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Instantaneous wave free ratio (i fr)

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In the first part of this study, we identified the existence of a diastolic interval in which intracoronary resistance at rest is equivalent to time-averaged resistance during FFR measurements. We hypothesize that pressure measurements obtained selectively at this specific interval of the cardiac cycle would allow a new pressure-derived index of stenosis severity that does not require pharmacologic vasodilation; we term this the instantaneous wave-free ratio (iFR). In the second part of the study, this hypothesis was tested in a larger population by comparing iFR and FFR measurements.

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Instantaneous wave free ratio (i fr)

  1. 1. FOCUS ISSUE: TRANSCATHETER CARDIOVASCULAR THERAPEUTICS Coronary Disease 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 Sayan Sen, MBBS,* Javier Escaned, MD, PHD,† Iqbal S. Malik, MBBS, PHD,‡ Ghada W. Mikhail, MBBS, MD,‡ Rodney A. Foale, MD,* Rafael Mila, MD,† Jason Tarkin, MBBS,* Ricardo Petraco, MD,* Christopher Broyd, MBBS,* Richard Jabbour, MBBS,* Amarjit Sethi, MBBS, PHD,‡† Christopher S. Baker, MBBS, PHD,‡ Micheal Bellamy, MBBS, MD,‡ Mahmud Al-Bustami, MD,‡ David Hackett, MD,‡ Masood Khan, MB, BCHIR, MA,‡ David Lefroy, MB, BCHIR, MA,‡ Kim H. Parker, PHD,§ Alun D. Hughes, MBBS, PHD,* Darrel P. Francis, MB, BCHIR, MA, MD,* Carlo Di Mario, MD, PHD,ʈ Jamil Mayet, MBCHB, MD, MBA,* Justin E. Davies, MBBS, PHD* London, United Kingdom; and Madrid, Spain Objectives The purpose of this study was to develop an adenosine-independent, pressure-derived index of coronary stenosis severity. Background Assessment of stenosis severity with fractional flow reserve (FFR) requires that coronary resistance is stable and mini- mized. This is usually achieved by administration of pharmacological agents such as adenosine. In this 2-part study, we determine whether there is a time when resistance is naturally minimized at rest and assess the diagnostic effi- ciency, compared with FFR, of a new pressure-derived adenosine-free index of stenosis severity over that time. Methods A total of 157 stenoses were assessed. In part 1 (39 stenoses), intracoronary pressure and flow velocity were measured distal to the stenosis; in part 2 (118 stenoses), intracoronary pressure alone was measured. Measure- ments were made at baseline and under pharmacologic vasodilation with adenosine. Results Wave-intensity analysis identified a wave-free period in which intracoronary resistance at rest is similar in variability and magnitude (coefficient of variation: 0.08 Ϯ 0.06 and 284 Ϯ 147 mm Hg s/m) to those during FFR (coefficient of variation: 0.08 Ϯ 0.06 and 302 Ϯ 315 mm Hg s/m; p ϭ NS for both). The resting distal-to-proximal pressure ratio during this period, the instantaneous wave-free ratio (iFR), correlated closely with FFR (r ϭ 0.9, p Ͻ 0.001) with excel- lent diagnostic efficiency (receiver-operating characteristic area under the curve of 93%, at FFR Ͻ0.8), specificity, sen- sitivity, negative and positive predictive values of 91%, 85%, 85%, and 91%, respectively. Conclusions Intracoronary resistance is naturally constant and minimized during the wave-free period. The instantaneous wave-free ratio calculated over this period produces a drug-free index of stenosis severity comparable to FFR. (Vasodilator Free Measure of Fractional Flow Reserve [ADVISE]; NCT01118481) (J Am Coll Cardiol 2012;59: 1392–402) © 2012 by the American College of Cardiology Foundation From the *International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College London, London, United Kingdom; †Cardiovascular Institute, Hospital Clı´nico San Carlos, Madrid, Spain; ‡Imperial College Healthcare NHS Trust, Hammersmith Hospital, London, United Kingdom; §Physiological Flow Unit, Imperial College London, London, United Kingdom; and the ʈRoyal Brompton and Harefield NHS Trust, London, United Kingdom. This study was supported by the Volcano Corporation. This study was funded by the NIHR Biomedical Research Centre and the Coronary Flow Trust. Dr. Sen is a Medical Research Council fellow (G1000357). Dr. Davies (FS/05/006), Dr. Francis (FS 04/079), and Dr. Petraco (FS/11/46/28861) are British Heart Foundation fellows. Dr. Mikhail is on the Steering Committee for a trial conducted by Abbott Vascular. Drs. Davies and Mayet hold patents pertaining to this technology. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received September 26, 2011; revised manuscript received November 3, 2011, accepted November 3, 2011. Journal of the American College of Cardiology Vol. 59, No. 15, 2012 © 2012 by the American College of Cardiology Foundation ISSN 0735-1097 Published by Elsevier Inc. doi:10.1016/j.jacc.2011.11.003 Open access under CC BY-NC-ND license. Open access under CC BY-NC-ND license.
  2. 2. Intracoronary physiologic indices enable cardiologists to circumvent the limitations of angiography when assessing the hemodynamic impact of stenoses (1,2). Functional assessment of stenoses in the catheterization laboratory can be performed by measuring intracoronary flow velocity (coronary flow velocity reserve), pressure (fractional flow reserve [FFR]), or both (hyperemic stenotic resistance) (3,4). FFR is the most widely used index in clinical practice, being supported by a large body of evidence demonstrating See page 1403 its value in clinical decision making. When used to guide percu- taneous interventions, FFR has been shown to improve clinical outcomes and procedural cost-efficiency (5–7). The cornerstone of FFR is the linear relationship be- tween pressure and flow under conditions of constant (and minimized) intracoronary resistance (4). Under such condi- tions, pressure and flow are assumed to be directly propor- tional, and a decrease in pressure across a stenosis reflects a decrease in blood flow to the dependent myocardium. However, even after administration of potent pharmaco- logic agents such as adenosine, intracoronary resistance is not static, but instead fluctuates in a phasic pattern (akin to im- pedance in an alternating-current electrical circuit) throughout the cardiac cycle (Figs. 1 and 2). These fluctuations reflect the in- teraction between the myocar- dium and microvasculature dur- ing systole (high intracoronary resistance, compression of microvasculature) and diastole (lower intracoronary resis- tance, decompression of the microvasculature) (8). Accord- ingly, to minimize these effects, FFR is calculated during hyperemia (maximal flow to the vascular bed) and time- averaged over several cardiac cycles to ensure constant and minimal intracoronary resistance. Although time-averaging and the administration of phar- macologic vasodilators were a pragmatic solution to achiev- ing appropriate conditions in which to calculate FFR when computational power was limited, it may now be unneces- sary if a time period could be identified from the resting pressure waveform when resistance is naturally constant and minimized. Theoretically, during such a period in the cardiac cycle, intracoronary pressure and flow would be propor- Abbreviations and Acronyms FFR ‫؍‬ fractional flow reserve iFR ‫؍‬ instantaneous wave-free ratio -6 -4 -2 0 2 4 Waveintensity (Wx10-5m-2s-2) 0 20 40 Separatedpressure abovediastole (mmHg) 0 100 200 300 400 100 150 200 Pressure (mmHg) 0 100 200 300 400 0.3 0.4 0.5 1200 300 600 Resistance (mmHgs/m) Time (ms) proximal-originating compression wave microcirculatory-originating compression waves proximal-originating pressure microcirculatory -originating pressure Pressure WAVE FREE PERIOD Flow velocity microcirculatory-originating decompression wave 500 600 700500 600 700 0.1 0.2 Velocity (m/s) A B C D Figure 1 Identification of Wave-Free Period in the Cardiac Cycle Wave-intensity analysis (A) demonstrates the proximal and microcirculatory (distal) originating waves generated during the cardiac cycle. A wave-free period can be seen in diastole when no new waves are generated (shaded). This corresponds to a time period in which there is minimal microcirculatory (distal)–originating pressure (B), minimal and constant resistance (C), and a nearly constant rate of change in flow velocity (D). (Separated pressure above diastole is the residual pulsatile separated pressure component after subtraction of the diastolic pressure.) 1393JACC Vol. 59, No. 15, 2012 Sen et al. April 10, 2012:1392–402 Adenosine-Free Measure of Stenosis Severity
  3. 3. tional. Consequently, a ratio of trans-stenotic pressures during this time would provide a measure of the severity of a coronary stenosis. Identification of such a period would negate the need for administration of pharmacologic agents such as adenosine, saving time, reducing costs and side effects, and leading to improved adoption in the cardiac catheter laboratory. In the first part of this study, we identified the existence of a diastolic interval in which intracoronary resistance at rest is equivalent to time-averaged resistance during FFR measurements. We hypothesize that pressure measurements obtained selectively at this specific interval of the cardiac cycle would allow a new pressure-derived index of stenosis severity that does not require pharmacologic vasodilation; we term this the instantaneous wave-free ratio (iFR). In the second part of the study, this hypothesis was tested in a larger population by comparing iFR and FFR measurements. Methods Study population. This multicenter international, nonran- domized study included 131 patients (age 63 Ϯ 10 years, 85% male) scheduled for coronary angiography or percuta- neous coronary intervention at 3 sites (Imperial College Healthcare NHS trust, London, United Kingdom; Cardio- vascular Institute, Hospital Clı´nico San Carlos, Madrid, Spain; and Royal Brompton and Harefield NHS trust, London, United Kingdom). The patient demographics are consistent with the broad entry criteria used in recruitment (Table 1). Exclusion criteria were limited to significant valvular pathology, previous coronary artery bypass surgery, contraindication to adenosine administration (e.g., asthma, chronic obstructive pulmonary disease, heart rate Ͻ50 beats/min, and systolic blood pressure Ͻ90 mm Hg), increased troponin, and weight Ͼ200 kg. All subjects gave written informed consent in accordance with the protocol approved by the local ethics committee (NRES ref: 09/ H0712/102; NCT01118481). Study protocol. CARDIAC CATHETERIZATION. In this 2-part study, patients were divided into 2 groups, providing a total of 157 stenoses (part 1, 39 stenoses; part 2, 118 stenoses) (Fig. 3). 0 0.2 0.4 Velocity (m/s) 50 100 150 200 Pressure (mmHg) 0 1000 2000 Resistance (mmHgs/m) 0 30 60 Time (s) Figure 2 Coronary Velocity, Aortic and Coronary Pressures, and Resistance in the Right Coronary Artery A typical example of the pressure, flow velocity, and resistance data obtained from a patient with an intermediate right coronary artery stenosis (arrow, right panel). The effect of hyperemia can be seen with concomitant increase in flow velocity (left, top panel) and decrease in intracoronary pressure (left, middle panel), stable intracoro- nary resistance is subsequently achieved (left, bottom panel). Patient Demographic DataTable 1 Patient Demographic Data Group 1: Pressure/Flow Velocity Group 2: Pressure Only Overall No. of stenoses 39 118 157 Age, yrs 64.6 Ϯ 9.9 59.2 Ϯ 16.1 62.6 Ϯ 10.2 Male 35 (89.7) 96 (81.4) 131 (83.4) Diabetes 21 (53.9) 33 (28) 54 (34.4) Smoker 6 (15.4) 28 (23.7) 34 (21.7) Hypertension 23 (59) 65 (55) 88 (56.1) Impaired LV function (EF Ͻ50%) 4 (10.3) 9 (7.6) 13 (8.3) Stable angina 35 (89.7) 116 (98.3) 151 (96.2) Unstable angina 4 (10.3) 2 (1.7) 6 (3.8) Single vessel 16 (41) 92 (78) 108 (68.8) Multivessel 23 (59) 26 (22) 49 (31.2) Coronary artery LAD 21 (54.1) 48 (40.7) 69 (44) Cx 11 (27) 32 (27.1) 43 (27.1) RCA 7 (18.9) 38 (32.2) 45 (28.9) Adenosine (route) Intracoronary 0 (0) 94 (79.7) 94 (59.9) Intravenous 39 (100) 24 (20.3) 63 (40.1) Values are n, mean Ϯ SD, or n (%). Cx ϭ circumflex artery; EF ϭ ejection fraction; LAD ϭ left anterior descending artery; LV ϭ left ventricular; RCA ϭ right coronary artery. 1394 Sen et al. JACC Vol. 59, No. 15, 2012 Adenosine-Free Measure of Stenosis Severity April 10, 2012:1392–402
  4. 4. In part 1, cardiac catheterization was undertaken via the femoral approach. After diagnostic angiography, a 0.014- inch pressure- and Doppler sensor–tipped wire (ComboWire XT, Volcano Corporation, San Diego, California) was passed into the target vessel via a guiding catheter. Pressure equalization was performed at the tip of the catheter before its advancement distal to the stenosis. Pressure and flow velocity recordings were then made at baseline. Adenosine was then infused (140 ␮g/kg/min) via a femoral venous sheath, and pressure and flow velocity measurements repeated under con- ditions of maximal pharmacologic vasodilation. In part 2, cardiac catheterization was undertaken via either the femoral or radial approach. Adenosine doses of 140 ␮g/mg/min (via the femoral vein) or 120 ␮g (intracoronary) were used to induce vasodilation. After diagnostic angiogra- phy, a 0.014-inch pressure sensor–tipped wire (PrimeWire, Volcano Corporation, or Radi PressureWire, St. Jude Medical, Minneapolis, Minnesota) was equalized and then advanced distally. Pressure measurements were made at baseline and under maximal pharmacologic vasodilation. In both groups, 5,000 IU intravenous heparin was given at the start of the procedure and 300 ␮g of intracoronary nitrates were routinely given before hemodynamic measurements. Hemodynamic recordings. When the ComboWire or PrimeWire pressure wire was used, the electrocardiogram, pressures, and flow velocity signals were directly extracted from the digital archive of the device console (ComboMap, Volcano Corporation). When the Radi PressureWire sys- tem was used, continuous digital acquisition and storage of the electrocardiograms and aortic and intracoronary pres- sures were performed using a 12-bit resolution analog-to- digital converter (DI-200 PGL, DataQ Instruments, Ak- ron, Ohio) controlled by dedicated software (WinDaq 200, DataQ Instruments) in a personal computer. The sampling rate was 114 Hz per channel. At the end of each recording, the pressure sensor was returned to the catheter tip to ensure that there was no pressure drift. When drift was identified, the measurements were repeated. Data were analyzed offline using a custom software package designed with Matlab (Mathworks, Inc., Natick, Massachusetts). Identification of period of constant and minimal resistance. Changes in coronary hemodynamics over the cardiac cycle were assessed by calculating instantaneous resistance and by applying wave-intensity analysis. An index of resistance was calculated as the ratio between pressure and flow velocity. Wave-intensity analysis was performed according to the meth- odology described previously (8) to identify wave-free periods (Fig. 1A). During this wave-free period, the onset of minimal resistance was identified and its value calculated for each patient. It was not possible to calculate resistance in 2 patients due to poor tracking of the velocity envelope during diastole. Mean intracoronary resistance and its coefficient of variation were then calculated over a minimum of 3 beats. To minimize any selection bias and truly assess the diag- nostic efficiency of our index, we designed this study to include all the cardiac patients that FFR is used in routinely in clinical practice (including single-vessel, multivessel, and diabetic pa- tients). We used both intracoronary and intravenous adenosine and pressure wires from St. Jude Medical and Volcano. FFR was measured in the standard way (5,6) and used to guide the clinical case. However, the invasive measurement team was blinded to the iFR value, which was calculated offline using a fully automated Matlab algorithm (Mathworks, Inc.). Calculation of the instantaneous wave-free ratio (iFR). Wave-intensity analysis was used to identify the backward- traveling waves (Equation 1). The onset of diastole was identified from the dicrotic notch, and the diastolic window was calculated beginning 25% of the way into diastole and ending 5 ms before the end of diastole. This time was chosen to reflect the wave-free period in diastole when resistance is naturally minimized (see Results and Discussion) (Fig. 1). iFR was calculated as the mean pressure distal to the stenosis during the diastolic wave-free period (Pd wave-free period) divided by the mean aortic pressure during the diastolic wave-free period (Pa wave-free period) (Equation 2). All analyses were performed in a fully automated manner, eliminating the need for manual selection of data time points. Backward-traveling waves ϭ WI _ ϭ Ϫ 1 4pcͩdp dt Ϫ pc du dt ͪ2 [1] The wave-free period runs from time (WIϪ[diastole] ϭ 0) to the end of diastole Ϫ 5 ms. iFR ϭ Pd៮ wave-free period Pa៮ wave-free period [2] where ␳ is the density of blood (taken as 1050 kgϪ3 ), c is the wave speed calculated using the single-point equation (8), Figure 3 The ADVISE Study Protocol ADVISE ϭ ADenosine Vasodilator Independent Stenosis Evaluation; FFR ϭ frac- tional flow reserve; iFR ϭ instantaneous wave-free ratio. 1395JACC Vol. 59, No. 15, 2012 Sen et al. April 10, 2012:1392–402 Adenosine-Free Measure of Stenosis Severity
  5. 5. dP is the incremental change in coronary artery pressure, and dU is the incremental change in blood velocity. Data analysis. Processing of digital data (pressure, flow velocity, electrocardiogram) for the calculation of the vari- ous indices and intervals discussed (wave-intensity analysis, coronary resistance, FFR, selection of wave-free diastolic interval, iFR) was performed at a workstation using Matlab (Mathworks, Inc.). Statistical analysis was performed using STATA version 11 (StataCorp, College Station, Texas). A paired Student t test was used to compare within patients. The proportional change in resistance during the cardiac cycle was referenced to the baseline mean resistance. The relationship between the FFR and iFR for the entire patient population and all subsequent subgroup analyses was quan- tified with a Pearson’s product moment correlation coeffi- cient. Receiver-operating characteristic curves were used to estimate diagnostic efficiency of iFR and to identify the most appropriate cutoff value compared with the FFR treatment threshold of 0.8. Mean values are expressed as mean Ϯ SD. A repeated-measures analysis was performed by comparing the iFR from the first half of the recording with the value from the second half of the recording using a paired Student t test. The relationship of heart rate and blood pressure to iFR was quantified with a Pearson product moment correlation coefficient. A p value Ͻ0.05 was deemed significant. Results Identification of period of stable resistance in the cardiac cycle. In each of the stenoses included in part 1, intracoro- nary pressure, flow velocity, and resistance were analyzed before and during the administration of adenosine (Fig. 2). Wave-intensity analysis allowed identification of a wave- free period after the backward decompression wave when wave intensity and microcirculatory-originating pressure return to zero (Figs. 1A and 1B). The mean duration of this period was 354 Ϯ 78 ms (75 Ϯ 6% of diastole), starting 112 Ϯ 26 ms after the onset of diastole. Intracoronary resistance remained minimized and stable throughout this wave-free period (Fig. 1C). Resistance throughout the cardiac cycle at rest and with pharmacologic vasodilation. Adenosine administration caused the mean intracoronary resistance over the entire cardiac cycle to decrease by 51% (613 Ϯ 310 mm Hg s/m vs. 302 Ϯ 315 mm Hg s/m, p Ͻ 0.001). This was predominantly due to a 75% reduction in the systolic contribution to resistance (⌬ systolic resistance 461 mm Hg s/m, p Ͻ 0.001) (Fig. 4). Both the magnitude and variability of intracoronary resistance identified during the wave-free period were sim- ilar to those achieved over the entire cardiac cycle during pharmacologic vasodilation. The magnitude of resistance during the wave-free period was 284 Ϯ 147 mm Hg s/m compared with 302 Ϯ 315 mm Hg s/m during pharmaco- logic vasodilation (p ϭ 0.70) (Fig. 5A). The coefficient of variation of resistance during the wave-free period was 0.08 Ϯ 0.06 compared with 0.08 Ϯ 0.06 during pharmacologic vasodilation (p ϭ 0.96) (Fig. 5B). Reproducibility and diagnostic characteristics of iFR. The iFR was calculated for each stenosis using the wave-free time window, as defined previously, and this was compared with the FFR. The iFR was found to be closely correlated with the FFR (r ϭ 0.90, y ϭ 1.0x ϩ 0.03) (Fig. 6). Using the established FFR cutoff threshold of 0.8 to define a positive result, a receiver-operating characteristic curve was used to identify the optimal iFR cutoff (0.83) with the greatest diag- nostic efficiency. The receiver-operating characteristic area under curve was 93% (Fig. 7). False-negative and false-positive data for the iFR is demonstrated in Figure 8B; the positive predictive value of the iFR was 91% and the negative predictive value was 85%, with a sensitivity and specificity of 85% and 91%, respectively. Furthermore, the close correlation of iFR with FFR remained with left coronary (r ϭ 0.90) and right (r ϭ 0.89) coronary arteries, with a diagnostic accuracy in the right coronary artery of 91%, consistent with the entire cohort (Fig. 8). This relationship persisted throughout our sub- group analysis, with similar levels of correlation indepen- dent of the type of pressure wire, route of pharmacologic vasodilator administration, single- or multivessel disease (Table 2). Furthermore, iFR was found to be independent of heart rate (range 46 to 120/min; r2 ϭ 0.016), systolic (r2 ϭ 0.001), and diastolic (r2 ϭ 0.005) pressure. Indeed, the iFR was also found to be stable in patients with ectopy and large changes in blood pressure due to respiration (Fig. 9). Figure 4 Reduction in Systolic Resistance With Intravenous Adenosine Administration There was a significant reduction in the systolic component of intracoronary resistance with adenosine (⌬ systolic resistance: 461 mm Hg s/m, p Ͻ 0.001), which was the dominant contributor to the mean reduction in resistance during the cardiac cycle. 1396 Sen et al. JACC Vol. 59, No. 15, 2012 Adenosine-Free Measure of Stenosis Severity April 10, 2012:1392–402
  6. 6. Bland-Altman analysis also demonstrates good agree- ment between measures with a mean difference between the FFR and iFR of Ϫ0.05 Ϯ 0.19. A repeated-measures analysis of the iFR was made in 149 stenoses, which demonstrated a close relationship between the 2 successive measurements (r ϭ 0.996, p Ͻ 0.001) (Fig. 10), with a mean difference between iFR measurements of Ϫ0.0005 Ϯ 0.002 (p ϭ 0.78). Discussion The main conclusions of this study are that: 1) when selectively measured within a defined diastolic wave-free period, resting coronary resistance values are similar to those observed during adenosine-mediated FFR; and 2) the ratio Figure 5 Intracoronary Resistance During Pharmacologic Vasodilation Compared With Resistance During the Wave-Free Period (A) Compared with baseline, there was a significant reduction in resistance with both pharmacologic vasodilation and during the wave-free period. (A, B) There was no significant difference in the magnitude or variability of resistance with pharmacologic vasodilation (as used for fractional flow reserve) compared with the wave-free period (as used for instantaneous wave-free ratio). All values are reported as mean Ϯ SE. Figure 6 Correlation of iFR With FFR The wave-free period was calculated using a fully automated algorithm. The instantaneous wave-free ratio (iFR) was calculated by dividing the mean Pd by Pa during the wave-free period under basal conditions. The iFR was found to closely agree with the fractional flow reserve (FFR) (r ϭ 0.9, p Ͻ 0.001). The dotted lines represent the threshold cutoff values for the iFR and FFR. Figure 7 Diagnostic Characteristics of the iFR A receiver-operating characteristic curve was calculated using FFR as the refer- ence gold-standard variable. The threshold cutoff for FFR was taken as 0.80. The receiver-operating characteristic was found to have an area under the curve of 93%, suggesting high accuracy of iFR as a diagnostic test. Abbrevia- tions as in Figure 6. 1397JACC Vol. 59, No. 15, 2012 Sen et al. April 10, 2012:1392–402 Adenosine-Free Measure of Stenosis Severity
  7. 7. of distal-to-proximal pressures during this wave-free period produces an index (iFR) that correlates closely with FFR. Importance of constant intracoronary resistance in the functional assessment of stenoses. Coronary blood flow is unique in that it is determined not only by variations in pressure arising proximally (as in the aorta and other systemic arteries) but also concurrent variations arising distally in the microcirculation (Fig. 11) (8). It is con- sidered inaccurate to assess the severity of a coronary stenosis by simply measuring the decrease in mean or peak pressure across a stenosis under basal conditions over the entire cardiac cycle because distal coronary pressure is not simply a residuum of the pressure trans- mitted from the aortic end of the vessel (Fig. 11A), but is also due to a pressure component arising from active compression and decompression of the coronary micro- Subgroup Analysis: Close Agreement Between the iFR and FFR Across Subgroups AnalyzedTable 2 Subgroup Analysis: Close Agreement Between the iFR and FFR Across Subgroups Analyzed Stenoses Male Age, yrs Diabetes Hypertension Adenosine r ValueIC IV Single vessel 108 (68.8) 88 (81.5) 57.7 Ϯ 16.3 35 (32.4) 57 (52.8) 74 (68.5) 34 (31.5) 0.89 Multivessel 49 (31.2) 43 (87.8) 66.7 Ϯ 8.7 19 (38.8) 31 (63.3) 20 (40.8) 29 (59.2) 0.92 Coronary artery LAD 69 (44.0) 59 (83.6) 62.4 Ϯ 10.3 20 (28.4) 43 (61.2) 39 (56.5) 30 (43.5) 0.89 Cx 43 (27.3) 40 (92.7) 63.3 Ϯ 11.3 18 (41.5) 27 (63.4) 21 (48.8) 22 (51.2) 0.91 RCA 45 (28.7) 39 (88.1) 62.2 Ϯ 8.9 19 (42.9) 22 (50.0) 34 (76.2) 11 (23.8) 0.89 Adenosine (route) Intracoronary 94 (59.9) 77 (80.2) 60.9 Ϯ 9.7 23 (24.0) 49 (51.0) 100 — 0.88 Intravenous 63 (40.1) 54 (88.5) 65.0 Ϯ 10.3 31 (50.8) 39 (63.9) — 100 0.90 Diabetes 54 (34.4) 45 (83.3) 63.5 Ϯ 8.0 54 (100.0) 40 (74.1) 23 (42.6) 31 (57.4) 0.88 Smoker 34 (21.7) 31 (91.1) 57.1 Ϯ 10.1 6 (17.6) 19 (55.9) 8 (23.5) 26 (76.5) 0.85 Hypertension 88 (56.1) 73 (83.0) 64.0 Ϯ 9.8 40 (45.5) 88 (100.0) 49 (55.7) 39 (44.3) 0.92 Values are n (%) or mean Ϯ SD. IC ϭ intracoronary; IV ϭ intravenous; other abbreviations as in Table 1. Figure 8 Correlation and Diagnostic Characteristics of the iFR With FFR According to the Coronary Artery The iFR was found to correlate closely with FFR (r ϭ 0.9). This was consistent in both the right (r ϭ 0.89, red dots) and left (r ϭ 0.90, black dots) coronary arteries (A). An assessment of false-positive and false-negative results comparing iFR with FFR was then made (B). The treatment categorization of iFR agreed closely with that of FFR. Specifically, iFR had a diagnostic accuracy, positive predictive value, negative predictive value, sensitivity, and specificity of 88%, 91%, 85%, 85%, and 91%, respec- tively. This was also independent of the right or left coronary artery. Abbreviations as in Figure 6. 1398 Sen et al. JACC Vol. 59, No. 15, 2012 Adenosine-Free Measure of Stenosis Severity April 10, 2012:1392–402
  8. 8. circulation (Fig. 11B). These distal influences cause dramatic variations in the instantaneous ratio between pressure and flow (a simple index of intracoronary resis- tance). Wave-intensity analysis can be used to distinguish distal microcirculatory-originating influences from prox- imally originating influences transmitted from the aorta (8). The most extreme examples of such variations are the rapid increase in pressure in early systole and the rapid decrease in early diastole. In early systole, pressure increases rapidly but flow does not, and so the index of intracoronary resistance increases rapidly. The rapid in- crease in pressure without a corresponding increase in flow is caused by near-perfect matching of compression waves arising from the aorta and coronary microcircula- tion during most of systole (8) (Fig. 1A). In early diastole, the converse happens; pressure decreases while flow accelerates, and so the index of intracoronary resis- tance decreases rapidly. This occurs because the micro- vasculature is suddenly decompressed, causing blood to be sucked in to the coronary microcirculation (Fig. 1). After this brief, but rapid, phase of pressure decrease, pressure and flow then passively decrease together slowly. During this gradual decline, which extends for the majority of diastole, the index of coronary resistance is close to minimal and is stable because there is no further wave activity arising from either end of the coronary artery. Pressure-derived flow indices of coronary stenosis severity such as FFR depend on the proportional relationship of pressure to flow, which occurs when resistance is stable (5); this is only the case for part of the cardiac cycle. Pioneering scientists seeking clinically applicable methods developed highly refined approaches to circumvent the computational limitations of the day by administering pharmacologic agents such as adenosine (5,9,10). As we demonstrate, these potent vasodilator agents reduce the dramatic variation in resistance predominantly by reducing the systolic portion of resistance (Figs. 4 and 5) to obtain a stable and mini- mized resistance value. Recent advances in real-time processing now permit automatic selection of the diastolic wave-free period, using measurements of pressure alone, that provides this stable and minimal resistance value without having to administer vasodilator agents. During this diastolic wave-free period, 60 120 0 5 10 0 0.5 1.0 75 150 0 5 10 15 0 0.5 1.0 PaandPd Pressure (mmHg) iFR PaandPd Pressure (mmHg) iFR 0 0 Time (s) A B Figure 9 Stability of the iFR During Hemodynamic Perturbation The iFR provides a beat-to-beat pressure ratio during the wave-free window, comparing each distal pressure with its corresponding aortic pressure. This ensures accuracy regardless of arrhythmia (A, ectopy) or variations in blood pressure and heart rate (B, tachycardia and respiratory variation in blood pressure). Abbreviations as in Figure 6. 1399JACC Vol. 59, No. 15, 2012 Sen et al. April 10, 2012:1392–402 Adenosine-Free Measure of Stenosis Severity
  9. 9. coronary flow is predominantly determined by the passive pressure gradient between the proximal and distal ends of the vessel, analogous to water flowing down a pipe. This natural state of stable and minimized resistance occurs spontaneously in every cardiac cycle, creating an opportunity to calculate a pressure-derived index without the need for pharmacologic intervention. Identification of the wave-free diastolic window. We identified in all patients a period in diastole when resistance is stable. Across all individual patients, the start of this window was 112 Ϯ 26 ms after the onset of diastole (25 Ϯ 6% into diastole), and the end was the end of diastole. For automatic computation, we consider it practical to use an algorithmic definition of the time window that begins 25% of the way into diastole (after the early unwanted variations) and ends 5 ms before the end of diastole, allowing 75% of diastole during which pressure measurements can be made. iFR as a tool for instant diagnosis: the challenge of minor uncertainty of FFR. Using an all-comers selection criteria similar to the FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) study (6), iFR was found to agree closely with FFR with a diagnostic efficiency (area under the curve) of 93%. This was seen consistently Figure 10 Repeated-Measures Analysis of the iFR and Bland-Altman Plot The baseline pressure data were split in half, and the iFR for each half was calculated. The correlation of iFR 1with iFR 2 demonstrates high reproducibility across the entire range of stenosis severity (B, mean difference between measures Ϫ0.0005 Ϯ 0.002, p ϭ 0.78). The Bland-Altman plot demonstrates good agreement between the iFR and FFR across the entire range of stenosis severity. Abbreviations as in Figure 6. Figure 11 Schematic Illustrating the Importance of Microcirculatory (or Distal Originating) Pressure in the Coronary Arteries In all blood vessels, blood flows down a pressure gradient. In the systemic circulation, a pressure wave is generated after a ventricular contraction traveling from the proximal to distal end of the vessel. Although most of this wave energy travels in an anterograde direction, a small proportion is reflected back at the site of impedance mismatch from the distal circulation (A). This contrasts with the coronary circulation where a pressure wave is generated at both the proximal and distal ends of the ves- sel at differing times in the cardiac cycle. Thus, intracoronary pressure distal to a stenosis is a composite of residual proximally originating pressure and the distal origi- nating pressure from compression of the intramyocardial vessels. The iFR is calculated during the wave-free period in diastole, when distal originating pressure in minimized (Fig. 1). The size of the arrows pointing in the direction of wave travel denote the contribution of proximal or distal pressure to total pressure, with proximal pressure predominant in the systemic artery (A) and equal contribution to total pressure from both the proximal and distal ends in the coronary artery (B). 1400 Sen et al. JACC Vol. 59, No. 15, 2012 Adenosine-Free Measure of Stenosis Severity April 10, 2012:1392–402
  10. 10. across all subgroups analyzed (multivessel, single vessel, right and left coronary arteries) and independent of the method of assessment (intracoronary vs. intravenous aden- osine or RADI vs. Volcano pressure wire) (Table 1). FFR is itself known to vary slightly from one measure- ment to the next, and therefore no technique can correlate perfectly with it. FFR has a coefficient of variation of 4.8% (95% confidence interval: 3.5 to 7.4) and a mean difference between repeated measures of 0.01 Ϯ 0.04 (11). iFR compares favorably with a very small mean difference between repeated measures Ϫ0.0005 Ϯ 0.002 (p ϭ 0.78). Although the variability in FFR is small, that in the iFR is smaller. We speculate that this occurs for 2 main reasons. First, spontaneous beat-to-beat fluctuations are most exag- gerated during systole (included in FFR, but excluded by definition in iFR). Second, when ectopics or other un- wanted disturbances occur, the FFR relies on averaging multiple beats to “dilute” their effects, whereas the iFR matches proximal and distal pressures on a beat-by-beat basis by performing a paired comparison between each “mother” aortic diastolic pressure component and its own corresponding “daughter” distal diastolic pressure compo- nent, resulting in more stable values, even during arrhyth- mia (Fig. 9). Categorization using iFR was found to agree with categorization using FFR in 88% of cases treating FFR as the gold standard. However, if the previously discussed, well-documented intrinsic variability of FFR is accounted for, the adjusted iFR diagnostic accuracy would increase to around 95% with positive and negative predictive values of 97% and 93%, respectively (11). Clinical implications of iFR. FFR has been revolutionary in implementing intracoronary physiology in clinical prac- tice. Its success is a reflection of the simplicity of the technique and accumulation of clinical evidence demon- strating the safety of adopting an FFR-guided approach to revascularization (6,10,12,13). FFR is currently recom- mended as a surrogate for ischemia detection tests in the catheterization laboratory in clinical practice guidelines (14) and, compared with angiography guidance, improves pa- tient outcomes, while decreasing procedural time and costs when used in percutaneous coronary interventions (6,7). Despite this, use of the FFR is far from universal, being performed in only 6% of percutaneous coronary intervention procedures in the United States (14). The need to admin- ister adenosine has been highlighted as one of the reasons for this poor adoption rate (15). There are several reasons that may explain the reluctance of physicians to use aden- osine. First, in addition to costs, the clinical effort of administering adenosine is not trivial, and so it has to be actively chosen on each occasion. Second, some patients have contraindications such as asthma, severe chronic ob- structive pulmonary disease, hypotension, and bradycardia. Third, most patients find it uncomfortable. Fourth, it may require central venous access, which might otherwise not be necessary for the procedure (16). Finally, initial adenosine response may be incomplete in some patients, and this may be difficult to predict reliably in advance (17–19). Thus, a wider use of intracoronary physiology would be expected if the technique is simplified even further. iFR would circum- navigate these issues, permitting the benefits of FFR to be accessible to a wider population at lower cost, with less patient discomfort and shorter procedural times. This study’s cohort of patients reflects a wide demo- graphic spectrum and is similar to that of the FAME study (6). The results of this study could be followed by further validation of iFR in a larger cohort to better establish the diagnostic efficiency of each technique in the same study population. Although this appears to be a prerequisite before iFR can be proposed as an alternative to FFR in all contexts, the excellent reproducibility and agreement in classification with FFR (within the biological variability of FFR) suggest that iFR will expand intracoronary functional assessment to circumstances in which administration of adenosine is not desirable. A final word should be dedicated to previous research on the use of diastolic pressures for FFR calculation, the so-called diastolic FFR (20,21). The validation of diastolic FFR demonstrated that diastolic-only pressure measure- ments can be used to estimate stenosis severity with the same diagnostic efficiency as FFR, which uses cycle- averaged pressure measurements (19). This supports the concept that systolic flow can be neglected in the pressure- derived indices like diastolic FFR and iFR. The optimal cutoff value to identify ischemia-generating stenoses in that study was slightly higher for diastolic FFR (0.76) than for FFR (0.75) (19), a fact that is in agreement with the differences found in our study between the (0.83) and the currently recommended 0.80 FFR cutoff value. However, major differences between the diastolic FFR and iFR should be noted: 1) like FFR, diastolic FFR requires the use of adenosine; and 2) measurements were obtained throughout diastole and not selectively at a specific wave-free interval. As discussed previously, the use of this wave-free period by iFR, when coronary resistance remains unchanged and minimal, provides a measure that closely correlates with FFR. Study limitations. There is no gold-standard ischemia test. We chose FFR because it is quantitative and specific to a vessel, has been validated against 3 noninvasive tests, has robust long-term clinical outcome data, and is the investigation recommended by cardiology guidelines for the assessment of intermediate stenoses in the cardiac catheter laboratory. However, there remains a possibility that any disagreement between the 2 indices may reflect the diagnostic accuracy of FFR rather than iFR. This pilot study suggests that an iFR value of 0.83 provides optimal agreement with an FFR of 0.8. Several hypotheses can be put forward to explain this difference in optimal cutoff values. First, since the optimal cutoff value for diastolic FFR, a diastolic-only pressure–derived method such as the iFR, is also slightly higher than that of FFR (19), it is possible that this difference may be genuinely due 1401JACC Vol. 59, No. 15, 2012 Sen et al. April 10, 2012:1392–402 Adenosine-Free Measure of Stenosis Severity
  11. 11. to differences in how the indices are calculated. Second, it may result from subtle differences between pharmacologic stabilization of resistance compared with that that occurs naturally in the wave-free period. Finally, the possibility that it may be artifactual, given the relatively small size of our study, cannot be ruled out. With a larger patient population, any differences might be further explored, and this cutoff value may change in a manner similar to that of FFR during its development. Therefore, future studies are needed to address the diagnostic accuracy between FFR and iFR and the best cutoff value for iFR. Intracoronary and intravenous administration of adeno- sine can have differing effects on peripheral and coronary arterial circulations. To mitigate potential confounding from either of these administration routes, we decided to include both intravenous and intracoronary administration in our study. In subanalyses of our results, we found no significant differences between either routes of administra- tion (Table 2). Finally, a similar agreement between iFR and FFR values was documented in the right and left coronary artery despite the more predominant systolic com- ponent of flow in the right coronary artery. Conclusions The existence of a wave-free period in diastole when coronary resistance is constant and minimal opens the possibility of performing pressure-derived stenosis assessment without the need for pharmacologic vasodilation. iFR, a new index based on this principle, has an excellent diagnostic efficiency in identifying stenoses with an FFR Ͻ0.80 and could be used for intracoronary functional assessment when admin- istration of adenosine is not desirable. Acknowledgments The authors acknowledge the support of the NIHR Bio- medical Research Centre funding scheme and Helen Davies for mathematical assistance. 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