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`Vol. 334 No. 26
`
`FRACTIONAL FLOW RESERVE TO ASSESS SEVERITY OF CORONARY-ARTERY STENOSIS
`
`1703
`
`MEASUREMENT OF FRACTIONAL FLOW RESERVE TO ASSESS THE FUNCTIONAL SEVERITY
`OF CORONARY-ARTERY STENOSES
`, M.D.,
` P
`, M.D., P
`.D., B
`
` B
`, M.D., K
` H.J. P
`N
`EELS
`ATHINKA
`RUYNE
`DE
`ERNARD
`H
`IJLS
`ICO
` H.
`
` V
`, M.D., H
` J.R.M. B
`, M.D., P
`.D., J
` B
`, M.D.,
`ARTUNEK
`OZEF
`VAN
`EPIJN
`DER
`OORT
`ANS
`ONNIER
`H
` J
` J. K
`, M.D., P
`.D.
`AND
`ACQUES
`OOLEN
`H
`
`P
`
`Abstract
`The clinical significance of cor-
`Background.
`onary-artery stenoses of moderate severity can be diffi-
`cult to determine. Myocardial fractional flow reserve (FFR)
`is a new index of the functional severity of coronary ste-
`noses that is calculated from pressure measurements
`made during coronary arteriography. We compared this
`index with the results of noninvasive tests commonly
`used to detect myocardial ischemia, to determine the
`usefulness of the index.
`Methods.
`In 45 consecutive patients with moderate
`coronary stenosis and chest pain of uncertain origin, we
`performed bicycle exercise testing, thallium scintigraphy,
`stress echocardiography with dobutamine, and quantita-
`tive coronary arteriography and compared the results
`with measurements of FFR.
`Results.
`In all 21 patients with an FFR of less than
`0.75, reversible myocardial ischemia was demonstrated
`
`I
`
`N patients with chest pain and stenosis of moderate
`severity as assessed by coronary angiography, eval-
`uation and treatment are challenging. Often, many di-
`agnostic tests are performed and no clear diagnosis of
`the cause of the chest pain results. In a considerable
`number of patients, coronary revascularization is per-
`formed without definite evidence that the coronary ste-
`nosis is causing the symptoms.
`
`1,2
`On the basis of pressure–flow analysis of coronary
`stenoses during maximal flow,
` the concept of myocar-
`3,4
`dial fractional flow reserve (FFR) has been developed
`as an invasively determined index of the functional se-
`verity of coronary stenoses.
` FFR is defined as the
`5-10
`maximal blood flow to the myocardium in the presence
`of a stenosis in the supplying coronary artery, divided
`by the theoretical normal maximal flow in the same
`distribution. This index represents the fraction of the
`normal maximal myocardial flow that can be achieved
`despite the coronary stenosis.
`FFR can be derived easily from the ratio of the mean
`distal coronary-artery pressure to the aortic pressure
`during maximal vasodilatation.
` This index is inde-
`5,6
`pendent of changes in systemic blood pressure and
`heart rate and is unaffected by conditions known to in-
` In addition, FFR
`crease the base-line myocardial flow.
`7
`takes into account the contribution of the collateral
`blood supply to maximal myocardial perfusion.
` The
`5,8
`normal value of the index is 1.0, regardless of the pa-
`tient or the specific vessel studied.
` Furthermore, in se-
`9
`lected patients undergoing percutaneous transluminal
`
`From the Department of Cardiology, Catharina Hospital, Eindhoven, the
`Netherlands (N.H.J.P., K.P., P.H.V., H.J.R.M.B., J.J.K.), and the Cardiovascular
`Center, Aalst, Belgium (B.B., J.B.). Address reprint requests to Dr. Pijls at the
`Department of Cardiology, Catharina Hospital, P.O. Box 1350, 5602 ZA Eind-
`hoven, the Netherlands.
`Supported in part by a grant (94-004) from the Stichting Vrienden van het
`Hart, Eindhoven, the Netherlands.
`
`unequivocally on at least one noninvasive test. After cor-
`onary angioplasty or bypass surgery was performed, all
`the positive test results reverted to normal. In contrast,
`21 of the 24 patients with an FFR of 0.75 or higher tested
`negative for reversible myocardial ischemia on all the
`noninvasive tests. No revascularization procedures were
`performed in these patients, and none were required dur-
`ing 14 months of follow-up. The sensitivity of FFR in the
`identification of reversible ischemia was 88 percent, the
`specificity 100 percent, the positive predictive value 100
`percent, the negative predictive value 88 percent, and
`the accuracy 93 percent.
`Conclusions.
`In patients with coronary stenosis of
`moderate severity, FFR appears to be a useful index of the
`functional severity of the stenoses and the need for coro-
`nary revascularization. (N Engl J Med 1996;334:1703-8.)
`
`1996, Massachusetts Medical Society.
`
`coronary angioplasty an FFR of less than approximate-
`ly 0.75 identified functionally important stenoses —
`that is, stenoses associated with inducible myocardial
`ischemia.
`
`9,10
`We investigated the usefulness of FFR in making
`clinical decisions concerning patients with ambiguous
`clinical symptoms, contradictory or inconclusive results
`of noninvasive testing, and moderate stenosis in one
`large coronary artery as determined angiographically.
`M
`
`ETHODS
`
`Study Patients
`The study population consisted of 45 consecutive patients (28 men
`⫾
`⫾
`and 17 women) with a mean (
`SD) age of 54
`8 years (range, 36 to
`74). To be eligible for the study, each patient was required to have
`chest pain; an angiographically detectable stenosis of moderate sever-
`ity (defined as approximately 50 percent by visual examination) in the
`proximal part of one major coronary artery; normal left ventricular
`function; and uncertainty about whether the chest pain was related to
`reversible ischemia caused by the moderate stenosis. The study pro-
`tocol was approved by the institutional review board, and informed
`consent for all tests was obtained from all the participants.
`
`Study Protocol
`All medications were stopped for seven days, except that patients
`were allowed to take 80 mg of aspirin daily. Within 48 hours after the
`end of the seven-day period, bicycle exercise testing, thallium scintig-
`raphy, stress echocardiography with dobutamine, and coronary arte-
`riography with intracoronary-pressure measurements and the calcu-
`lation of FFR were performed in all patients. The clinical decision to
`perform myocardial revascularization (percutaneous transluminal
`coronary angioplasty or bypass surgery) was made when the FFR was
`less than 0.75, a value selected on the basis of the results of earlier
`studies.
` In the patients in whom revascularization procedures were
`9,10
`performed, all the noninvasive tests that had yielded positive results
`were repeated within six weeks after the procedure. None of the pa-
`tients had previously undergone any form of revascularization.
`
`Exercise Testing and Thallium Scintigraphy
`Bicycle exercise testing was performed at an initial workload of
`20 W, which was increased by 20 W every minute. A 12-lead electro-
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on October 4, 2017. For personal use only. No other uses without permission.
`
` Copyright © 1996 Massachusetts Medical Society. All rights reserved.
`
`CATHWORKS EXHIBIT 1014
`Page 1703 of 1708
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`

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`1704
`
`THE NEW ENGLAND JOURNAL OF MEDICINE
`
`June 27, 1996
`
`Table 1. Characteristics of the Patients, Results of
`Noninvasive Tests, and Quantitative Angiographic
`
`Measurements.*
`
`TUDY
`
`S
`⭓
`0.75
`FFR
`⫽
`(
`24)
`N
`
` G
`
`ROUP
`
`⬍
`0.75
`FFR
`⫽
`(
`21)
`N
`
`13/11
`⫾
`55
`9
`
`1
`10
`
`15/6
`⫾
`54
`8
`
`1
`14
`
`24
`
`⫾
`3.10
`0.63
`⫾
`41
`8
`⫾
`1.78
`0.41
`
`49
`
`⫾
`0.67
`3.31
`⫾
`44
`9
`⫾
`1.94
`0.47
`
`⫾
`19†
`162
`⫾
`12
`104
`16
`12
`
`⫾
`13
`147
`⫾
`8
`95
`10
`
`1
`13
`7
`
`⫾
`146
`⫾
`95
`
`18
`12
`
`21
`
`⫾
`11
`149
`⫾
`98
`7
`0
`
`24
`
`00
`
`V
`
`ARIABLE
`
`Sex (M/F)
`Age (yr)
`Affected artery (no. of patients)
`Left main
`Left anterior descending
`Left circumflex
`Right coronary
`Reference diameter (mm)
`Percent stenosis
`Minimal luminal diameter (mm)
`Exercise test and thallium scanning
`Heart rate
`Beats/min
`Percentage of age-adjusted rate
`Positive exercise tests (no.)
`Positive thallium scans (no.)
`Stress echocardiography
`Heart rate
`Beats/min‡
`Percentage of age-adjusted rate
`Positive tests (no.)
`Treatment
`Medicine only
`Angioplasty
`Bypass surgery
`
`⫾
`
`SD.
`*Plus–minus values are means
`⫽
`†P
`0.033 for the comparison with the group with an FFR of 0.75 or
`higher.
`‡Adequate stress-echocardiographic images could not be obtained in
`four patients.
`
`clearly positive result and reverted to normal after successful coro-
`nary angioplasty or bypass surgery.
`We further postulated that there was no functionally important ste-
`nosis (and therefore no inducible ischemia) if and only if all the non-
`invasive tests were negative. Patients with one or more positive results
`of noninvasive testing but in whom the FFR exceeded 0.75 were con-
`sidered to have false negative results with respect to FFR.
`Composite information from sequentially performed noninvasive
`tests has a diagnostic accuracy of almost 100 percent, according to se-
`⭓
`⬍
` FFR values (
`0.75 or
`0.75)
`quential Bayesian considerations.
`30-35
`were compared with the composite test results.
`
`Statistical Analysis
`Angiographically determined indexes of stenosis and heart rate
`were compared between the two study groups by the two-tailed Stu-
`dent unpaired t-test. P values of less than 0.05 were considered to in-
`dicate statistical significance. All numerical data are presented as
`⫾
`means
`SD.
`
`R
`
`ESULTS
`
`Clinical Results
`The characteristics of the patients, the results of non-
`invasive testing, and the angiographic data are shown
`in Table 1. All the patients had normal electrocardio-
`grams while resting. There was no difference in the
`percentage of stenosis or the minimal luminal diameter
`between the patients with an FFR below 0.75 and those
`with higher values. Figure 1 shows representative coro-
`nary angiograms and coronary-pressure tracings typi-
`cal of those used to calculate FFR.
`The FFR was 0.75 or higher in 24 patients, and in
`these patients revascularization was not performed.
`The FFR was less than 0.75 in 21 patients. In 20 of
`
`cardiogram was recorded continuously. The test was considered pos-
`itive when horizontal or downsloping ST depression of at least 0.1 mV
`was recorded 80 msec after the J point by two adjacent leads. At peak
`exercise, 2.0 mCi (73 MBq) of thallium chloride Tl 201 was adminis-
`tered in a large antecubital vein. Exercise was maintained for one
`more minute, and then planar imaging was performed in the three
` After three hours, 1.0 mCi (37 MBq) of thallium
`standard views.
`11
`chloride Tl 201 was injected again, and redistribution images were ob-
`tained.
` All the images obtained by thallium scintigraphy were eval-
`12
`uated independently by two experienced reviewers unaware of any
`other study data.
`
`Dobutamine Stress Echocardiography
`Stress echocardiography with dobutamine was performed by a four-
`screen comparison technique showing identical views.
` An intrave-
`13,14
`nous infusion of dobutamine was started at a rate of 10
`g per kilo-
`m
`gram of body weight per minute and was increased by 10
`g per
`m
`kilogram per minute every three minutes until either wall-motion ab-
`normalities were observed or a maximal rate of 50
`g per kilogram
`m
`per minute was reached. In patients who did not reach 90 percent of
`their age-adjusted maximal heart rates and had no objective signs of
`ischemia, 1 mg of atropine was administered intravenously while the
`dobutamine infusion was continued.
` The occurrence of wall-motion
`15
`abnormalities was evaluated as previously described
`by two inde-
`16,17
`pendent echocardiographers unaware of any other study data.
`
`Pressure Measurements and Calculation of FFR
`
`At the time of catheterization, a 6-to-8-French coronary catheter
`was introduced into one femoral artery and advanced into the ostium
`of the coronary artery. A 0.46-mm (0.018-in.) fiberoptic pressure-
`monitoring guide wire (Pressureguide, Radi Medical, Uppsala, Swe-
`den) was set at zero, calibrated, advanced through the catheter, intro-
`duced into the coronary artery, and positioned distal to the stenosis
`as previously described.
` Adenosine was then infused intrave-
`9,10,18-20
`nously (140
`g per kilogram per minute) to induce maximal coronary
`m
`blood flow, corresponding with minimal distal coronary pressure.
`21-24
`When steady-state hyperemia was achieved, FFR was calculated as
`the ratio of the mean distal intracoronary pressure measured by the
`wire to the mean arterial pressure measured by the coronary catheter,
`as described previously.
`
`5,6,9
`If the FFR was 0.75 or higher, no revascularization procedure was
`performed. If the FFR was below 0.75, myocardial revascularization
`was recommended. If the lesion was suitable for coronary angioplasty,
`that procedure was performed during the same session, and FFR was
`measured again 15 minutes after successful angioplasty. If the lesion
`was not considered suitable for coronary angioplasty (i.e., because of
`stenosis of the left main coronary artery or a long ostial stenosis of
`the left anterior descending coronary artery), coronary bypass surgery
`was performed within four weeks.
`
`Quantitative Coronary Arteriography
`Quantitative coronary arteriography was performed in all patients
`in two orthogonal views.
` The percent stenosis, area of stenosis, ref-
`25
`erence diameter of the adjacent normal segment, and minimal lumi-
`nal diameter were calculated as the mean of the values obtained in
`the two views.
`
`Definition of Inducible Ischemia Based on the Results of
`the Noninvasive Tests
`
`Despite the excellent sensitivity and specificity of thallium exercise
`testing and stress echocardiography in patients with angiographically
`important coronary stenosis, these tests are known to be less accurate
`in patients with atypical chest pain or only moderate coronary steno-
`ses on angiography.
` It is thus difficult to establish the value of
`12,17,26-29
`any new method to assess the functional severity of coronary artery
`disease, because there is no single unequivocal or gold standard. This
`is especially true of our study population with moderate stenoses.
`To overcome this problem, we compared the value of the new inva-
`sive index, FFR, with that of the information derived from a combi-
`nation of noninvasive indexes. We postulated that functionally impor-
`tant stenoses (indicative of potentially inducible myocardial ischemia)
`were present if and only if at least one of the noninvasive tests had a
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on October 4, 2017. For personal use only. No other uses without permission.
`
` Copyright © 1996 Massachusetts Medical Society. All rights reserved.
`
`CATHWORKS EXHIBIT 1014
`Page 1704 of 1708
`
`

`

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`
`Vol. 334 No. 26
`
`FRACTIONAL FLOW RESERVE TO ASSESS SEVERITY OF CORONARY-ARTERY STENOSIS
`
`1705
`
`these 21, coronary angioplasty or bypass surgery was
`performed (in 13 and 7 patients, respectively); all non-
`invasive tests that had previously been positive were
`then repeated, and the results all reverted to normal. In
`one patient with an FFR of 0.40 and a stenosis in the
`proximal portion of the left anterior descending coro-
`nary artery, revascularization was recommended, but
`the patient declined to undergo the procedure.
`In the patients who underwent coronary angioplas-
`ty, FFR was measured again 15 minutes after the pro-
`
`cedure. In every case it increased to a value greater
`⫾
`⫾
`SD], 0.87
`0.06; range, 0.77 to 0.96),
`than 0.75 (mean [
`in accordance with the normal results of noninvasive
`testing.
`
`Comparison of FFR with the Results of Noninvasive Tests
`The relation between FFR and the results of the non-
`invasive tests is shown in Figure 2. In all 21 patients
`with an FFR below 0.75, signs of myocardial ischemia
`could be induced by at least one noninvasive test. All
`
`Pressure (mm Hg)
`
`150
`
`100
`
`50
`
`0
`
`A
`
`B
`
`C
`
`Calibration
`
`Aortic pressure
`
`Resting
`
`Aortic pressure
`
`Hyperemia
`
`FFR ⫽ 0.51
`
`Transstenotic pressure
`
`Venous pressure (⫻10)
`
`E
`
`Aortic pressure
`
`Transstenotic pressure
`
`Transstenotic pressure
`
`150
`
`100
`
`50
`
`0
`
`150
`
`100
`
`50
`
`0
`
`(mm Hg)
`Pressure
`
`D
`
`(mm Hg)
`Pressure
`
`F
`
`Figure 1. Coronary Angiograms and Simultaneously Obtained Recordings of Aortic and Transstenotic Pressure in
`a 65-Year-Old Woman.
`The patient had moderately severe stenosis of the left main and left anterior descending coronary arteries (Panels A and B, respec-
`tively). The pressure recordings in Panel D were obtained with the sensor located at the tip of the coronary catheter to verify that
`equal pressures were obtained at that location by both the catheter and the guide wire. Subsequently, the fiberoptic wire was ad-
`vanced across the stenosis in the left main coronary artery and a large resting gradient (22 mm Hg) was found (Panel E), which
`increased further after an intravenous infusion of adenosine. At steady-state maximal hyperemia, the aortic pressure was 101 mm Hg
`and the transstenotic pressure 52 mm Hg, resulting in an FFR of 0.51, which indicated that the stenosis was functionally important.
`Panels C and F show how the wire was slowly advanced across the stenosis and then withdrawn, indicating the site and severity of
`the stenosis exactly and reproducibly. The arrow in Panel C indicates the location of the pressure sensor.
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on October 4, 2017. For personal use only. No other uses without permission.
`
` Copyright © 1996 Massachusetts Medical Society. All rights reserved.
`
`CATHWORKS EXHIBIT 1014
`Page 1705 of 1708
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`

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`1706
`
`THE NEW ENGLAND JOURNAL OF MEDICINE
`
`June 27, 1996
`
`positive tests in this group were repeated after revascu-
`larization, and the results reverted to normal.
`In 21 of the 24 patients with an FFR of 0.75 or higher,
`all the noninvasive tests were negative. Of the remain-
`ing three patients, two had positive exercise electrocar-
`diograms and one had a positive thallium scan. In these
`
`three patients the FFR method yielded false negative
`results, because evidence of inducible ischemia was pres-
`ent despite an FFR of 0.75 or higher. The overall sensi-
`tivity, specificity, positive and negative predictive val-
`ues, and accuracy of FFR were 88, 100, 100, 88, and 93
`percent, respectively.
`
`Clinical Follow-up of Patients with FFR of 0.75 or Higher
`Myocardial revascularization was not performed in
`the patients with an FFR of 0.75 or higher. Seventeen
`were treated with aspirin alone, and seven with a com-
`bination of aspirin and a calcium-channel blocker. At
`follow-up visits four weeks later, the functional class of
`these patients, when measured according to the classi-
`fication system of the Canadian Cardiovascular Socie-
`ty, had improved substantially, from 2.8 to 1.3. After a
`⫾
`mean follow-up of 14
`5 months (range, 5 to 21), there
`were no ischemic events in any of these patients, no re-
`vascularization was necessary, and 17 were asympto-
`matic.
`
`D
`ISCUSSION
`Our study supports the concept that FFR reliably in-
`dicates functionally significant coronary stenoses. This
`index performed well as compared with standard non-
`invasive tests for myocardial ischemia. Decisions made
`on the basis of the FFR resulted in excellent clinical
`outcomes in the patients in whom unnecessary revascu-
`larization was averted. Such decisions are often difficult
`in patients with coronary stenoses of moderate severity.
`In most patients with coronary artery disease, the de-
`cision to perform revascularization procedures should
`be based not only on the coronary anatomy but also on
`the functional severity of a lesion.
` This is especially
`36-38
`true in patients with narrowings of intermediate severi-
`ty demonstrated on coronary angiograms. If, when such
`a lesion is present, myocardial ischemia can be clearly
`demonstrated by exercise or pharmacologic stress test-
`ing, revascularization is appropriate when medical ther-
`apy fails to control symptoms.
` In some patients, how-
`37,38
`ever, noninvasive tests are inconclusive. Moreover, both
`exercise thallium scintigraphy and stress echocardiog-
`raphy have limited sensitivity in such patients. When
`chest pain persists despite repeatedly negative tests, con-
`fusion often arises about the clinical importance of the
`lesions.
` Therefore, it would be useful to have a meas-
`1,2
`urement that is easily obtainable at the time of diag-
`nostic coronary angiography that would indicate clearly
`whether the coronary stenosis is responsible for revers-
`ible ischemia.
`Myocardial FFR is such an index of the effect of an
`epicardial coronary-artery stenosis on maximal myo-
`cardial perfusion.
` In previous studies of selected pa-
`5-10
`tients undergoing percutaneous transluminal coronary
`angioplasty, a cutoff FFR value of approximately 0.75
`distinguished lesions associated with inducible ischemia
`from other lesions, and there was minimal overlap be-
`tween the two groups.
` Our study extends previous
`9,10
`observations by assessing the clinical application of
`FFR. The results indicate that FFR performed well in
`assessing the functional severity of coronary stenoses.
`As previously demonstrated, the risk associated with
`
`Positive
`Negative
`
`1.0
`
`0.9
`
`0.8
`
`0.7
`
`0.6
`
`0.5
`
`0.4
`
`0.3
`
`Fractional Flow Reserve
`
`Exercise
`test
`
`Thallium
`scan
`
`Stress
`echocardiogram
`
`Type of Test
`
`Figure 2. Relation between Myocardial FFR in the Study Pa-
`tients and the Results of Three Noninvasive Tests.
`The test results for each patient are shown on one line accord-
`ing to that patient’s FFR. The dashed line representing an FFR
`of 0.75 indicates the cutoff between the two groups assessed in
`this study. Adequate stress-echocardiographic images could not
`be obtained in four patients.
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on October 4, 2017. For personal use only. No other uses without permission.
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` Copyright © 1996 Massachusetts Medical Society. All rights reserved.
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`CATHWORKS EXHIBIT 1014
`Page 1706 of 1708
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`Vol. 334 No. 26
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`FRACTIONAL FLOW RESERVE TO ASSESS SEVERITY OF CORONARY-ARTERY STENOSIS
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`1707
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`advancing a sensor-tipped guide wire across a coronary
`stenosis is extremely low
` and is offset by the
`2,6,9,10,19,39,40
`important clinical information gained, especially in the
`case of a moderate stenosis in the proximal portion of
`a large coronary artery. With such a stenosis, omitting
`an intervention that is indicated and performing one
`that is not indicated can both be harmful.
`The calculation of FFR from measurements of pres-
`sure is limited by the presence of small-vessel disease,
`diffuse coronary artery disease, and left ventricular hy-
`pertrophy.
` These conditions restrict the increase
`5,6,9,10,41
`in blood flow after pharmacologic vasodilatation and
`the corresponding decrease in distal coronary pressure.
`Under these conditions, therefore, the severity of the ste-
`nosis may be underestimated because of the limited in-
`crease in flow and the associated limitation in the pres-
`sure gradient. Also, in some patients exercise-induced
`vasospasm may occur during physical exercise.
` In
`42
`those patients, the hyperemia induced by adenosine in
`the catheterization laboratory is not necessarily equiv-
`alent to exercise-induced maximal hyperemia in daily
`life. This mechanism could have played a part in the
`patients with positive exercise tests but FFR values of
`0.75 or higher.
`Our study indicates that measuring FFR during cor-
`onary arteriography is useful in determining whether an
`angiographically moderate stenosis is functionally im-
`portant and may therefore be responsible for reversible
`myocardial ischemia. In this study, the accuracy of FFR
`for this purpose was equivalent to that of the informa-
`tion provided by a combination of all the noninvasive
`tests currently used. We therefore believe that myocar-
`dial FFR may be useful in making clinical decisions
`about revascularization procedures in patients with mod-
`erate coronary stenoses when other objective evidence
`of reversible ischemia is lacking.
`
`We are indebted to Morton J. Kern, M.D., for his constructive com-
`ments; to Eduard Van Hagen, R.N., Gert Hendrix, R.N., and Berry
`Van Gelder, Ph.D., for their assistance with the invasive procedures;
`and to Anne Hol for her assistance in preparing the manuscript.
`R
`
`EFERENCES
`
`1. Topol EJ, Ellis SG, Cosgrove DM, et al. Analysis of coronary angioplasty
`practice in the United States with an insurance-claims data base. Circulation
`1993;87:1489-97.
`2. Kern MJ, Donohue TJ, Aguirre FV, et al. Clinical outcome of deferring an-
`gioplasty in patients with normal translesional pressure-flow velocity meas-
`urements. J Am Coll Cardiol 1995;25:178-87.
`3. Kirkeeide RL, Gould KL, Parsel L. Assessment of coronary stenoses by
`myocardial perfusion imaging during pharmacologic coronary vasodilation.
`VII. Validation of coronary flow reserve as a single integrated functional
`measure of stenosis severity reflecting all its geometric dimensions. J Am
`Coll Cardiol 1986;7:103-13.
`4. Gould KL, Kirkeeide RL, Buchi M. Coronary flow reserve as a physiologic
`measure of stenosis severity. J Am Coll Cardiol 1990;15:459-74.
`5. Pijls NHJ, van Son JAM, Kirkeeide RL, De Bruyne B, Gould KL. Experi-
`mental basis of determining maximum coronary, myocardial, and collateral
`blood flow by pressure measurements for assessing functional stenosis se-
`verity before and after percutaneous transluminal coronary angioplasty.
`Circulation 1993;87:1354-67.
`6. De Bruyne B, Baudhuin T, Melin JA, et al. Coronary flow reserve calculated
`from pressure measurements in humans: validation with positron emission
`tomography. Circulation 1994;89:1013-22.
`7. De Bruyne B, Paulus WJ, Pijls NHJ. Rationale and application of coronary
`transstenotic pressure gradient measurements. Cathet Cardiovasc Diagn
`1994;33:250-61.
`8. Pijls NHJ, Bech GJW, el Gamal MIH, et al. Quantification of recruitable
`coronary collateral blood flow in conscious humans and its potential to pre-
`dict future ischemic events. J Am Coll Cardiol 1995;25:1522-8.
`
`9. Pijls NHJ, Van Gelder B, Van der Voort P, et al. Fractional flow reserve: a
`useful index to evaluate the influence of an epicardial coronary stenosis on
`myocardial blood flow. Circulation 1995;92:3183-93.
`10. De Bruyne B, Bartunek J, Sys SU, Heyndrickx GR. Relation between myo-
`cardial fractional flow reserve calculated from coronary pressure measure-
`ments and exercise-induced myocardial ischemia. Circulation 1995;92:39-
`46.
`11. Ritchie JL, Bateman TM, Bonow RO, et al. Guidelines for clinical use of
`cardiac radionuclide imaging: a report of the American Heart Association/
`American College of Cardiology Task Force on Assessment of Diagnostic
`and Therapeutic Cardiovascular Procedures, Committee on Radionuclide
`Imaging, developed in collaboration with the American Society of Nuclear
`Cardiology. Circulation 1995;91:1278-1303.
`12. Dilsizian V, Rocco TP, Freedman NMT, Leon MB, Bonow RO. Enhanced
`detection of ischemic but viable myocardium by the reinjection of thallium
`after stress–redistribution imaging. N Engl J Med 1990;323:141-6.
`13. Salustri A, Fioretti PM, Pozzoli MMA, McNeill AJ, Roelandt JR. Dobuta-
`mine stress echocardiography: its role in the diagnosis of coronary artery
`disease. Eur Heart J 1992;13:70-7.
`14. Sawada SG, Segar DS, Ryan T, et al. Echocardiographic detection of coro-
`nary artery disease during dobutamine infusion. Circulation 1991;83:1605-
`14.
`15. McNeill AJ, Fioretti PM, el-Said SM, Salustri A, Forster T, Roelandt JR.
`Enhanced sensitivity for detection of coronary artery disease by addition of
`atropine to dobutamine stress echocardiography. Am J Cardiol 1992;70:41-
`6.
`16. Bourdillon PDV, Broderick TM, Sawada SG, et al. Regional wall motion in-
`dex for infarct and noninfarct regions after reperfusion in acute myocardial
`infarction: comparison with global wall motion index. J Am Soc Echocar-
`diogr 1989;2:398-407.
`17. Marwick T, Willemart B, D’Hondt A-M, et al. Selection of the optimal
`nonexercise stress for the evaluation of ischemic regional myocardial dys-
`function and malperfusion: comparison of dobutamine and adenosine us-
`ing echocardiography and 99mTc-MIBI single photon emission computed
`tomography. Circulation 1993;87:345-54.
`18. Emanuelsson H, Dohnal M, Lamm C, Tenerz L. Initial experiences with a
`miniaturized pressure transducer during coronary angioplasty. Cathet Car-
`diovasc Diagn 1991;24:137-43.
`19. Lamm C, Dohnal M, Serruys PW, Emanuelsson H. High-fidelity transle-
`sional pressure gradients during percutaneous transluminal coronary angio-
`plasty: correlation with quantitative coronary angiography. Am Heart J
`1993;126:66-75.
`20. Serruys PW, Di Mario C, Meneveau N, et al. Intracoronary pressure and
`flow velocity with sensor-tip guidewires: a new methodologic approach for
`assessment of coronary hemodynamics before and after coronary interven-
`tions. Am J Cardiol 1993;71:41D-53D.
`21. Wilson RF, Wyche K, Christensen BV, Zimmer S, Laxson DD. Effects of
`adenosine on human coronary arterial circulation. Circulation 1990;82:
`1595-606.
`22. Kern MJ, Deligonul U, Tatineni S, Serota H, Aguirre FV, Hilton TC. Intra-
`venous adenosine: continuous infusion and low dose bolus administration
`for determination of coronary vasodilator reserve in patients with and with-
`out coronary artery disease. J Am Coll Cardiol 1991;18:718-29.
`23. Uren NG, Melin JA, De Bruyne B, Wijns W, Baudhuin T, Camici PG. Re-
`lation between myocardial blood flow and the severity of coronary-artery
`stenosis. N Engl J Med 1994;330:1782-80.
`24. Redberg RF, Sobol Y, Chou TM, et al. Adenosine-induced coronary vaso-
`dilation during transesophageal Doppler echocardiography: rapid and safe
`measurement of coronary flow reserve ratio can predict significant left an-
`terior descending coronary stenosis. Circulation 1995;92:190-6.
`25. Reiber JHC, Serruys PW, Kooijman CJ, et al. Assessment of short-, medi-
`um-, and long-term variations in arterial dimensions from computer-assist-
`ed quantitation of coronary cineangiograms. Circulation 1985;71:280-8.
`26. Marwick T, D’Hondt AM, Baudhuin T, et al. Optimal use of dobutamine
`stress for the detection and evaluation of coronary artery disease: combina-
`tion with echocardiography, scintigraphy or both? J Am Coll Cardiol 1993;
`22:159-67.
`27. Picano E, Parodi O, Lattanzi F, et al. Assessment of anatomic and physio-
`logical severity of single-vessel coronary artery lesions by dipyridamole
`echocardiography: comparison with positron emission tomography and
`quantitative arteriography. Circulation 1994;89:753-61.
`28. PET compared to other imaging modalities. In: Gould KL. Coronary artery
`stenosis. New York: Elsevier, 1991:197-207.
`29. Detrano R, Janosi A, Lyons KP, Marcondes G, Abbassi N, Froelicher VF.
`Factors affecting sensitivity and specificity of a diagnostic test: the exercise
`thallium scintigram. Am J Med 1988;84:699-710.
`30. Fryback DG. Bayes’ theorem and conditional nonindependence of data in
`medical diagnosis. Comput Biomed Res 1978;11:423-34.
`31. Hamilton GW, Trobaugh GB, Ritchie JL, Gould KL, DeRouen TA, Williams
`thallium: an analysis of clinical usefulness
`201
`DL. Myocardial imaging with
`based on Bayes’ theorem. Semin Nucl Med 1978;8:358-64.
`32. Melin JA, Piret LJ, Vanbutsele RJM, et al. Diagnostic value of exercise elec-
`trocardiography and thallium myocardial scintigraphy in patients without
`previous myocardial infarction: a Bayesian approach. Circulation 1981;63:
`1019-24.
`
`The New England Journal of Medicine
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`Downloaded from nejm.org on October 4, 2017. For personal use only. No other uses without permission.
`
` Copyright © 1996 Massachusetts Medical Society. All rights reserved.
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`CATHWORKS EXHIBIT 1014
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`THE NEW ENGLAND JOURNAL OF MEDICINE
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`June 27, 1996
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`33. Weintraub WS, Madeira SW Jr, Bodenheimer MM, et al. Critical analysis
`of the application of Bayes’ theorem to sequential testing in the noninvasive
`diagnosis of coronary artery disease. Am J Cardiol 1984;54:43-9.
`34. Detrano R, Leatherman J, Salcedo EE, Yiannikas J, Williams G. Bayesian
`analysis versus discriminant function analysis: their relative utility in the di-
`agnosis of coronary disease. Circulation 1986;73:970-7.
`35. Patterson RE, Horowitz SF. Importance of epidemiology and biostatistics in
`deciding clinical strategies for using diagnostic tests: a simplified approach
`using examples from coronary artery disease. J Am Coll Cardiol 1989;13:
`1653-65.
`36. Klocke FJ. Cognition in the era of technology: “seeing the shades of gray.”
`J Am Coll Cardiol 1990;16:763-9.
`37. Ryan TJ, Faxon DP, Gunnar RM, et al. Guidelines for percutaneous trans-
`luminal coronary angioplasty: a report of the American College of Car-
`diology/American Heart Association Task Force on Assessment of Di-
`agnostic and Therapeutic Cardiovascular Proc