Author + information
- Received April 2, 2018
- Revision received June 17, 2018
- Accepted June 20, 2018
- Published online September 10, 2018.
- Yuhei Kobayashi, MDa,
- Jacob Lønborg, MDb,
- Andy Jong, MDc,
- Takeshi Nishi, MD, PhDa,
- Bernard De Bruyne, MD, PhDd,
- Dan Eik Høfsten, MD, PhDb,
- Henning Kelbæk, MDb,
- Jamie Layland, MDc,
- Chang-Wook Nam, MDe,
- Nico H.J. Pijls, MD, PhDf,
- Pim A.L. Tonino, MD, PhDf,
- Julie Warnøe, MDb,
- Keith G. Oldroyd, MDc,
- Colin Berry, MDc,g,
- Thomas Engstrøm, MDb,
- William F. Fearon, MDa,∗ (, )@StanfordMed,
- on behalf of the DANAMI-3-PRIMULTI, FAME, and FAMOUS-NSTEMI Study Investigators
- aDivision of Cardiovascular Medicine, Stanford University Medical Center and Stanford Cardiovascular Institute, Stanford, California
- bDepartment of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- cWest of Scotland Heart and Lung Centre, Golden Jubilee National Hospital, Glasgow, Scotland, United Kingdom
- dCardiovascular Center Aalst, Aalst, Belgium
- eKeimyung University College of Medicine, Dongsan Medical Center, Daegu, South Korea
- fCatharina Hospital, Heartcenter, Eindhoven, the Netherlands
- gBritish Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom
- ↵∗Address for correspondence:
Dr. William F. Fearon, Division of Cardiovascular Medicine, Stanford University Medical Center, 300 Pasteur Drive, H2103, Stanford, California 94305-5218.
Background The residual SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) score (RSS) quantitatively assesses angiographic completeness of revascularization after percutaneous coronary intervention (PCI) and has been shown to be a predictor of events after angiography-guided PCI. In stable patients undergoing functionally complete revascularization with fractional flow reserve (FFR) guidance, RSS did not predict outcome. Whether this is also true in patients with acute coronary syndromes (ACS) is unknown.
Objectives The purpose of this study was to determine whether the RSS could predict outcomes in patients with ACS.
Methods From the DANAMI-3-PRIMULTI (Primary PCI in Patients With ST-elevation Myocardial Infarction and Multivessel Disease: Treatment of Culprit Lesion Only or Complete Revascularization), FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation), and FAMOUS-NSTEMI (Fractional Flow Reserve Versus Angiographically Guided Management to Optimise Outcomes in Unstable Coronary Syndromes) trials, 547 patients presented with ACS and underwent functionally complete revascularization. Major adverse cardiac events (MACE) were defined as the composite endpoint of all-cause death, nonfatal myocardial infarction, and any repeat revascularization. The RSS was based on the recalculation of the SYNTAX score after PCI. We compared differences in 2-year outcome by the RSS subgroups: 0, 1 to <5, 5 to <10, ≥10 (RSS = 0 represents angiographically complete revascularization).
Results The study population consisted of 271 patients with unstable angina/non–ST-segment elevation myocardial infarction and 276 with ST-segment elevation myocardial infarction. The mean RSS was 6.7 ± 5.8. MACE at 2 years occurred in 69 patients (12.6%). Patients with and without MACE had similar RSS after PCI (RSS: 7.2 ± 5.5 vs. 6.6 ± 5.9; p = 0.23). Kaplan-Meier curve analysis showed a similar incidence of MACE regardless of the RSS subgroups (p = 0.54). With and without adjustment of clinical variables, RSS was not a significant predictor of MACE or of each component of MACE.
Conclusions After complete revascularization of functionally significant stenosis by FFR, the extent of residual angiographic disease is not associated with subsequent ischemic events in patients presenting with ACS. These results suggest that the concept of functionally complete revascularization is applicable even in ACS patients. (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation [F.A.M.E.] NCT00267774; Fractional Flow Reserve Versus Angiographically Guided Management to Optimise Outcomes in Unstable Coronary Syndromes [FAMOUS NSTEMI] NCT01764334; Primary PCI in Patients With ST-elevation Myocardial Infarction and Multivessel Disease: Treatment of Culprit Lesion Only or Complete Revascularization [DANAMI-3-PRIMULTI]; NCT01960933)
The residual SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) score (RSS) (1,2) was developed to quantitatively assess the degree and complexity of residual stenoses, based on recalculating the SYNTAX score from coronary angiography after percutaneous coronary intervention (PCI) (3,4). The intention of this index is to quantitatively assess the angiographic completeness of revascularization. Higher RSS has been associated with worse outcome in patients undergoing angiography-guided PCI (1,2,5,6).
Recent studies have found that the functional significance of a lesion based on fractional flow reserve (FFR) is a more important determinant of future adverse cardiac events than angiographic severity (7,8). PCI of lesions that are angiographically significant but not functionally significant based on FFR can be deferred safely with good long-term outcomes in stable patients (9). For example, in our previous study of stable angina patients undergoing FFR-guided PCI, residual angiographic disease as assessed by the RSS was not predictive of adverse outcome, supporting the concept of functionally complete revascularization (10,11).
However, whether this is also true in patients presenting with acute coronary syndromes (ACS), who have functionally insignificant but potentially active nonculprit plaques, is unknown. Accordingly, the primary goal of the present study is to investigate the prognostic value of RSS in patients presenting with ACS, who undergo functionally complete revascularization with FFR guidance.
Study design and patient population
The present study is a patient-level, post hoc, pooled analysis of the FFR-guided revascularization/deferral cohorts from 3 randomized controlled trials (Figure 1) (12–14). The detailed study protocols for each study have been published previously (15–17).
In brief, FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) is a prospective, randomized, controlled, multicenter trial investigating the superiority of FFR-guided PCI over angiography-guided PCI in patients presenting with stable angina, unstable angina, or non–ST-segment elevation myocardial infarction (NSTEMI) (NCT00267774) (12,15). In patients with multivessel coronary artery disease amenable to PCI, the investigators indicated which lesions had at least 50% diameter stenosis and were thought to require PCI. Thereafter, patients were randomly assigned to either FFR- or angiography-guided PCI. FAMOUS-NSTEMI (Fractional Flow Reserve Versus Angiographically Guided Management to Optimise Outcomes in Unstable Coronary Syndromes) is a prospective, randomized, controlled, multicenter trial comparing an FFR- versus angiography-guided revascularization strategy in patients presenting with NSTEMI (NCT01764334) (13,16). Patients were randomized immediately after coronary angiography to either FFR- or angiography-guided management, which included PCI, coronary artery bypass grafting, or medication. DANAMI-3-PRIMULTI (Primary PCI in Patients With ST-elevation Myocardial Infarction and Multivessel Disease: Treatment of Culprit Lesion Only or Complete Revascularization) is a prospective, randomized, controlled, multicenter trial comparing FFR-guided complete revascularization versus treatment of the infarct-related artery only (NCT01960933) (14,17) in patients presenting with ST-segment elevation myocardial infarction (STEMI) and at least 1 nonculprit vessel coronary stenosis after primary PCI. Patients were randomized to FFR-guided complete revascularization or deferral of PCI of the nonculprit lesion(s).
In the 3 studies, patients assigned to the FFR-guided group underwent revascularization of infarct- and noninfarct-related arteries with an FFR ≤0.80 or very tight lesions (>90% by visual assessment), which does not necessitate an FFR measurement; lesions with FFR >0.80 were intentionally left untreated. Because the purpose of this study is to investigate the prognostic value of residual coronary disease after functionally complete revascularization, patients presenting with ACS who underwent successful FFR-guided PCI were enrolled from the 3 studies (Figure 1). Therefore, patients who were randomized to the angiography-guided group or the culprit-only PCI group were not included in this analysis. Patients were further excluded from the present study if the clinical outcome data and/or post-procedural angiogram data were not available or if a PCI attempt was unsuccessful.
The original studies were approved by an institutional review committee from each participating site, and informed consent was obtained from all patients.
FFR measurement and treatment
PCI was performed according to standard coronary interventional techniques primarily with drug-eluting stents. In the DANAMI-3-PRIMULTI trial, patients presenting with STEMI and randomized to FFR-guided complete revascularization were brought back to the cardiac catheterization laboratory within 48 h after the index procedure. In all patients in the current analysis, FFR was measured with a 0.014-inch pressure sensor guidewire (then St. Jude Medical, Uppsala, Sweden). After intracoronary injection of nitroglycerin, equalization to the guide catheter pressure with the sensor positioned at the ostium of the coronary artery was performed, and the pressure guidewire was advanced beyond the stenosis in the target coronary artery. To induce maximal hyperemia, intravenous adenosine was administered at 140 μg/kg/min. Simultaneous measurement of the mean proximal coronary pressure with the guide catheter and the mean distal coronary pressure with the pressure guidewire was performed. FFR was calculated as the ratio of the mean distal to proximal coronary pressure during hyperemia. All patients received dual antiplatelet therapy for at least 1 year after PCI (15–17).
Calculation of RSS
The detailed methodology for calculating the SYNTAX score can be found elsewhere (3,4). In brief, the SYNTAX score can be calculated from the pre-procedural angiogram, in which each coronary lesion producing ≥50% diameter stenosis in vessels ≥1.5 mm by visual estimation is scored separately using the SYNTAX score algorithm from the website, and they are added together to obtain the overall SYNYAX score.
For the calculation of the RSS, post-procedural angiograms were reviewed on all patients enrolled in this study by a dedicated interventional cardiologist who was blinded to the baseline clinical characteristics, procedural data including FFR values, and clinical outcomes. From the post-procedural angiogram, each coronary lesion producing ≥50% diameter stenosis in vessels ≥1.5 mm by visual estimation but left untreated was scored separately, and individual scores were added to provide the RSS (2). A higher RSS value suggests more coronary artery disease left untreated after PCI, and RSS = 0 suggests angiographic complete revascularization. Post-procedural angiograms from 50 patients were randomly selected and reanalyzed by the same interventional cardiologist (Y.K.) and by a second independent interventional cardiologist (T.N.) to assess the intraobserver and interobserver variability of the RSS.
An independent clinical events committee was prospectively established in the design of each of the trials. The clinical events committee members who were blinded to treatment strategy adjudicated all events. The primary endpoint of this study was major adverse cardiac events (MACE), defined as a composite of all-cause death, myocardial infarction, or any repeat revascularization at 2 years after the index procedure.
Categorical variables, including the primary endpoint and its individual components, are presented as counts and percentages. The chi-square test was used for comparisons of categorical variables. Continuous variables are presented as mean and SD. Normality of the continuous variables was confirmed with the Shapiro-Wilk test. Depending on the result of Levene test for homoscedasticity, 2-sets of variables with normal distribution were compared with the Student’s t-test or Welch t-test, as appropriate. If the normality test failed, 2-sets of variables were compared with the Mann-Whitney U test. An overall difference of variables among the subgroups was determined by 1-way analysis of variance or Jonckheere-Terpstra test. The reproducibility of the RSS was evaluated by calculating intraobserver and interobserver variability using the intraclass correlation. Kaplan-Meier curves are shown for the time-to-event distributions of MACE as stratified by RSS subgroups. Patients without event were censored at 2 years (730 days). Cox-proportional hazards model was used to estimate unadjusted and adjusted hazard ratios of RSS as a continuous variable. Adjustment was performed using the 2 models. Model 1 included the following key clinical variables: age, sex, diabetes, hypertension, hypercholesterolemia, previous myocardial infarction, presentations, and culprit vessel. Model 2 included the same variables as model 1 and the pre-defined additional following continuous variables: creatinine, peak troponin T, and ejection fraction. A p value < 0.05 was considered statistically significant. Statistical analyses were performed using SPSS version 21 software (SPSS, Chicago, Illinois).
A total of 547 patients who presented with ACS from the FFR-guided PCI cohort of the FAME, FAMOUS-NSTEMI, and DANAMI-3-PRIMULTI were enrolled in this study (Figure 1). Overall, the mean age was 63 ± 11 years, 78% were male, and 77% of patients completed the 2-year follow-up. The mean and median RSS was 6.7 ± 5.8 and 6.0 (2.0 to 10.0), respectively. The intraobserver variability of the RSS using the intraclass correlation analysis was 0.94, 95% confidence interval: 0.90 to 0.97 (p < 0.001), and the interobserver variability of the RSS using the intraclass correlation analysis was 0.95, 95% confidence interval: 0.91 to 0.97 (p < 0.001).
About one-half of the patients (n = 271, 49.5%) presented with unstable angina or NSTEMI and the remaining one-half (n = 276, 50.5%) presented with STEMI (13). The mean RSS was similar between the 2 groups (6.6 ± 6.0 vs. 6.8 ± 5.6; p = 0.35).
Clinical characteristics of the patients in the 3 trials are summarized in Online Table 1. Although there were significant differences in some clinical characteristics such as age, comorbidities, and previous history of myocardial infarction or PCI, as might be expected, the mean RSS was similar (FAME vs. FAMOUS-NSTEMI vs. DANAMI-3-PRIMULTI: 6.9 ± 6.0 vs. 6.3 ± 6.0 vs. 6.8 ± 5.6; p = 0.65).
Comparisons of baseline data among RSS subgroups
Comparisons of clinical characteristics among RSS subgroups (RSS = 0, 1 to <5, 5 to <10, ≥10) are summarized in Table 1. Baseline patient clinical characteristics were similar among RSS subgroups, except for age (p for trend <0.01) and incidence of diabetes (p for trend <0.01). The incidence of diabetes was lowest in patients with RSS = 0, which represents angiographically complete revascularization. The proportion of presentations was also similar among RSS subgroups (p for trend = 0.37).
MACE occurred in 69 patients (12.6%) during 2-year follow-up. RSS was similar between patients with and without MACE (RSS: 7.2 ± 5.5 vs. 6.6 ± 5.9; p = 0.23). As shown in Table 2, MACE and each component of MACE was not different among the RSS subgroups. Kaplan-Meier curves stratified by the RSS subgroups showed no significant separation (log-rank p for trend = 0.54) (Figure 2), and RSS = 0 and the highest RSS subgroups were superimposed.
Table 3 summarizes the unadjusted hazard ratio of RSS in predicting MACE and each component of MACE. By univariable Cox proportional hazards model, RSS was not predictive of MACE and each component of MACE (all p > 0.05). Online Table 2 summarizes the adjusted hazard ratio of RSS in predicting MACE and each component of MACE. After adjusting for patient age, sex, risk factors, previous myocardial infarction, presentation, and culprit vessel (model 1), RSS was not predictive of MACE or each component of MACE (all p > 0.05). In this model, diabetes was a significant predictor of MACE (p = 0.04) and repeat revascularization (p = 0.02). Similarly, age was a significant predictor of death (p = 0.003) and hypercholesterolemia was a significant predictor of myocardial infarction (p = 0.003) and death or MI (p = 0.009). After adjusting for parameters included in model 1, creatinine, peak troponin T, and ejection fraction (model 2), RSS was not predictive of MACE and each component of MACE (all p > 0.05). In this model, peak troponin T was a predictor of MACE (p = 0.01) and death or myocardial infarction (p = 0.01). Similarly, age was a significant predictor of death (p = 0.01).
The principal finding of the present study is that the RSS is not a significant predictor of MACE or each component of MACE at 2-year follow-up in patients who underwent functionally complete revascularization with FFR guidance after presenting with an ACS (Central Illustration). The RSS of our population was similar to or higher than previous studies showing prognostic value of RSS after angiography-guided PCI (1,2). These results suggest that an FFR-guided PCI strategy offers an appropriate level of revascularization even in ACS patients with potentially vulnerable nonculprit stenoses.
There has been concern regarding the safety and accuracy of FFR measurements in the ACS setting. This stems in part from the potential for transient coronary microvascular dysfunction in the culprit vessel territory, which theoretically could involve nonculprit territories as well, leading to a blunted maximal coronary flow down the nonculprit vessels and a falsely elevated FFR. Deferral of PCI on unrecognized significant disease could lead to increased event rates. Concern also stems from the possibility that nonculprit disease, which is not hemodynamically significant based on FFR, might be more likely to cause events in the ACS setting because of systemic inflammation and plaque vulnerability. In the study by Hakeem et al. (18), deferring PCI using FFR in patients presenting with ACS was associated with significantly worse outcomes than in patients with stable angina; however, this may be due to the inherently higher risk of patients presenting with ACS than stable angina. The data from the current study and from a recent animal study do not support these concerns, at least in patients treated with dual antiplatelet therapy for 1 year (19).
This current study builds on data from previous trials. As first shown in a FAME substudy, the benefit of using FFR to guide PCI is similar in an unstable angina/NSTEMI population as compared with a stable angina population (20). Subsequently, the use of FFR including the culprit lesion of NSTEMI was shown to be feasible and safe in the randomized controlled trial setting (13). In the STEMI population, 2 large-scale randomized controlled trials have demonstrated the feasibility and safety of using FFR to assess nonculprit disease after primary PCI (14,21). These trials and other previous studies compared either an angiographically or functionally complete revascularization strategy against a culprit-only revascularization strategy (14,21–23). In this context, the current study may broaden the applicability of functionally complete revascularization to the ACS population by showing that residual coronary disease is not predictive of outcome in this population either.
As previously shown by Nam et al. (24), the prognostic value of the angiography-based SYNTAX score measured before PCI is enhanced by integrating functional information and calculating the “functional SYNTAX score.” We did not explore the predictive value of the SYNTAX score or functional SYNTAX score in this study, because these scoring systems are not universally used in ACS, especially STEMI, due to the large effect of culprit lesion location (total occlusion) on both the score and the clinical outcome (25).
First, given the pooled analysis, differences in trial design, such as the definition of myocardial infarction (26,27), revascularization strategy, or antiplatelet therapy, may have affected the results. Second, we do not have a clear answer about whether single-staged or multistaged PCI (and FFR measurement) is preferable in a STEMI population, whereas Sardella et al. (28) showed the superiority of single-staged complete revascularization in the NSTEMI population. Third, although this pooled analysis involves more than 500 patients presenting with ACS, the statistical power may not be adequate to prove our hypothesis. Nevertheless, the fact that typical variables associated with outcome were significant but RSS was not suggests that RSS will not be a stronger predictor than these well-known variables. Fourth, although the goal in this study was to achieve functionally complete revascularization based on FFR guidance, likely some functionally significant lesions were left untreated due to disease complexity, procedural failure, or operator discretion. As shown in a recent study, a “functional” RSS assessed by post-PCI FFR measurements is related to adverse outcome (29). Therefore, the results of the current study could be even more robust if all patients achieved a functionally complete revascularization by post-PCI FFR measurements. Finally, because this study is a post hoc analysis of the FFR-guided PCI arm of the 3 clinical trials, which were not designed to assess the impact of residual lesions after FFR-guided PCI, the results of the present study should be interpreted as hypothesis-generating.
After complete revascularization of functionally significant stenoses by FFR, the extent of residual angiographically significant but functionally insignificant disease is not a predictor of subsequent ischemic events in patients presenting with ACS. These results suggest that functionally complete revascularization is applicable even in ACS patients with potentially vulnerable nonculprit stenoses.
COMPETENCY IN PATIENT CARE: After revascularization of significant stenoses based on FFR measurements in patients presenting with ACS, the extent of residual angiographic disease is not associated with subsequent ischemic events.
TRANSLATIONAL OUTLOOK: Prospective studies are needed to compare the prognostic implications of FFR-guided versus angiography-guided revascularization in patients with ACS.
The DANAMI-3-PRIMULTI trial was funded by the Danish Agency for Science, Technology and Innovation, and the Danish Council for Strategic Research (EDITORS, grant 09-066994). The FAME study was sponsored by St. Jude Medical (now Abbott). The FAMOUS-NSTEMI study was supported by grants from the British Heart Foundation (RE/13/5/30177 and PG/11/55/28999), and St. Jude Medical (now Abbott) provided the pressure wires. Dr. De Bruyne has received institutional consultancy fees and research support from Abbott/St. Jude Medical, Boston Scientific, Biotronik, and Opsens; and has equities in Siemens, Bayer, Philips, GE, HeartFlow, Edwards Lifesciences, Sanofi, and Celyad. Dr. Layland has served in an advisory role for Medtronic. Dr. Nam has received institutional research support from Pfizer, Medtronic, and Biosensors; and has served as a consultant for Pfizer, Abbott Vascular, and Boehringer Ingelheim. Dr. Pijls has received institutional grant support from Abbott/St. Jude Medical; has served as a consultant for Abbott/St. Jude Medical and Opsens; and possesses equity in Philips, GE, ASML, and HeartFlow. Dr. Oldroyd has received speaker fees from Abbott Vascular. Dr. Berry has received institutional research grant support and served as a consultant for Abbott/St. Jude Medical; and his institution holds research and consultancy agreements with companies with interests in interventional cardiology, including Abbott Vascular, Coroventis, and Opsens. Dr. Engstrøm has received speaker fees from AstraZeneca, Boston Scientific, and Abbott; has served as consultant for Novo Nordisk; and has received advisory board fees from Bayer AS. Dr. Fearon has received institutional research support from Abbott, Medtronic, and CathWorks; has a consulting relationship with Boston Scientific; and has minor stock options with HeartFlow. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- acute coronary syndromes
- fractional flow reserve
- major adverse cardiac event(s)
- percutaneous coronary intervention
- residual SYNTAX score
- Received April 2, 2018.
- Revision received June 17, 2018.
- Accepted June 20, 2018.
- 2018 American College of Cardiology Foundation
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