, Roche

Corporation. The sponsor of the study had no role in the study design, data ac

All analyses were independently performed by the core laboratory (Cardialysi

at educational events for Volcano Corporation and St. Jude Medical. Dr. Ech

events organized by Volcano Corporation and St. Jude Medical. Dr. van de

organized by Volcano Corporation, St. Jude Medical, and Boston Scientific. D

Systems Inc. Dr. von Birgelen has served as a consultant to Abbott Vascular

fees or travel expenses); has received travel expenses from Biotronik; has re

his institution has received research grants from Abbott Vascular, Biotronik

served as a consultant to Volcano Corporation. Dr. Mishkel has served as a s

has received a research grant from Volcano Corporation and St. Jude Medical

Volcano to support an NIH project. All other authors have reported that they

paper to disclose.

Manuscript received July 14, 2014; revised manuscript received December 2

METHODS

ADVISE II was a prospective, international,multicenter (n ¼ 45) study that aimedto assess the diagnostic value of iFR tocharacterize, without concomitant admini-stration of hyperemic agents, coronary ste-nosis severity as determined by the FFR(NCT01740895). The Ethics Committeesand Institutional Review Boards of eachparticipating center approved the study,and all patients gave written informedconsent.

Paul, Minnesota; xxCardiovascular Research of North

ardiology, Medisch Spectrum Twente, and Health

e Netherlands; {{Wake Heart and Vascular Institute,

ity, Cairo, Egypt; ***Stony Brook University Medical

e, South Carolina; zzzHospital Universitario la Paz,

Netherlands; kkkPrairie Heart Institute, St. John’s

g Harbor Township, New Jersey; ###Hospital Uni-

ton Valley Medical Center, Kingsport, Tennessee;

ardiovascular Center, Emory University School of

Imaging, Division of Cardiovascular Diseases, and

ster, Minnesota. This study was funded by Volcano

quisition, data analysis or writing of the manuscript.

s). Dr. Escaned has had consultancies/been a speaker

avarría-Pinto has served as a speaker at educational

Hoef has served as a speaker at educational events

r. Kaul has served as a consultant to Cardiovascular

, Boston Scientific, and Medtronic (including lecture

ceived lecture fees from Merck Sharp & Dohme; and

, Boston Scientific, and Medtronic. Dr. Jeremias has

peaker/trainer for Volcano Therapeutics. Dr. Samady

. Dr. Lerman has received an unrestricted grant from

have no relationships relevant to the contents of this

3, 2014, accepted January 10, 2015.

PATIENT SELECTION AND PRESSURE TRACES

ACQUISITION. Patients eligible for enrollment wereage 18 to 85 years, suitable for coronary angiographyand percutaneous coronary intervention (PCI), andhad coronary stenosis (>40% diameter stenosis byvisual assessment) in 1 or more native major epicar-dial vessel or its branches. Stable angina or acutecoronary syndromes (only nonculprit vessels and>48 h from symptoms onset in case of myocardialinfarction) were allowed. Complete inclusion andexclusion criteria are provided in the OnlineAppendix. Data acquisition included electrocardio-graphic (ECG) signal recording (required by theiFR calculation algorithm) and setting the readingof mean aortic pressure (Pa) at 3 beats. After

FIGURE 1 Example of the Methodology for Pressure and Electrocardiogram Acquisition

Example of the methodology for pressure traces acquisition in the ADVISE II study. First, correct normalization was recorded (in this case, in the label fractional flow

reserve [FFR] ¼ 0.99). Then, a single electrocardiogram and pressure recording included baseline pressures for a minimum of 20 s, adenosine infusion for a minimum of

2 min, and pressure wire pullback maneuver. Three bookmarks for core laboratory analyses were placed: 1) when adenosine infusion started; 2) when the pullback

maneuver started; and 3) when the pressure sensor reached the tip of the guiding catheter. The operator was blinded to instantaneous wave-free ratio (iFR), which was

calculated off-line at the core laboratory. IV ¼ intravenous; Pa ¼ aortic pressure; Pd ¼ distal pressure; Pd/Pa ¼ baseline distal-to-aortic pressure ratio.

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intracoronary nitrates (300 mg) and acquisition ofcoronary angiograms, Pa and intracoronary distalpressure (Pd) were recorded as follows (Figure 1).First, the pressure wire was zeroed and equalized,and its correct equalization (Pd/Pa ratio of 1.0 � 0.02)confirmed during a 10 s acquisition. Afterward, thepressure sensor was positioned distal to the indexstenosis and the guiding catheter was flushed withsaline. Baseline pressures were recorded for at least20 s before inducing hyperemia. Adenosine adminis-tration through a large vein at a rate of 140 mg/kg/minfor a minimum of 2 min and pressure wire pullbackmaneuver to check for pressure drift were bothmandatory. In the same pressure recording, 3 book-marks for core laboratory analyses were placed: 1)when adenosine infusion started; 2) when the pull-back maneuver started; and 3) when the pressuresensor reached the tip of the guiding catheter. If a Pd/Pa ratio <0.98 or >1.02 at the catheter tip was docu-mented, the protocol mandated repeat assessment.The s5/s5i console and PrimeWire Prestige PLUS cor-onary pressure wire (Volcano Corporation, San Diego,California) were used in all cases.

iFR AND FFR CALCULATION. All pressure recordingswere analyzed by an independent Core Laboratory(Cardialysis, Rotterdam, the Netherlands) using iFRcalculation software (HARVEST, Volcano Corpo-ration) fully consistent with online commercial sys-tems. This computational algorithm performsautomated analyses on the basis of a synchronizedECG signal and determines the appropriate diastolicintervals for pressure measurements. By automaticidentification of fiducial time points in the cardiaccycle, the diastolic window for pressure measurementis calculated beginning 25% into diastole and ending5 ms before end diastole. iFR is then calculated asPd/Pa ratio during this pre-specified period of time,within mid to late diastole under nonhyperemicconditions—the wave-free period—when it has beenshown that intrabeat microvascular resistance is sta-ble and minimized (1,6,10).

FFR was experimentally and clinically validatedunder conditions of maximum and stable hyperemia(11) and is automatically calculated by currentcomputational software as the minimum Pd/Pa ratiofound in the pressure recording. However, during

J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S V O L . 8 , N O . 6 , 2 0 1 5 Escaned et al.M A Y 2 0 1 5 : 8 2 4 – 3 3 Prospective Assessment of iFR Diagnostic Accuracy

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intravenous adenosine infusion, the minimum hy-peremic Pd/Pa ratio might develop before stabilizationof hyperemia, a situation that flaws the theoreticalframework of FFR, as neither driving nor distal pres-sures are stable (12). Hence, conforming to its originalvalidation (11,13), core laboratory analyses included athorough review of pressure recordings to corroboratethat FFRwas calculated: 1) after initiation of adenosineinfusion; 2) within stable hyperemia; and 3) before thepullback maneuver. Stable hyperemia was defined asthe plateau in mean Pa after stabilization of changinghemodynamics following the initiation of adenosineinfusion and before the pullback maneuver (12). If aplateau was not clearly observed, stable hyperemiawas then defined as the period of pressure recording inwhich no further systematic fall in Pa was observed,following the initiation of adenosine infusion butbefore the initiation of the pullback (12). Within stablehyperemia, the minimum Pd/Pa ratio was then labeledas FFR.

Core laboratory analyses included an exhaustiveevaluation of pressure waveforms to confirm thatnone of the following exclusion criteria were present:inappropriate normalization of the pressure wire(Pd/Pa ratio <0.98 or >1.02), ECG artifacts or signifi-cant arrhythmias in the first 20 s of the recording(“iFR calculation window”), loss of Pa or Pd signals atany point during the recording, automatic calculationpitfalls (identification of FFR during ectopic beats, Pa

or Pd noise, wire whipping artifacts, and so on),dampening of Pa or Pd waveforms, pressure drifthigher than <0.98 or >1.02, and absence of ECG orpressure-pullback recording.

HYBRID iFR-FFR APPROACH. This hybrid iFR-FFRdiagnostic strategy was designed to increase adop-tion of physiology-guided PCI by decreasing the needfor vasodilators whereas maintaining a very highclassification agreement with a lone-FFR strategy (3).Two independent iFR values with very high negativeand positive predictive values to exclude (defer-iFRvalue) and identify (treatment-iFR value) FFR-significant stenoses were investigated, assuming thusthat only those stenoses with iFR values in-betweenwould require vasodilator drugs for standard FFRclassification. On the grounds of retrospectively-acquired data, it was found that a treatment iFRvalue #0.85, a deferral iFR value $0.94, and the useof FFRwithin the 0.86 and 0.93 iFR values (“adenosinezone”) resulted in an overall 95% classification agree-ment with a lone-FFR strategy and obviated the needfor vasodilators in 57% of patients.

ENDPOINTS. The primary endpoint of the study wasthe percentage of stenoses properly classified by the

iFR values #0.85 and $0.94, as proposed by thehybrid iFR-FFR approach. Hemodynamic severitywas defined as FFR #0.80. Pre-specified secondaryendpoints were: 1) the diagnostic performance of theiFR 0.89 cut-off; 2) the optimal iFR cut-off againstFFR #0.80 derived from receiver-operating charac-teristic (ROC) curve analyses; 3) the minimum iFRexclusion ranges around the iFR 0.89 cut-off in whichthe iFR and FFR agreement was $80%, $90%, and$95%; 4) the correlation coefficient between iFR andFFR; and 5) the proportion of stenosis and patientsfree from vasodilator drugs expected from thepreviously-mentioned pre-specified hybrid iFR-FFRapproach.

STATISTICAL ANALYSIS. For quantitative variables,data are expressed as mean � SD. Non-normal data arereported as the median with first and third quartiles(Q1, Q3). For categorical data, counts and percentagesare provided. The 95% confidence intervals (CIs) ofthe means of continuous variables and percentages ofcategorical variables were calculated with t tests andClopper-Pearson (Exact) approaches, respectively.ROC curve analyses were performed to determine theoptimal iFR cut-off against FFR #0.80, defined as thevalue that maximized correct classification. Pearson’scorrelation coefficient (r) between iFR and FFR wascomputed, and the Fisher Z transformation was usedto provide its 95% CIs. Linear regression was used tofurther characterize the iFR and FFR relationship, andbeing as this was a multicenter study, between–centervariability was assessed by adding participating cen-ter as random effect. However, a significant effectparameter was not found for any of the centers, andthe total effect of adding such a center effect to theanalysis was nonsignificant (p ¼ 0.165). We, therefore,concluded that the center effect could be ignored. TheSAS version 9.2 (SAS Institute Inc., Cary, North Car-olina) and STATA 12.1 (StataCorp, College Station,Texas) statistical software packages were used.Applicable tests were 2-tailed, and differences wereconsidered significant at p < 0.05.

RESULTS

STUDY POPULATION. Between January 9, 2013, andJune 28, 2013, 919 stenoses from 797 patients wereinvestigated and included in the study. Of these ste-noses, 229 (24.9%) met at least 1 of the pre-definedcore laboratory exclusion criteria, leaving 690 steno-ses from 598 patients for final analyses. A STARD-type (STAndards for the Reporting of DiagnosticAccuracy Studies) (14) flow chart depicting this pro-cess is provided in Figure 2. Clinical and angiographic

FIGURE 2 Process Followed by Eligible Stenosis

A STARD-type flow diagram showing the process followed by eligible stenosis from inclusion to final results. ECG ¼ electrocardiogram; other

abbreviations as in Figure 1.

TABLE 1 General Characteristics of the Study Population

(n ¼ 598)

Mean � SD or % 95% CI*

Baseline demographics

Age (yrs) 63.6 � 10.8 62.7–64.5

Male 68.9 65.0–72.6

Medical history

Prior myocardial infarction 35.2 31.3–39.2

Prior PCI 49.1 45.0–53.2

Prior CABG 4.7 3.2–6.7

Congestive heart failure 8.4 6.3–11.0

Hypertension 78.8 75.3–82.1

Diabetes mellitus 35.0 31.1–39.0

Current smoker (#6 months) 22.6 19.3–26.3

History of other vascular disease 17.4 14.4–20.8

Renal dysfunction(serum creatinine >2.0)

2.9 1.7–4.6

Pulmonary disease 12.0 9.5–14.9

Clinical presentation

Stable angina 53.5 49.4–57.6

Unstable angina 25.3 21.8–28.9

Silent ischemia 13.1 10.5–16.1

NSTEMI (>48 h before enrollment) 5.6 3.9–7.7

STEMI (>48 h before enrollment) 2.5 1.4–4.1

*95% confidence intervals (CIs) of the mean.

CABG ¼ coronary artery bypass graft; NSTEMI ¼ non–ST-segment elevationmyocardial infarction; PCI ¼ percutaneous coronary intervention; STEMI ¼ST-segment elevation myocardial infarction.

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Prospective Assessment of iFR Diagnostic Accuracy M A Y 2 0 1 5 : 8 2 4 – 3 3

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characteristics of the study population are shown inTables 1 and 2. Overall, mean age was 63.6 � 10.8years, and 68.9% were male patients. The mostcommon clinical presentation was chronic stableangina (53.5%), followed by unstable angina (25.3%),and the left anterior descending artery was the mostcommonly interrogated vessel (54.5%). Figure 3shows the distribution of the FFR values in the

TABLE 2 General Characteristics of Epicardial Stenosis Included

in Study (n ¼ 690)

% or Mean � SD 95% CI*

Vessel

Left anterior descending artery 54.5 50.7–58.3

Left circumflex 25.7 22.4–29.1

Right coronary artery 19.9 16.9–23.0

Stenosis characteristics†

Lesion length (mm) 14.0 � 7.9 13.40–14.59

Reference vessel diameter (mm) 3.0 � 0.50 2.93–3.01

Percentage of diameter stenosis 60.0 � 13.0 58.7–60.7

Lesion type (AHA)

A 34.9 31.3–38.6

B1/B2 52.2 48.4–56.0

C 12.9 10.4–15.6

Current in-stent restenosis 7.1 5.3–9.3

*95% confidence intervals (CIs) of the mean. †Visual assessment.

AHA ¼ American Heart Association.

FIGURE 3 Distribution of the FFR Values Observed in the Study

Frequency histogram with superimposed normal distribution

of the fractional flow reserve (FFR) values in study population.

Please note the unimodal FFR distribution as well as data

clustering around the FFR 0.80 cut-off point.

J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S V O L . 8 , N O . 6 , 2 0 1 5 Escaned et al.M A Y 2 0 1 5 : 8 2 4 – 3 3 Prospective Assessment of iFR Diagnostic Accuracy

829

study. In general, the study population wascomposed of stenoses of intermediate angiographic(diameter stenosis: 60 � 13% by visual assessment)and physiological severity (FFR: mean 0.83 � 0.11;

FIGURE 4 iFR Versus FFR Relationship

FFR

iFR

FFR=0.782*iFR+0.121R2=0.65, p<0.001

A B

(A) The scatterplot of the relationship between iFR and FFR. Vertical line

0.86 and 0.93). The horizontal line is placed at the clinically-adopted 0

of iFR against FFR#0.80. The optimal iFR cut-off identified in the ADVIS

Figure 1.

median 0.84 [Q1 0.77, Q3 0.90]). Finally, 248 (35.9%)vessels had FFR #0.80.

DIAGNOSTIC ACCURACY OF iFR AGAINST FFR.

Figure 4A shows the scatterplot of the relationshipbetween iFR and FFR. There was a strong linear cor-relation between both indexes (r ¼ 0.81, 95% CI: 0.78to 0.83, p < 0.001). ROC analyses identified 0.89 asthe optimal iFR cut-off, with an area under the ROCcurve (C statistic) of 0.90 (95% CI: 0.88 to 0.92,p < 0.001) (Figure 4B). Notably, the optimal iFR cut-off observed in the study matched the pre-specifiedone. This 0.89 iFR cut-off correctly classified 82.5%of total stenoses, with a sensitivity of 73.0% andspecificity of 87.8%. For the study prevalence(FFR #0.80, 35.9%), the positive predictive andnegative predictive values of this cut-off were 77.0%and 85.3%, respectively.

STUDY ENDPOINTS. The iFR treatment (#0.85) anddeferral ($0.94) values correctly classified 88.1%(95% CI: 81.6% to 92.9%) and 93.1% (95% CI: 89.8% to95.6%) of the stenoses, respectively. Thus, the overallproportion of stenoses properly classified by iFRoutside such pre-specified iFR treatment (#0.85)and deferral ($0.94) values was 91.6% (95% CI:88.8% to 93.9%) (Figure 5). The best iFR exclusionrange around the pre-specified 0.89 cut-off toachieve $80% diagnostic accuracy was this cut-off

Sensivity

1-Specificity

Area under the curve:0.90 (95% CI: 0.88 to 0.92), p<0.001

s are placed at the boundaries of the “adenosine zone” (iFR values of

.80 FFR cut-off value. (B) The receiver-operating characteristic curve

E II study was 0.89. CI ¼ confidence interval; other abbreviations as in

FIGURE 5 Primary Endpoint of the Study and Hybrid

iFR-FFR Approach

The iFR treatment (#0.85) and deferral ($0.94) values correctly

classified 88.1% and 93.1% of investigated stenoses, respectively.

Theoverall proportionof stenosesproperly classifiedby iFRoutside

of the pre-specified iFR values was 91.6%. This value increased to

94.2% after including standard classification with FFR in-between

(hybrid iFR-FFR approach). Abbreviations as in Figure 1.

FIGURE 6 Absolute Counts of Stenoses Across Categories of

iFR and FFR

Please note how most of the between-indexes disagreement

was located within the FFR “gray zone” (FFR values between

0.75 and 0.80), where the ischemic potential of the interro-

gated stenosis is known to be less certain. Abbreviations as

in Figure 1.

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itself, because it correctly classified 82.5% of totalstenoses. To achieve 90% and 95% classificationagreement with FFR, the minimum iFR exclusionranges below and above the optimal 0.89 cut-offwere #0.86 (to predict FFR #0.80) and $0.94 (to pre-dict FFR >0.80), which provided a percentage agree-ment of 91.0%, and #0.78 (to predict FFR #0.80)and $0.95 (to predict FFR >0.80), which provided apercent agreement of 95.3%. Finally, Figure 6 demon-strates how most of the classification disagreementbetween iFR and FFRwas located within the FFR “grayzone” (FFR values between 0.75 and 0.80), where theischemic potential of the stenosis is known to be lesscertain (15).

HYBRID iFR-FFR APPROACH. The percentage of ste-noses properly classified by the pre-specified hybridiFR-FFR approach was 94.2% (95% CI: 92.2% to95.8%), and it had associated sensitivity, specificity,and positive and negative predictive values of 90.7%,96.2%, 93.0%, and 94.9%, respectively (Figure 5). Theestimated proportion of patients and stenoses freefrom vasodilator agents by such a pre-specifiedhybrid iFR-FFR approach amounted to 65.1% (95%CI: 61.1% to 68.9%) and 69.1% (95% CI: 65.5% to72.6%), respectively.

DISCUSSION

The results of the ADVISE II study support the diag-nostic value of iFR in establishing the hemodynamic

severity of coronary stenoses and highlight itscomplementariness with FFR when used in a hybridiFR-FFR approach.

iFR AS AN ALTERNATIVE FOR PHYSIOLOGICAL

ASSESSMENT OF CORONARY STENOSIS. Althoughdecision-making on the basis of intracoronary physi-ology was initiated 20 years ago with Doppler-tippedguide wires (15), the demonstration that intra-coronary physiology is not only safe, but also resultsin better patient outcomes, came from studiescomparing FFR with coronary angiography (16,17).This clinical evidence has made FFR the technique ofchoice for physiological assessment of coronary ste-noses (18). Hence, the introduction of iFR took placeat a time in which FFR constituted the paradigm (andfor many the synonym) of intracoronary physiology,which was concomitantly facilitated by many com-mon aspects between the 2 techniques. iFR is derivedfrom the same theoretical framework as FFR (i.e., therelationship between the translesional pressure ratioand the impairment in myocardial blood supplycaused by the interrogated stenosis) and is obtainedwith conventional pressure wires and appropriatesoftware (1,11). Without a doubt, the main attrac-tiveness of iFR is the avoidance of vasodilator drugs,identified as a cumbersome requirement for FFRinterrogation (19). Thus, iFR appeared to many to be apotential step ahead toward the simplification ofphysiological stenosis assessment introduced by FFRmany years ago.

J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S V O L . 8 , N O . 6 , 2 0 1 5 Escaned et al.M A Y 2 0 1 5 : 8 2 4 – 3 3 Prospective Assessment of iFR Diagnostic Accuracy

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The publication of the first study on iFR generatedsignificant interest among interventional cardiologists(1–8). The RESOLVE (Multicenter Core LaboratoryComparison of the Instantaneous Wave-free Ratio andResting Pd/Pa with Fractional Flow Reserve) study (8),a recent pooled-retrospective analysis, provides anexcellent perspective of published and unpublishediFR versus FFR comparisons performedwithin the firstyear after the publication of the ADVISE study (1). InRESOLVE, data from individual studies was rean-alyzed after standardization and application of inclu-sion and exclusion criteria, and iFR was recalculatedusing the original iFR calculation algorithm. There wasrelatively little variation in the diagnostic accuracy ofiFR among the 6 independent research groups (n ¼1,593), and it was proposed that these differencesprobably resulted from inconsistencies in data collec-tion and analysis inherently linked to the retrospectivedesign—including nonuniform patient and lesionscharacteristics, varying acquisition equipment andprotocols, absence of ECG and final pressure wirepullback to exclude pressure drift, among others—ashighlighted by the investigators.

The ADVISE II study was designed to address thelimitations of retrospective studies like RESOLVEthrough a prospective, multicenter design, withrigorous, standardized methodology and indepen-dent analysis at a core laboratory. Key differentialaspects included FFR technique standardization,corroboration of appropriate pre-measurementequalization, the acquisition of a single ECG andpressure recording encompassing baseline, inductionand achievement of hyperemia, pressure wire pull-back, and persistence of calibration at the cathetertip. This rigorous methodology becomes highlightedby the high exclusion rate (nearly 25% of tracings) inADVISE II, superior to that reported in RESOLVE(17%), which is probably explained by the fact that inRESOLVE, exclusions due to ECG were not consid-ered. In our study, nearly one-half (48%) of theexcluded traces resulted from ECG pitfalls, probablymirroring a lack of awareness by catheterization lab-oratory personnel on the relevance of ECG for accu-rate iFR calculation and indicating an importantmethodological difference with RESOLVE. Impor-tantly, in consonance with FFR theoretical framework(11), ADVISE II mandated FFR calculation as theminimal Pd/Pa ratio during the steady-state hyper-emic plateau. Finally, a higher C statistic (0.90) inADVISE II than in RESOLVE (0.81) was documented,and a very similar optimal iFR cut-off value wasfound (0.89 in ADVISE II, 0.90 in RESOLVE). Thisprovides further evidence on the appropriateness ofthe use of this cut-off value in future studies.

Finally, RESOLVE also reported a good diagnosticperformance of the largely neglected baseline Pd/Pa

ratio. As the interest in the diagnostic performance ofbaseline Pd/Pa emerged when ADVISE II was alreadyinitiated, baseline Pd/Pa analyses were not includedas pre-specified endpoints of the study. Yet, toinvestigate the value of this nonhyperemic index, apost-hoc analysis of ADVISE II data with the samemethodology applied to the iFR versus FFR compar-ison reported in this paper has been performed, and isdiscussed in detail elsewhere (20).

USE OF THE HYBRID iFR-FFR APPROACH. The sim-plest way of assessing the diagnostic accuracy of iFRis to use FFR dichotomized at 0.80 as the referencestandard. However, this approach is fraught by thelimitations of dichotomizations in biological contin-uous systems (2,3,21). This makes comparisons sen-sitive to the characteristics of coronary stenosispopulations, where lower intertechnique and intra-technique agreements are, by definition, expectedwhen used in unimodal distributions peaking aroundcut-offs, as compared with broader distributionswhere more very severe and minimal stenoses arepresent (21). In this regard, it is important toacknowledge that the distribution of FFR values inADVISE II was intermediate (diameter stenosis:60 � 13%; FFR: 0.83 � 0.1) (Figure 3), which is themost challenging for the purpose of establishingthe diagnostic accuracy of iFR, as data clustering nearthe FFR cut-off helps small differences lead to clas-sification disagreement (2,3,21).

To overcome these limitations, a hybrid iFR-FFRapproach has been proposed as a way to translateinto practice the potential value of iFR as a diagnostictool. The ADVISE II study supports the diagnosticvalue of this hybrid iFR-FFR diagnostic approach, asit properly classified 94.2% of total stenosis, withvalues of specificity, sensitivity, and positive andnegative predictive values >90%. With this strategy,adenosine would not be required in 69% of the ste-noses, and in 65% of patients, adenosine would notbe needed at all. These figures support the potentialof iFR to ease catheterization laboratory workflowand to reduce costs associated with ischemia-drivenrevascularization.

IMPLICATIONS OF ADVISE II RESULTS FOR CLINICAL

PRACTICE. The ADVISE II study probably constitutesthe definitive direct comparison between iFR and FFR.Because the low adoption of FFR (22) is clearly the firstobstacle for translating the benefits of ischemia-drivenrevascularization to patients, the results of ADVISE IImay contribute to increase its implementation, parti-cularly when used synergistically with FFR. This is an

PERSPECTIVES

WHAT IS KNOWN? iFR is a novel adenosine-free

index developed to simplify stenosis severity assess-

ment and to expand the use of physiology in the

catheterization laboratory. Although previous studies

suggested a good overall classification agreement

between iFR and FFR in terms of functional stenosis

severity, a marked variability was noted between in-

dividual studies. ADVISE II was designed to validate

the accuracy of iFR by applying a rigorous methodol-

ogy that addressed methodological limitations of

previous studies.

WHAT IS NEW? The study identified that the pre-

specified hybrid iFR-FFR approach properly classified

94.2% of the stenoses and obviated vasodilator need

in 69.1% (95% CI: 65.5% to 72.6%) stenoses.

WHAT IS NEXT? Further to using FFR as a reference

technique to assess iFR, as in ADVISE II, future studies

must focus on demonstrating noninferiority of iFR

with respect to FFR in terms of clinical outcomes

when it is used as a decision-making tool.

Escaned et al. J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S V O L . 8 , N O . 6 , 2 0 1 5

Prospective Assessment of iFR Diagnostic Accuracy M A Y 2 0 1 5 : 8 2 4 – 3 3

832

urgent task, because recent studies like RIPCORD(Does Routine Pressure Wire Assessment InfluenceManagement Strategy at Coronary Angiography forDiagnosis of Chest Pain?) have demonstrated thatrevascularization decisions on the basis of angiog-raphy and available clinical information are modifiedin >30% of cases when physiological interrogation isperformed (23). At a time that FFR is used in a minorityof cases and, therefore, similar rates of misdiagnosisshould be expected in non-FFR practices, a huge netbenefit would be expected if a hybrid iFR-FFRapproach is adopted, even if 5.8% stenoses would notbe properly classified according to FFR (24).

A second obstacle to translate available evidenceon the benefit of FFR to patients is the restriction ofphysiological interrogation to intermediate stenosis,and not to all potential revascularization targets,irrespective of their angiographic appearance. It isimportant to note that, in randomized studies, FFRhas been measured in all stenoses regardless of theirangiographic severity (16,17,25). However, as high-lighted by observational studies including ADVISE II,most interventional cardiologists do not measure FFRin stenoses judged as clearly severe or nonsevere onthe grounds that it interferes with catheterizationlaboratory workflow and increases costs. Althoughthe cost-effectiveness analysis of the FAME (Frac-tional Flow Reserve Versus Angiography for Multi-vessel Evaluation) study has clearly demonstratedthat the latter perception is wrong (25), the sharpdecrease in the need for adenosine found in ADVISE IIconstitutes a potential solution for the formerobstacle. Indeed, the forthcoming multicenterSYNTAX II trial (NCT02015832) that applies ischemia-driven revascularization to patients with triple-vesseldisease treated with PCI has opted for a hybrid iFR-FFR approach to reduce procedural time in this typeof complex procedure.

STUDY LIMITATIONS. The ADVISE II study is the firstprospective, core laboratory–based intracoronaryphysiology study. Therefore, being a validationanalysis, stringent core-laboratory criteria wereapplied. Although this approach reduces the potentialfor bias and threats to statistical internal validity, itmight also limit the generalization of the findings to

different populations. However, the fact that thediagnostic accuracy of iFR observed in clinical retro-spective registries shows very little variations fromthat observed in this meticulous prospective study isreassuring.

CONCLUSIONS

The ADVISE II study observed a high diagnostic ac-curacy of iFR as compared to FFR and, therefore,supports the diagnostic value of this nonhyperemicindex in establishing the hemodynamic severity ofcoronary stenoses and highlight its complementari-ness with FFR when used in a hybrid iFR-FFRapproach.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Javier Escaned, Hospital Clinico San Carlos, 28040Madrid, Spain. E-mail: escaned@secardiologia.es.

RE F E RENCE S

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KEY WORDS adenosine, coronary arterydisease, fractional flow reserve,instantaneous wave-free ratio, physiology,vasodilation

APPENDIX For inclusion/exclusion criteriaand a list of participating centers, please seethe online version of this article.