Author + information
- Received November 6, 2016
- Revision received March 15, 2017
- Accepted March 23, 2017
- Published online July 17, 2017.
- Mitsuaki Matsumura, BSa,
- Nils P. Johnson, MDb,
- William F. Fearon, MDc,
- Gary S. Mintz, MDa,
- Gregg W. Stone, MDa,d,
- Keith G. Oldroyd, MDe,
- Bernard De Bruyne, MDf,
- Nico H.J. Pijls, MD, PhDg,h,
- Akiko Maehara, MDa,d and
- Allen Jeremias, MD, MSca,i,∗ ()
- aCardiovascular Research Foundation, New York, New York
- bMcGovern Medical School at UT Health and Memorial Hermann Hospital, Houston, Texas
- cStanford University Medical Center, Stanford, California
- dColumbia University Medical Center, New York, New York
- eWest of Scotland Heart and Lung Centre, Golden Jubilee Hospital, Clydebank, United Kingdom
- fCardiovascular Center Aalst, OLV Clinic, Aalst, Belgium
- gCatharina Hospital, Eindhoven, the Netherlands
- hEindhoven University of Technology, Eindhoven, the Netherlands
- iSt. Francis Hospital, Roslyn, New York
- ↵∗Address for correspondence:
Dr. Allen Jeremias, St. Francis Hospital, Department of Cardiology, 100 Port Washington Boulevard, #105, Roslyn, New York 11576.
Objectives The aim of this study was to compare site-reported measurements of fractional flow reserve (FFR) with FFR analysis by an independent core laboratory (CL).
Background FFR is an index of coronary stenosis severity that has been validated in multiple trials and is widely used in clinical practice. However, the incidence of suboptimal FFR measurements is unknown.
Methods Patients undergoing FFR assessment within the CONTRAST (Can Contrast Injection Better Approximate FFR Compared to Pure Resting Physiology) study had paired, repeated measurements of multiple physiological metrics per local practice. An independent central physiology CL analyzed blinded pressure tracings off-line in a standardized fashion for comparison.
Results A total of 763 patients were included in the study; 4,946 distal coronary artery pressure/aortic pressure (nonhyperemic) and FFR tracings were analyzed by the CL (mean 6.5 tracings per patient). Pull-back data were available for 616 patients (80.7%), of whom 108 (17.5%) had signal drift, defined as distal coronary artery pressure/aortic pressure (nonhyperemic) <0.97 or >1.03. Among the remaining 4,217 tracings without evidence of signal drift, 222 (5.3%) were noted to have ventricularization of the aortic waveform, and 168 (4.0%) had aortic waveform distortion. Excluding cases with signal drift and waveform distortion, there was excellent agreement between CL-calculated and site-reported FFR, with a mean difference of 0.003 ± 0.02. Predictors of distorted waveforms were smaller guiding catheter size (odds ratio: 6.30; 95% confidence interval: 3.22 to 12.32; p < 0.001) and intracoronary adenosine use (odds ratio: 0.13; 95% confidence interval: 0.05 to 0.33; p < 0.001).
Conclusions This FFR CL analysis showed that almost 10% of tracings demonstrated waveform artifacts, and an additional 17.5% had signal drift. Among adequate tracings, there was a close correlation between site-reported and CL-analyzed FFR values. Attention to detail is critical for FFR studies to ensure adequate technique and optimal results.
The use of a pressure wire to calculate fractional flow reserve (FFR) is a technique to assess the functional severity of an epicardial coronary artery stenosis (1). Multiple randomized clinical trials and observational data have demonstrated that FFR-guided revascularization improves clinical outcomes (2–5), and both U.S. and European guidelines have endorsed its use (6,7).
Because of the relative simplicity of the FFR technique and need for an immediate guide to treatment, none of the clinical trials on which the recommendations have been based used a centralized core laboratory (CL). Although a CL adds to the cost and complexity of a study, this investment can be worthwhile if the CL serves as quality control and thus reduces the sample size of a trial by boosting signal or reducing noise for a primary or secondary outcome. Other considerations that favor the use of a CL include regulatory requirements and the potential for expanded post hoc analyses.
Every FFR assessment contains a small amount of uncertainty due to biologic variability (8). Additionally, bias due to pressure signal drift, waveform artifacts, or operator interpretation error can be superimposed (9). Real-world data on the incidence of these factors on the overall accuracy of FFR are lacking. The aim of this study was to compare the accuracy of clinically obtained FFR measurements versus a standardized FFR analysis in a central CL.
The present investigation was a multicenter, international study comparing the accuracy of contrast-induced hyperemia (contrast fractional flow reserve [cFFR]) versus standard FFR obtained with intravenous (IV) and intracoronary (IC) adenosine (CONTRAST [Can Contrast Injection Better Approximate FFR Compared to Pure Resting Physiology]; NCT02184117). Details of the study methodology and results have been published previously (10). Briefly, patients underwent routine physiological lesion assessment for clinical indications, and subsequent care proceeded on the basis of the clinical FFR measurement. Each subject gave informed consent as approved by the local Institutional Review Board of that participating center. Recruitment took place between June 2014 and April 2015. This study was investigator initiated and supported by funding from St. Jude Medical (St. Paul, Minnesota). The funding source was not involved in the design of the protocol or the analysis and interpretation of the results.
Patients with prior coronary bypass surgery, left ventricular ejection fractions <30%, left ventricular hypertrophy (septal wall thickness >13 mm), contraindications to adenosine, or renal insufficiency were excluded from the study. Only the first lesion interrogated with FFR in each subject was included in the analysis. Culprit lesions for an acute myocardial infarction were excluded, but nonculprit lesions were permitted.
For FFR measurements, a Certus or Aeris pressure wire and the QUANTIEN acquisition unit (St. Jude Medical) were used. Lesion selection for FFR was left to the individual operators on the basis of clinical necessity and study inclusion criteria. The pressure wire was prepared for FFR measurements according to the manufacturer’s recommendations. Vessel preparation included administration of IC nitroglycerin and anticoagulation per local practice. Equalization of the pressure wire and the aortic pressure was performed at the tip of the guiding catheter before all measurements. The pressure wire was then advanced distal to the stenosis in a stable location to ensure high-quality tracings.
As detailed previously, the complete physiology protocol consisted of duplicate measurements of resting physiology (whole-cycle distal coronary artery pressure/aortic pressure [nonhyperemic] [Pd/Pa] as well as the instantaneous wave-free ratio), cFFR, and FFR obtained with IC and IV adenosine (10). There was a minimum period of 1 min between measurements. Theoretically, the maximum number of measurements per subject was 8 if the entire protocol was carried out. However, not all FFR measurements were mandatory, and thus the number of physiology tracings submitted to the CL was typically <8 per subject. The IC adenosine dose was left to operator discretion, but a strong recommendation was made for 100 to 200 μg (11). Adenosine infusion was administered at a standard rate of 140 μg/kg/min via either a central or a peripheral IV line. The duration of the infusion was approximately 2 min but could be prolonged as necessary or abbreviated if a steady state had been reached or if not tolerated by the patient. At the end of the procedure, a drift check was recommended by pulling the pressure wire back to the tip of the guiding catheter to the same location as the initial equalization.
All pressure tracings were sent to the Cardiovascular Research Foundation (New York, New York) Physiology Core Laboratory for standardized and centralized review. Each subject’s physiology study was separated into individual pressure tracings (i.e., resting Pd/Pa, cFFR, or FFR with IC and IV adenosine) and submitted separately in random order to the CL in batches of 10 individual patients. The CL was blinded to both individual patients and their pressure tracings; thus, the CL carried out a post hoc analysis without knowledge of the locally determined Pd/Pa or FFR value, method of hyperemia, enrolling site, or subject and lesion characteristics. Because each section of the tracing was blinded and uncoupled from the rest, the CL remained unbiased by knowledge of the other measurements for that subject.
The RadiAnalyzer Xpress instrument (St. Jude Medical) was used for coronary pressure measurements. The Physiology Core Laboratory assessed each individual tracing for quality based on pre-specified criteria that included evaluation of the aortic and coronary pressure signal for waveform distortion or loss, aortic pressure ventricularization, and arrhythmia. Each tracing received a binary decision regarding adequate quality for inclusion, and Pd/Pa or FFR was calculated independently for each tracing. In cases in which a final drift check was performed, the quality of the pull-back was assessed along with the amount of drift. All tracings were overread by a physician experienced in physiology measurements (A.J. or A.M.) to ensure data quality.
FFR was independently calculated at the CL and compared with operator-reported measurements. Because measurements were performed in duplicate to assess reproducibility, the first FFR value with IV adenosine was used for FFR calculation. If the first measurement was not available or rejected by the CL, the second FFR value with IV adenosine was used. If both of these measurements were rejected, an acceptable measurement with IC adenosine was used for FFR calculation. Figure 1 displays the study flow chart for the CL analysis.
Pressure drift is defined as a separation from the initially equal aortic and coronary pressures (measured at the tip of the guiding catheter) at the end of the procedure. Before the advancement of the coronary wire distal to the stenosis, the 2 pressures are “equalized” to ensure that the pressure recordings agree (Pd/Pa = 1). After the FFR measurement, the coronary wire is pulled back into the guiding catheter, and Pd/Pa is recorded again. In the absence of any drift, Pd/Pa should be 1. An arbitrary range of 0.97 to 1.03 was used as acceptable values, and drift was defined as measurements <0.97 or >1.03 (Figure 2A).
Aortic pressure ventricularization was defined as diastolic dipping of the waveform, similar to a left ventricular pressure tracing (Figure 2B). This may occur in the presence of an ostial stenosis, large guiding catheter, small vessel size, or deep catheter engagement and can be rectified by partial disengagement of the guiding catheter.
Aortic waveform distortion is defined as a blunting of the aortic waveform with loss of the dicrotic notch and sinusoid appearance of the waveform (Figure 2C). Typically this is related to residual contrast in the guiding catheter or injector system, small catheters, or luminal obstruction by a device (second guiding wire or balloon catheter) inside the guiding catheter.
Data were summarized by descriptive statistics. Linear regression analysis and intraclass correlation analysis were performed to examine the relationship between operator and CL Pd/Pa and FFR measurements. Receiver-operating characteristic curves were constructed to identify the concordance between the measurements. Agreement between operator and CL measurements was assessed by Bland-Altman plots with corresponding 95% limits of agreement. To explore the predictors of suboptimal FFR measurements, we used a logistic regression model that incorporated clinically relevant parameters. The clustering of pressure tracings within patients was modeled by including the patient as a random effect. Similarly, the clustering of patients within sites was modeled by including the site as a random effect. SAS version 9.2 (SAS Institute, Cary, North Carolina) was used for all analyses, and a 2-tailed p value <0.05 was considered to indicate statistical significance.
A total of 763 patients were included in the study, and 4,946 pressure tracings were analyzed by the CL (mean 6.5 tracings per patient), including resting measurements (Pd/Pa and instantaneous wave-free ratio), cFFR, and FFR with IC or IV adenosine. Pull-back data were available for 616 patients (80.7%), among whom 108 (17.5%) had evidence of signal drift (Figure 3). Including the 147 patients who had no pull-back available, 4,217 tracings from 655 patients underwent waveform analysis and FFR calculation. Procedural characteristics and details of the study population are presented in Table 1.
Among the 4,217 tracings (n = 655) without evidence of signal drift, 222 tracings (5.3%) were noted to have ventricularization of the aortic waveform, and 168 (4.0%) had aortic waveform distortion. In a patient-level analysis, 130 patients (19.8%) had at least 1 disqualifying tracing demonstrating either aortic pressure ventricularization or a distorted aortic waveform. A total of 16 patients (2.4%) were identified, who had all analyzed waveforms meet at least 1 exclusion criteria.
Overall, 238 patients (31.2%) had either signal drift or abnormal waveforms affecting at least 1 tracing, and 124 patients (16.3%) had signal drift or abnormal waveforms in all tracings. However, repeating the analysis of the CONTRAST study, no significant difference was noted in the overall agreement between cFFR and adenosine FFR when including all tracings (area under the curve = 0.934) or only CL-accepted tracings (area under the curve = 0.928), indicating that overall study results in larger samples were not significantly affected by these abnormalities.
Comparison of FFR calculations
A total of 598 patients had acceptable waveforms and absence of significant drift and were included in the FFR analysis. Of those, 330 FFR measurements were obtained with IV adenosine and 268 tracings with IC adenosine. CL-calculated and operator-reported FFR were 0.79 ± 0.11 and 0.80 ± 0.11, respectively. There was a strong and linear correlation between CL and operator reported FFR (R2 = 0.969; intraclass correlation coefficient = 0.984; p < 0.001) (Figure 4A). The agreement between the FFR measurements was similarly good, with a mean difference of 0.003 ± 0.020 (Figure 4B). However, variation was noted in individual cases, with 39 patients (6.5%) demonstrating an FFR difference of 0.02, 16 patients (2.7%) a difference of 0.03, and 26 patients (4.3%) a difference of >0.03. Based on an FFR cutoff point of 0.80, 14 patients (2.3%) were recategorized based on Physiology Core Laboratory FFR calculation from ischemic to nonischemic or vice versa, but only 2 patients (0.3%) crossed over the ischemic gray zone of >0.80 to ≤0.75 or vice versa. The differences in FFR calculations between the CL and the clinical sites arise from the CL’s manually selecting the optimal cardiac cycle to determine the FFR, excluding any possible artifacts.
Predictors of aortic pressure ventricularization
No significant differences were noted with respect to age or body surface area for aortic pressure ventricularization. However, there was a modest trend for more frequent aortic pressure ventricularization in women (adjusted odds ratio [OR]: 1.72; p = 0.06) and with the use of larger guiding catheters (OR: 1.75; p = 0.17). Analyzing individual tracings, FFR with contrast, IV adenosine, and IC adenosine were stronger predictors of aortic pressure ventricularization compared with resting Pd/Pa (adjusted OR: 3.04, 7.30, and 2.54, respectively) (Table 2).
Predictors of aortic waveform distortion
The use of a smaller guiding catheter size (i.e., 5-F) was the only predictor of aortic waveform distortion (OR: 6.30; 95% confidence interval: 3.22 to 12.32; p < 0.0001). Female sex (OR: 0.46; 95% confidence interval: 0.21 to 1.01; p = 0.05) and the use of IC adenosine (OR: 0.13; p < 0.001) were associated with significantly fewer tracings demonstrating aortic waveform distortion (Table 3).
In this systematic CL analysis on the prevalence of erroneous or suboptimal FFR measurements in clinical practice, the principal findings were that: 1) almost one-fifth of FFR measurements had evidence of signal drift, defined as Pd/Pa <0.97 or >1.03 at the final pull-back; 2) almost 10% of tracings had either ventricularization or distortion of the aortic waveform; 3) after the exclusion of subjects with signal drift and waveform abnormalities, the overall agreement between CL-analyzed and operator-reported FFR was excellent; and 4) the predictors of abnormal pressure tracings included smaller guide catheter size and the use of IC adenosine.
FFR is a simple invasive index for the assessment of physiological lesion severity that can be rapidly and reliably obtained during cardiac catheterization. It is well validated against noninvasive ischemia testing (12) and has been shown to provide superior risk stratification and clinical outcomes compared with angiography alone (2). In addition, current guidelines recommend its use when evidence of inducible ischemia from noninvasive testing is not available (13–15). However, no guideline or consensus document on the appropriate measurement technique existed until recently (9), in part because obtaining an FFR measurement is considered a relatively simple procedure compared with other coronary interventions. In fact, until recently, no CL was available to analyze and verify these measurements, and none of the randomized physiology studies have used a CL for data analysis. This is in stark contrast to myriad studies in interventional cardiology that routinely submit data for a comprehensive CL analysis of quantitative coronary angiography, intravascular ultrasound, optical coherence tomography, and other techniques to independently verify the study results (16,17).
The present study demonstrates the value of an independent CL, as almost one-third of tracings had either significant drift or waveform abnormalities, diminishing the quality of the measurements. In clinical practice, alterations in waveform, drift, or FFR misinterpretations may have a significant impact on an individual basis, depending on the closeness to the cutoff point of 0.80. In FFR measurements that are clearly ischemic (i.e., FFR <0.70) or clearly nonischemic (i.e., FFR >0.90), minor ventricularization of the aortic waveform or even moderate drift may not alter clinical decision making. However, because FFR measurements are recommended predominantly for intermediate lesions, it is expected that the majority of measurements fall into the clinically important area of 0.7 to 0.9. Meticulous technique, including a thorough visual analysis of the aortic and distal waveforms as well as a pull-back to exclude wire drift at the completion of the measurement, is therefore critical to ensure an accurate and reliable FFR value on which clinical decisions can be confidently based. Other benefits of CL analysis include data accuracy, particularly for U.S. Food and Drug Administration studies, as well as rapid feedback to study sites to continuously improve data quality and thus reduce subject exclusions.
The clinical predictors of aortic pressure ventricularization showed a strong trend toward female sex and larger size guiding catheters, which could be explained by smaller coronary ostia in women and potentially significant obstruction from larger catheters (a 6- or 8-F guiding catheter potentially creates a stenosis of 43% or 77%, respectively) (18). Also, the use of contrast and adenosine versus resting Pd/Pa was associated with a significantly higher prevalence of aortic pressure ventricularization, likely because of the necessity of adequate catheter engagement to effectively deliver the drug into the coronary circulation or by catheter suction into the vessel from increased coronary blood flow. Aminian et al. (19) reported that disengagement of the guiding catheter during adenosine infusion led to a decrease in mean FFR values that was driven predominantly by an increase in proximal aortic pressure. It is important to remember to partially disengage the guiding catheter to avoid this problem. In contrast, smaller guiding catheters (i.e., 5-F) were associated with a significantly greater likelihood of a distorted aortic waveform. Meticulous flushing of the guiding catheter with saline after the injection of contrast will be critical to clear the catheter of contrast residue and thus avoid distortion of the waveform, especially in smaller caliber catheters.
Drift of the pressure sensor has been described since the introduction of the pressure wire (20). It is believed that this is related primarily to changes in the piezoelectric sensor during the measurement and can be minimized by flushing the wire with saline before its use. However, the prevalence of this problem has never been formally examined, and although considered a nuisance, it is not believed to have a major impact on the measurements. The present study indicates that this is not an uncommon problem, affecting nearly 20% of FFR measurements. Although the exact threshold for “significant” drift is arbitrary in a population, large drift could change a decision over the “gray zone” of 0.75 to 0.80, and hence a pull-back at the completion of the FFR study is critically important to validate the accuracy of the results. Nevertheless, within a large sample, study results are unlikely to be affected, as previously demonstrated in CONTRAST (10), as drift is a random noise with a median value of 0.99 and an SD of about 0.03. FFR values scatter around their true value without introducing a bias and, because the scatter is relatively small, the overall impact in CONTRAST was not affected by making tighter drift thresholds (0.05, 0.03, and 0.01).
Pull-backs were available in only about 80% of the population, and patients without pull-back were included in the analysis. Assuming a similar rate of drift among patients who did not have recorded pull-backs, some tracings were included that may have significant drift. Also, the clinical significance of these findings was not established, and it is unknown to what extent clinical decision making would have been altered by these results. The comparison of site-reported and CL-measured FFR values was limited to CL-accepted tracings, excluding subjects with significant drift or waveform abnormalities because the “true” FFR (i.e., FFR from artifact-free tracings) cannot be reproduced. Thus, the excellent correlation between the FFR assessments may represent an overestimate. Also, we were not able to determine the reason for the few cases of large discrepancy between site-reported and CL-determined FFR measurements, because the exact images on which the site-reported FFR measurements were based were not collected. Finally, we used only 1 commercially available pressure wire; it is not known whether the results would have been similar with other devices.
This Physiology Core Laboratory analysis of FFR measurements demonstrates a relatively high prevalence of imperfect FFR measurements either from signal drift or artifacts in the pressure waveform. This may have important implications on clinical decision making, and attention to detail and a strict standardization of methods are critical when measuring FFR to ensure optimal results.
WHAT IS KNOWN? FFR is a relatively simple procedure within the realm of interventional cardiology and has been shown to improve clinical outcomes and reduce cost.
WHAT IS NEW? In this CL analysis, we have demonstrated that suboptimal FFR measurements occur in almost one-third of tracings. Attention to detail is critical for the procedure, including a careful assessment of the waveforms as well as exclusion of signal drift.
WHAT IS NEXT? Development of automated software detecting waveform abnormalities and further refinement of the pressure sensor would substantially aid in increasing the accuracy of FFR measurements. Also, the use of a CL could help standardize the procedure and provide adequate quality control.
This study was an investigator-initiated study and supported financially by St. Jude Medical. Dr. Johnson has received internal funding from the Weatherhead PET Center for Preventing and Reversing Atherosclerosis and significant institutional research support from St. Jude Medical (for this study, NCT02184117) and Volcano/Philips Corporation (for NCT02328820), makers of intracoronary pressure and flow sensors. Dr. Fearon has received institutional research support from St. Jude Medical and Medtronic; has received honoraria from Medtronic; and has served as a consultant to HeartFlow. Dr. Mintz has received honoraria from Boston Scientific and ACIST Medical; and fellowship or grant support from Boston Scientific and St. Jude. Dr. Oldroyd has received speaking fees from St. Jude Medical, AstraZeneca, and Volcano Corporation. Dr. De Bruyne has received institutional consultancy fees and research support from St. Jude Medical. Dr. Pijls has received institutional grant support from St. Jude Medical; serves as a consultant for St. Jude Medical, Boston Scientific, and Opsens; and possesses equity in Philips, General Electric, and HeartFlow. Dr. Maehara has received research grants from and is consultant for Boston Scientific; and speaking fees from St. Jude Medical. Dr. Jeremias has served as a consultant and member of the Speakers Bureau for Volcano/Philips Corporation and St. Jude Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- contrast fractional flow reserve
- core laboratory
- fractional flow reserve
- odds ratio
- distal coronary artery pressure/aortic pressure (nonhyperemic)
- Received November 6, 2016.
- Revision received March 15, 2017.
- Accepted March 23, 2017.
- 2017 American College of Cardiology Foundation
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