International Journal of Cardiology 222 (2016) 606–610
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When should fractional ﬂow reserve be performed to assess the signiﬁcance of borderline coronary artery lesions: Derivation of a simpliﬁed scoring system Fadi A. Matar ⁎, Shayan Falasiri, Charles B. Glover, Asma Khaliq, Calvin C. Leung, Jad Mroue, George Ebra Department of Cardiovascular Sciences, The University of South Florida, Morsani College of Medicine, Tampa, FL, USA
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Article history: Received 4 June 2016 Accepted 27 July 2016 Available online 2 August 2016 Keywords: Coronary artery disease Coronary angiography Fractional ﬂow reserve Percutaneous coronary intervention
a b s t r a c t Objectives: To derive a simpliﬁed scoring system (SSS) that can assist in selecting patients who would beneﬁt from the application of fractional ﬂow reserve (FFR). Background: Angiographers base decisions to perform FFR on their interpretation of % diameter stenosis (DS), which is subject to variability. Recent studies have shown that the amount of myocardium at jeopardy is an important factor in determining the degree of hemodynamic compromise. Methods: We conducted a retrospective multivariable analysis to identify independent predictors of hemodynamic compromise in 289 patients with 317 coronary vessels undergoing FFR. A SSS was derived using the odds ratios as a weighted factor. The receiver operator characteristics curve was used to identify the optimal cutoff (≥3) to discern a functionally signiﬁcant lesion (FFR ≤ 0.8). Results: Male gender, left anterior descending artery apical wrap, disease proximal to lesion, minimal lumen diameter and % DS predicted abnormal FFR (≤0.8) and lesion location in the left circumﬂex predicted a normal FFR. Using a cutoff score of ≥3 on the SSS, a speciﬁcity of 90.4% (95% CI: 83.0–95.3) and a sensitivity of 38.0% (95% CI: 31.5–44.9) was generated with a positive predictive value of 89.0% (95% CI: 80.7%–94.6%) and negative predictive value of 41.6% (95% CI: 35.1%–48.3%). Conclusions: The decision to use FFR should be based not only on the % DS but also the size of the myocardial mass jeopardized. A score of ≥3 on the SSS should prompt further investigation with a pressure wire. © 2016 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Fractional ﬂow reserve (FFR) is increasingly being used to assess the hemodynamic signiﬁcance of borderline coronary artery stenosis at the time of angiography. FFR-guided percutaneous coronary intervention (PCI) has been associated with reduced major adverse cardiac events and to yield enhanced clinical outcomes in patients presenting with multi-vessel coronary artery disease (CAD) . Since the publication of the Fractional Flow Reserve versus Angiography for Multivessel Evaluation (FAME) trial , there has been an increased use of FFR. However, data from U.S. Medicare beneﬁciaries in 2012 reported that the percent of diagnostic catheterizations undergoing FFR remained low (4%) .
Abbreviations: AUC, area under the curve; CABG, coronary artery bypass grafting; CAD, coronary artery disease; CI, conﬁdence interval; DS, diameter stenosis; FFR, fractional ﬂow reserve; LAD, left anterior descending; LCX, left circumﬂex; MLD, minimum lumen diameter; NPV, negative predictive value; PCI, percutaneous coronary intervention; PPV, positive predictive value; RCA, right coronary artery; SSS, simpliﬁed scoring system. ⁎ Corresponding author at: University of South Florida, Morsani College of Medicine, 509 South Armenia Avenue Suite 200, Tampa, FL 33609, USA. E-mail address: [email protected]
http://dx.doi.org/10.1016/j.ijcard.2016.07.171 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.
A strategy of routine FFR measurement of all vessels with any degree of luminal narrowing in patients with stable angina at the time of diagnostic coronary angiography can change the number deemed signiﬁcant and required revascularization in 26% of patients . Operators may not deem that FFR of all diseased vessels to be feasible in routine daily practice environment given its impact on cost, procedure time, excess contrast load and reduced but deﬁnite procedural complication risk . During coronary angiography, the operator is often faced with deciding if a lesion is ischemic and whether hemodynamic severity assessment with FFR is warranted. These decisions are usually based on the operator's subjective interpretation of angiographic percent diameter stenosis (% DS) which is subject to wide inter and intra-observer variability [5,6]. Recent studies have shown that angiographic factors relating to the amount of myocardium at jeopardy, such as left anterior descending (LAD) artery apical wrap and proximal lesion location, may also be important factors affecting the hemodynamic impact of a stenosis [7–10]. The purpose of this study is to identify demographic/clinical and angiographic predictors of hemodynamically signiﬁcant lesions which can assist in targeted selection of patients who are more likely to beneﬁt from the application of FFR assessment during cardiac catheterization.
F.A. Matar et al. / International Journal of Cardiology 222 (2016) 606–610
Moreover, to develop a simpliﬁed scoring system (SSS) for the identiﬁcation of vessels warranting FFR assessment. 2. Methods 2.1. Study population From 2007 to 2012, 14,021 patients underwent diagnostic coronary angiography at a single center, of which 9728 were performed by faculty members of the University of South Florida, Morsani College of Medicine. From this cohort, 645 patients underwent clinically driven, FFR assessment. Excluded from this group were patients (n = 356) who had one or more of the following: left main lesion (≥50%), chronic total coronary artery occlusion anywhere in the coronary circulation, sequential lesions (two or more discrete and separate lesions 30% in diameter stenosis in the same vessel by visual assessment), a history of coronary artery bypass grafting, the presence of hemodynamically signiﬁcant valvular stenosis or regurgitation, history of acute or prior myocardial infarction or abnormal ventricular ejection fraction (b50%). The ﬁnal study population consisted of 289 patients with 317 single and multiple vessels undergoing FFR assessment. The study was approved by the Institutional Review Board and a written waiver of informed consent was granted. 2.2. Study procedures Following informed consent, coronary angiography was performed through radial or femoral access based on patient suitability and operator discretion. A 6 Fr. Guiding catheter was used for the initial angiography prior to FFR assessment. If the systolic blood pressure was over 100 mm Hg, 100 to 200 microgram intracoronary nitroglycerine was generally administered prior to FFR measurement. Intravenous anticoagulants with either heparin or bivalirudin were also administered prior to the introduction of the pressure wire. Maximum hyperemia was achieved by intravenous adenosine infusion at 140 μg/kg/min. The St. Jude Radi wire (St. Jude Medical Inc., Saint Paul, MN, USA) was used for FFR measurement in all patients. FFR was deﬁned as the ratio between the mean coronary pressure distal to an observed coronary artery stenosis and the mean aortic pressure at maximum hyperemia. An FFR cutoff of ≤0.8 was used to determine myocardial ischemia and generally in need of revascularization. 2.3. Angiographic analysis Coronary angiograms were retrospectively subjected to qualitative and quantitative analysis using computerized automated edge detection (QAngio XA, Leiden, Netherlands) with the contrast-ﬁlled guiding catheter as a calibration reference. A lesion was identiﬁed to be in a main branch if it was located in a major epicardial vessel such as the LAD, right coronary artery (RCA) or left circumﬂex artery (LCX); or in a side branch if located in a diagonal, obtuse marginal, posterior descending or posterolateral branch. Lesions were considered proximal if present in the main vessel proximal to the ﬁrst major diagonal in the LAD, prior to the ﬁrst major acute marginal in the RCA or prior to the ﬁrst obtuse marginal in the LCX. LAD apical wrap was deﬁned as one that terminated more than one-third of the way on the diaphragmatic surface. Disease proximal to the lesion included moderate, non-discrete luminal irregularities (30–50% DS) proximal to the lesion being investigated. 2.4. Simpliﬁed scoring system for predicting FFR (≤0.8) A simpliﬁed scoring system (FFR-SSS) was devised to assist the operator in determining the need for FFR, based on selected demographic/clinical variables. The scoring scheme was based on the results of a multivariable model designed to predict the probability of a functionally signiﬁcant lesion (FFR ≤ 0.8). Each signiﬁcant demographic/clinical factor
generated from the multivariable analysis was assigned a value of “2”. An LAD apical wrap and a lesion in a non-LCX vessel were assigned a value of “1”. The ﬁnal score for a given lesion was based on the sum of the values assigned to each of the signiﬁcant variables (odds ratio N 1) and ranged from “0” to “10”. The higher the ﬁnal score, the greater the likelihood of a functionally signiﬁcant lesion. 2.5. Statistical analysis Data analyses were performed on a per-patient basis for demographic/clinical variables and on a per-lesion characteristic for the remainder of the calculations. Demographic, clinical and lesion-speciﬁc data are presented as frequency distributions and simple percentages. Values of continuous variables are expressed as mean ± the standard deviation. Two-sample unpaired Student's t-tests were used to assess the equality of means in continuous variables. To identify independent determinants of FFR ≤ 0.8, univariable analyses were performed using 18 demographic/clinical variables. Those with a probability value ≤0.10 were included in a multivariable logistic regression model, with ﬂow limitation (FFR ≤ 0.8) as the dependent variable. The ﬁnal multivariable logistic regression model included six covariates. The area under the curve (AUC) was determined by a receiver operator characteristic curve with 95% conﬁdence interval (CI) to detect FFR ≤ 0.8 from the value generated by the SSS. The results of this analysis was used to identify the optimal cut-off point of the scoring scheme to determine sensitivity, speciﬁcity, positive predictive value (PPV) and negative predictive value (NPV) with 95% CI. All probability values reported are two-sided and not adjusted for multiple testing. A probability value of 0.05 or less indicated a signiﬁcant difference between measures. All analyses were performed using the Number Cruncher Statistical Systems software (Version 9; NCSS, Kaysville, UT, USA). 3. Results There were 289 patients with 317 single and multiple vessels assessed with FFR of which 81 (28.0%) underwent revascularization. Among those 289 patients, 32 (11.1%) underwent PCI of additional vessels (n = 35) without FFR assessment. In the study group (N = 289), 175 (60.6%) were male and the mean age was 62.6 ± 10.9 years (range, 34 to 87). There were 97 (33.6%) patients who had diabetes mellitus, 226 (78.2%) hypertension and 147 (50.9%) a history of known coronary artery disease. Pre-procedure stress testing was performed in 144 (49.8%) patients. The patient baseline demographic/clinical characteristics are summarized in Table 1 and were similar to previously reported FFR studies [1–11]. The information in Table 2 presents the angiographic lesion characteristics of the study group. Of the 317 lesions that underwent FFR assessment, 91 (28.7%) were abnormal (≤0.8) and 226 (71.3%) normal. Fig. 1 shows the distribution of % DS in the normal and abnormal FFR groups. Although the mean % DS in the abnormal FFR group was higher than in the normal FFR group (53.3 ± 11.5 versus 47.5 ± 9.6; p b 0.001), there was signiﬁcant overlap in the two cohorts. There were 36 of 173 (20.7%) lesions with b50% DS that had an abnormal FFR and 88 of 143 (61.5%) with ≥50% DS with a normal FFR. The information in Table 3 displays the univariable and multivariable predictors of abnormal FFR in the 317 lesions subjected to pressure wire assessment as deemed by the operator to be angiographically indeterminate. Of the demographic/clinical, lesion/vessel and luminal dimension variables included in the multivariable model, six were found to be signiﬁcant: male gender (p = 0.002), disease proximal to the lesion (p = 0.014), LAD apical wrap (p b 0.001), MLD (p = 0.015) and % DS (p b 0.001). Lesion location in the LCX was independently predictive of a normal FFR (p = 0.024).
F.A. Matar et al. / International Journal of Cardiology 222 (2016) 606–610
Table 1 Baseline demographic and patient clinical characteristics. Study population Variable
No. of patients Sex Male Female Age (years) Preprocedure coronary risk factors Current smoker Hypertension Diabetes mellitus Dyslipidemia Preprocedure risk factors Chronic obstructive pulmonary disease Renal dysfunction Prior known coronary artery disease Stable angina Acute coronary syndrome Left ventricular ejection fraction (%) Stress test performed Abnormal stress test Non diagnostic stress test
175 114 62.6 ± 10.9
46 226 97 202
15.9 78.2 33.6 69.9
39 26 147 91 82 59.3 ± 5.5 144 113 4
13.5 9.0 50.9 32.9 29.6 49.8 78.5 2.8
The FFR-SSS generated a total score for each vessel based on the values assigned to the independent predictors (Table 4). The mean score for the study cohort was 4.57 ± 2.06. An ROC analysis demonstrated an AUC of 73.5% (95% CI: 67.3–78.8). The results of this analysis were used to assess the best cutoff value to identify functionally significant lesions using FFR. A score of ≥3 on the FFR-SSS tool was selected as an appropriate cut-off value to screen for abnormal FFR. Using this value, a speciﬁcity of 90.4% (95% CI: 83.0–95.3) and a sensitivity of 38.0% (95% CI: 31.5–44.9) was generated with a PPV of 89.0% (95% CI: 80.7%–94.6%) and NPV of 41.6% (95% CI: 35.1%–48.3%). 4. Discussion Historically, cardiologists who visually evaluate the angiographic appearance of the coronary artery tree during cardiac catheterization determine the treatment alternative of choice. The operator's ability to discriminate between lesions that are hemodynamically signiﬁcant on the basis of angiography only has been determined to be inaccurate. . FFR has become a valuable tool to provide a more accurate assessment of the functional severity of lesions identiﬁed through coronary
Table 2 Angiographic lesion characteristics of vessels undergoing fractional ﬂow reserve. Variable
Total FFR vessels LAD LCX RCA Lesion length (mm) Vessel diameter (mm) MLD (mm) Diameter stenosis (%) 30–39 40–49 50–69 70–89 90 or more In-stent restenosis Type B2/Ca Severe calciﬁcation
317 165 58 94 10.4 ± 5.4 2.8 ± 0.7 1.4 ± 0.5
100.0 52.1 18.3 29.7
61 113 133 10 0 48 191 26
19.2 35.7 42.0 3.2 0.0 15.1 60.3 8.2
FFR = fractional ﬂow reserve; LAD = left anterior descending, LCX = left circumﬂex; RCA = right coronary artery; MLD = minimum lumen diameter. a ACC/AHA lesion classiﬁcation.
Fig. 1. Scatter plot of % diameter stenosis (% DS) vs. abnormal FFR (≤0.80) in 317 vessels subjected to FFR assessment (normal FFR = 226, abnormal FFR = 91).
angiography. It is computed as the ratio of the coronary pressure distal and proximal to a stenosis. This is a simpliﬁcation of the true deﬁnition, which is the maximum myocardial blood ﬂow in the presence of a stenosis divided by the theoretical maximum ﬂow in the absence of stenosis . Blood ﬂow in a coronary segment is proportional to the amount of myocardial mass it supplies . The larger the mass, the smaller the degree of luminal narrowing required to compromise ﬂow. Conversely, the smaller the mass, the larger the degree of luminal narrowing required to cause hemodynamic compromise . Therefore, it is not surprising that measures of luminal narrowing, such as % DS, poorly correlate with FFR values as demonstrated in the present study and others [2,14–16]. This study demonstrated that the hemodynamic severity of intermediate coronary stenosis is not only determined by the degree of luminal narrowing such as MLD, % DS and proximal luminal disease, but also by other variables such as male gender, LAD apical wrap and LCX. This study has conﬁrmed that male gender is an independent predictor of abnormal FFR [8,11]. This may be attributed to an increased prevalence of microvascular disease in women which can result in higher FFR values or to males having a larger myocardial mass [17–19]. The latter explanation is more likely since Leone et al. noted that male gender was no longer an independent predictor of abnormal FFR, once indices of myocardial jeopardy were included in the prediction model . Lesion location in an LAD with apical wrap has also been found to be an independent predictor of an FFR ≤0.8 [7,15]. This is consistent with the fact that such vessels supply large myocardial distributions . A large myocardial mass with a plaque of even lesser degree of luminal narrowing can also cause compromise. This study also shows that a lesion located in a LCX was a negative predictor of abnormal FFR. This may be attributed to the fact that LCX coronary arteries supply a relatively smaller myocardial distribution. Therefore, a lesion in such a vessel is less likely to be hemodynamically signiﬁcant. To our knowledge, no other studies using FFR have shown such a relationship. The decision to perform ad hoc diagnostic FFR during coronary angiography integrates clinical presentation, stress test results if available and the operator's uncertainty regarding angiographic lesion severity. In the present study, less than one-half (49.8%) of the patients had a
F.A. Matar et al. / International Journal of Cardiology 222 (2016) 606–610 Table 3 Univariable and multivariable logistic regression analysis of predictors for ﬂow limitation (FFR ≤ 0.80) in 317 vessels subjected to fractional ﬂow reserve assessment. Univariable Variable Demographic Age Gender—male Clinical Diabetes mellitus Dyslipidemia Hypertension Current smoker Lesion/vessel characteristic Lesion in main vessel Disease proximal to lesion Proximal LAD LAD apical wrap LCX RCA Severe calciﬁcation Type B2/C lesion In-stent re-stenosis Luminal dimensions Lesion length ≥ 20 mm MLD b 1.4 mm Diameter stenosis ≥ 50%
Odds ratio (95% CL)
Odds ratio (95% CL)
0.99 (0.97–1.02) 1.98 (1.17–3.35)
−0.1310 0.0200 −0.3358 −0.1283
0.2672 0.2715 0.2940 0.3504
0.88 (0.51–1.46) 1.02 (0.60–1.74) 0.71 (0.40–1.27) 0.88 (0.44–1.75)
0.624 0.941 0.253 0.714
0.9476 0.5204 0.3943 1.0396 −1.0809 −0.5471 0.4827 0.3390 0.1435
2.5794 0.3049 0.2834 0.2582 0.4034 0.2901 0.4238 0.2590 0.3396
2.58 (1.16–5.72) 1.68 (0.93–3.06) 1.48 (0.85–2.58) 2.83 (1.71–4.69) 0.34 (0.15–0.75) 0.58 (0.33–1.02) 1.62 (0.71–3.72) 1.40 (0.84–2.33) 1.15 (0.59–2.25)
0.020 0.088 0.164 b0.001 0.007 0.059 0.255 0.191 0.673
3.50 (1.91–6.42) 0.36 (0.15–0.87)
0.3219 0.8744 0.8737
0.5234 0.2554 0.2541
1.38 (0.49–3.85) 2.40 (1.45–3.96) 2.39 (1.46–3.94)
0.539 b0.001 b0.001
2.04 (1.15–3.62) 2.82 (1.56–5.11)
SE = standard error, CL = conﬁdence limits, LAD = left anterior descending, LCX = left circumﬂex; RCA = right coronary artery; MLD = minimum lumen diameter.
stress test prior to coronary angiography. Similar ﬁndings have been reported by others [10,11]. Increased reliance on the degree of angiographic luminal obstruction for deciding whether FFR assessment should be performed is likely to lead to over-treatment with PCI in smaller supply areas or under-treatment of larger supply areas such as an LAD with apical wrap. Natsumeda et al. used QCA to derive a scoring system (STABLED Score-Stenosis 2 points, TAndem lesion 1 point, Bifurcation 1 point, LEsion length 1 point, Distance from ostium 1 point) to predict FFR abnormalities. No other surrogates of myocardial supply mass were included in this prediction model . Biasco et al. identiﬁed ﬁve angiographic parameters to independently predict ﬂow limitation, viz., 30–50% lesion proximal to the lesion of interest, lesion length N20 mm, distal take-off of all diagonal branches, N 2 mm diameter, apical wrap of LAD and collaterals to an occluded LCX/RCA. Based on these results, risk scores for prediction of ﬂow limitation in intermediate LAD lesions were determined. Their study was limited to LAD lesions and no other surrogates of myocardial supply mass such as gender were included in their predictive model . Wong et al. created the DILEMMA score to predict an FFR ≤ 0.8. It combined MLD, lesion length and BARI MJI (Bypass Angioplasty Revascularization Investigation [BARI] Myocardial Jeopardy Index [MJI]) as a surrogate of myocardial supply mass subtended by the stenotic coronary artery. The MJI was computed by assigning a value (0–3) to all terminal arteries based on their length and caliber. A value of “0” represented an almost insigniﬁcant vessel size, whereas a value of “3” deﬁned a large Table 4 Simpliﬁed scoring system for identifying abnormal FFR (N0.80) based on independent predictors. Predictor
Male gender MLD b 1.4 mm DS ≥ 50% Disease proximal to lesion Non LCX vessel LAD apical wrap Total Score
2 2 2 2 1 1 10
FFR = fractional ﬂow reserve; MLD = minimum lumen diameter; DS = diameter stenosis; LCX – left circumﬂex; LAD = left anterior descending.
artery with a length greater than two-thirds the distance between the cardiac base and the apex. However, computing such a complex index is not practical at the point of care by an operator in the catheterization laboratory . The proposed FFR-SSS is an easily administered scale that allows operators to make an informed decision concerning the need to perform FFR in a diseased coronary artery. Based on the results of multivariable and ROC analyses, a score of ≥3 on this tool represents a useful cut-off to screen for the need for FFR assessment. This tool is of value for lesions that do not appear narrowed enough by visual inspection to prompt the use of a pressure wire for myocardial ischemia assessment. The scale takes into account luminal compromise, e.g., MLD, % DS and disease proximal to the lesion, as well as indicators of jeopardized myocardial mass, e.g., male gender, LAD with apical wrap as surrogates of larger and LCX as an indicator of smaller territories. In the present study, a PPV of 89.0% (95% CI: 80.7%–94.6%) of vessels were correctly classiﬁed as abnormal and conﬁrmed on FFR. Moreover, a NPV 41.6% (95% CI: 35.1%–48.3%) of vessels were correctly classiﬁed as normal on FFR. 4.1. Limitations of the study Despite the valuable information generated from this study concerning the value of FFR, several important limitations must be acknowledged. The study was conceived as an observational, nonrandomized investigation, conducted by a retrospective review of prospectively collected data. Non-randomization may have introduced confounding clinical factors not accounted for in the study that may have contributed to the use of FFR. These results cannot be generalized to all lesions since patients with left ventricular systolic dysfunction, prior myocardial infarction, the presence of a chronic total occlusion and a history of CABG were excluded from the study cohort. All of these factors may likely inﬂuence the need for FFR. Although data for the current study were derived from a single-center database, several operators participated over time and these may have adversely affected the use of FFR. Single source data also may have inﬂuenced the analytical biases of FFR use. Moreover, the exclusion criteria may have limited the applicability of the results to a more general population. For example, the effect of impaired left ventricular hypertrophy on FFR was not assessed. In the present study, there is a small disparity in the
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number of patients and the lesions assessed by FFR. Further analysis with an increased sample size to assess the relationship between patient and lesion-speciﬁc characteristics may more clearly deﬁne the role of FFR in cardiac catheterization. Recognizing its inherent limitations, this study does have the advantage of representing a daily practice in an environment that serves a diverse patient population. Moreover, data collected on pre- and intra-procedure demographic/clinical variables were gathered in a standardized manner using speciﬁed deﬁnitions. This FFR-SSS warrants further investigation with an increased sample size to validate its appropriate use and its application to other clinical subgroups. 4.2. Clinical implications The decision to use FFR should be based on the severity of vessel stenosis and the size of the myocardial mass jeopardized. The FFR-SSS can serve as a valuable decision-making tool to discern further investigation with a pressure wire. It provides an easily administered quantitative technique for evaluating the physiologic signiﬁcance of a vessel stenosis. It can assist in cost-containment efforts, reduces potential risk exposure and enhance patient outcomes. Author disclosures This study was supported, in part, by an unrestricted grant from St. Jude Medical Inc., Saint Paul, Minnesota. Conﬂict of interest The authors report no relationships that could be construed as a conﬂict of interest. Acknowledgments The authors thank Dr. Debra D. Guest for her assistance in statistical analysis and manuscript preparation. References  N.H. Pijls, P. van Schaardenburgh, G. Manoharan, et al., Percutaneous coronary intervention of functionally nonsigniﬁcant stenosis: 5-year follow-up of the DEFER study, J. Am. Coll. Cardiol. 49 (21) (2007) 2105–2111.
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