Derivation and Validation of a Novel Adenosine-independent Index of Coronary Artery Stenosis Severity Resting Flow Reserve
Phase: NA
Conditions: Coronary; Ischemic
Sponsor: Columbia University

 
 
 
 
 
Derivation and Validation of a Novel Adenosine-Independent Index of Coronary 
Artery Stenosis Severity Resting Flow Reserve (RFR) 
PI: Ajay Kirtane, MD, SM 
 
 
Protocol Version 2 (20SEP2017) 
NCT03461705 

Version 2, Revised 9/20/17 
Derivation and Validation of a novel adenosine-independent index of coronary 
artery stenosis severity Resting Flow Reserve (RFR)  
 
Purpose: 
To evaluate the accuracy and precision of a novel adenosine-independent index of 
coronary artery stenosis, the resting flow reserve, against the instantaneous wave-free 
ratio and fractional flow reserve.  
 
Background: 
Fractional flow reserve (FFR) measurement under hyperemic conditions is the 
invasive gold standard for determining the physiologic extent of cardiac ischemia 
(1).FFR has been validated in several clinical outcomes studies as a way of optimizing 
case selection for PCI.(1, 2) Recently two large-scale randomized controlled trials using 
a non-hyperemic resting measurement, the instantaneous wave free ratio (iFR), showed 
non-inferiority in major adverse cardiovascular events (MACE) comparing iFR to FFR 
for physiological assessment of moderate coronary stenosis (3,4). Moreover, these 
studies demonstrated a dramatic reduction in patient discomfort by avoidance of 
adenosine, suggesting that iFR may be superior to FFR as a diagnostic tool in clinical 
practice. 
 
FFR is calculated as the ratio of the distal coronary pressure to the aortic 
pressure (Pd/Pa) during maximal microcirculatory relaxation, induced by 
pharmacological vasodilators (hyperemia). The iFR negates the time averaging and 
administration of vasodilators necessary for FFR by identifying from the resting pressure 
waveform a period when the native microcirculatory resistance is constant and 
minimized in diastole. Measurement of Pd/Pa during this time (iFR) is at a point of not 
only minimal resistance, but also high flow, thus allowing the resistance of an epicardial 
stenosis to be isolated from the microcirculation. 
 
While iFR has been shown to be non-inferior to FFR, it has a number of inherent 
limitations. The computational algorithm requires ECG gating or automated landmarking 
of components of the pressure waveform, thus being limited in clinical scenarios where 
the ECG is suboptimal or the rhythm is disturbed. Furthermore, iFR assumes that the 
maximal flow and minimal resistance occurs during diastole, which while true for the left 
coronary artery, is not constant in the right coronary artery.      
 
Here we aim to determine the accuracy, precision and clinical utility of an 
adenosine free resting measure of pressure during the point of absolute lowest Pd/Pa 
during the cardiac cycle, the resting flow reserve (RFR). The RFR represents the 
maximal relative pressure difference in the cardiac cycle, irrespective of systole or 
diastole and independent of the ECG, thus negating the limitations of iFR. This 
measurement thus represents a point of the cardiac cycle when the relative difference 
between native microcirculatory resistance and the flow is highest, allowing isolation of 
the resistance across the epicardial stenosis. Moreover, similar to iFR, as the RFR is 
measured each cardiac cycle it has the ability to display high sensitivity to small 
pressure changes enabling a pullback at rest separating the contribution of individual 
stenoses in a coronary vessel with multiple lesions.        
By performing the investigations described below, we aim to clarify the validity of 
RFR, determine its ability to detect ischemia compared to iFR and FFR and place it in 

Version 2, Revised 9/20/17 
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Version 2, Revised 9/20/17 
• Deliver 100-200mcg of intracoronary nitroglycerine to maximize epicardial 
dilation (if clinically indicated) 
• Advance the RFR wire to equalize position (guide disengaged) 
• Equalize RFR wire 
• Advance RFR wire across lesion with the sensor located at least 3 cm distal from 
the lesion 
• Advance the iFR wire to equalize position (guide disengaged) 
• Equalize iFR wire 
• Advance iFR wire across lesion with the sensor located at least 3 cm distal from 
the lesion 
• Disengage guiding catheter if necessary 
Record basal Pd/Pa 
• Record RFR Pd/Pa (RFR value) and iFR Pd/Pa (iFR value) 
If administration of adenosine is clinically indicated: 
o Administer intravenous adenosine at a rate of 140mcg/min to achieve 
maximal hyperemia 
o Measure hyperemic FFR using RFR and iFR wires 
o Stop adenosine 
o Wait 3 minutes 
• Perform simultaneous resting flow pullback of RFR wire and iFR wire 
• Stop recording on both systems 
 
If PCI is indicated perform PCI per standard of care.  
 
Devices: 
SJM Medical Aeris FFR Pressure wire system for RFR 
Volcano Verrata Pressure wire system for iFR  
 
Study Population: 
The study population will consist of patients who are referred for coronary angiography 
and require physiological assessment of intermediate lesions for clinical indications 
based on the local standard of care. A patient becomes a subject once he/she has been 
fully informed about the study, has agreed to participate, has signed & dated the 
consent, and has been determined to meet all the inclusion criteria and none of the 
exclusion criteria.   
 
1. Inclusion Criteria Age ≥ 18 years. 
2. Patient provides signed written informed consent before any study-specific 
procedure. 
3. Undergoing coronary angiography, for silent ischemia, stable angina, acute coronary 
syndrome, or other acceptable indication per the local standard of care. 
4. Angiographically 40%-90%  stenosis present in at least one native coronary artery. 
5. Undergoing physiological assessment for standard clinical or diagnostic indications 
 

Version 2, Revised 9/20/17 
Exclusion Criteria 
 
1. Aorto-ostial lesion location within 3 mm of the aorta junction (both right and left). 
2. Left main stenosis 
3. Vessel(s) and lesion(s) not amenable for PCI, for example diffuse disease. 
4. Saphenous vein graft, chronic total occlusion 
5. Haemodynamic instability at the time of intervention (heart rate<50 beats per minute, 
systolic blood pressure <90mmHg), balloon pump 
6. Currently participating in another clinical study that interferes with study results. 
7. Pregnant or nursing subjects and those who plan pregnancy in the period up to 1 
year following index procedure.   
8. Any other medical condition that in the opinion of the investigator will interfere with 
patient safety or study results. 
9. High degree A-V block, sinus node disease. 
10. Asthma/COPD with active wheeze 
11. Known hypersensitivity to adenosine 
12. STEMI within 48 hours. 
 
Power:  
The primary hypothesis is: 
Null-  
• mean RFR measurements = mean iFR measurements  
• Δ ±0.05 
 
A sample size of 92 patients will provide 90% power to detect a 95% agreement 
between RFR and iFR to detect ischemia  
 
Data Collection:  
Data will be collected at baseline/screening, during angiography, and at discharge. 
 
Duration: 
The total duration of the study is expected to be 1 year.   
 
 
Flow Chart 
 
Baseline/ 
Procedure 
Discharge 
 
Hospital 
Hospital 
Demographics 
X 
 

Version 2, Revised 9/20/17 
 
Baseline/ 
Procedure 
Discharge 
Pregnancy Test 
if female of child 
bearing age 
X 
 
Medical  
History (incl. 
physical exam) 
X 
 
Angiogram 
X 
 
FFR (PW and 
PC) 
X 
 
Investigator 
Treatment 
Decisions 
X 
 
Adverse Events 
Assessment 
X 
X 
 
References 
 
1. 
Tonino PA, De Bruyne B, Pijls NH, Siebert U, Ikeno F, van' t Veer M, Klauss V, 
Manoharan G, Engstrom T, Oldroyd KG, et al. Fractional flow reserve versus 
angiography for guiding percutaneous coronary intervention. The New England 
journal of medicine. 2009;360(3):213-24. 
2. 
De Bruyne B, Pijls NH, Kalesan B, Barbato E, Tonino PA, Piroth Z, Jagic N, Mobius-
Winkler S, Rioufol G, Witt N, et al. Fractional flow reserve-guided PCI versus medical 
therapy in stable coronary disease. The New England journal of medicine. 
2012;367(11):991-1001.   
 
   3.       Davies JE1, Sen S1, Dehbi HM1, Al-Lamee R1, Petraco R1, Nijjer SS1, Bhindi R1, 
Lehman SJ1, Walters D1, Sapontis J1, Janssens L1, Vrints CJ1, Serruys P1, Escaned J1. 
Use of the Instantaneous Wave-free Ratio or Fractional Flow Reserve in PCI. N Engl J 
Med. 2017 May 11;376(19):1824-1834. doi: 10.1056/NEJMoa1700445. Epub 2017 
Mar 18 Instantaneous Wave-free Ratio versus Fractional Flow Reserve to Guide PCI 
   4.          Matthias Götberg, M.D., Ph.D., Evald H. Christiansen, M.D., Ph.D., Ingibjörg J. 
Gudmundsdottir, M.D., D.M., Lennart Sandhall, M.D., Mikael Danielewicz, M.D., Lars 
Jakobsen, M.D., Ph.D., Ole Fröbert, M.D., Ph.D., for the iFR-SWEDEHEART 
Investigators*Instantaneous Wave-free Ratio versus Fractional Flow Reserve to 
Guide PCI. N Engl J Med 2017; 376:1813-1823May 11, 2017DOI: 
10.1056/NEJMoa1616540