Author + information
- Received December 31, 2018
- Revision received January 25, 2019
- Accepted February 18, 2019
- Published online May 13, 2019.
- Joo Myung Lee, MD, MPH, PhDa,
- Ki Hong Choi, MDa,
- Bon-Kwon Koo, MD, PhDb,c,∗ (, )@SNUnow,
- Jonghanne Park, MDb,
- Jihoon Kim, MDa,
- Doyeon Hwang, MDb,
- Tae-Min Rhee, MDb,
- Hyung Yoon Kim, MDd,
- Hae Won Jung, MDe,
- Kyung-Jin Kim, MDf,
- Kawase Yoshiaki, MDg,
- Eun-Seok Shin, MD, PhDh,i,
- Joon-Hyung Doh, MD, PhDj,
- Hyuk-Jae Chang, MD, PhDk,
- Yun-Kyeong Cho, MD, PhDl,
- Hyuck-Jun Yoon, MD, PhDl,
- Chang-Wook Nam, MD, PhDl,
- Seung-Ho Hur, MD, PhDl,
- Jianan Wang, MD, PhDm,
- Shaoliang Chen, MD, PhDn,
- Shoichi Kuramitsu, MDo,
- Nobuhiro Tanaka, MD, PhDp,
- Hitoshi Matsuo, MD, PhDg and
- Takashi Akasaka, MD, PhDq
- aDivision of Cardiology, Department of Internal Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
- bDepartment of Internal Medicine and Cardiovascular Center, Seoul National University Hospital, Seoul, Korea
- cInstitute on Aging, Seoul National University, Seoul, Korea
- dDepartment of Cardiovascular Medicine, Chonnam National University Hospital, Gwangju, Korea
- eDepartment of Cardiology, Daegu Catholic University Medical Center, Daegu, Korea
- fDepartment of Internal Medicine, Ewha Womans University Medical Center, Ewha Womans University School of Medicine, Seoul, Korea
- gDepartment of Cardiology, Gifu Heart Center, Gifu, Japan
- hDepartment of Cardiology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
- iDivision of Cardiology, Ulsan Hospital, Ulsan, Korea
- jDepartment of Medicine, Inje University Ilsan Paik Hospital, Goyang, Korea
- kDivision of Cardiology, Severance Cardiovascular Hospital, Yonsei-Cedars-Sinai Integrative Cardiovascular Imaging Research Center, Yonsei University College of Medicine, Seoul, Korea
- lDepartment of Medicine, Keimyung University Dongsan Medical Center, Daegu, Korea
- mDepartment of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- nDepartment of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
- oDepartment of Cardiology, Kokura Memorial Hospital, Kitakyushu, Japan
- pDepartment of Cardiology, Tokyo Medical University, Tokyo, Japan
- qWakayama Medical University, Wakayama, Japan
- ↵∗Address for correspondence:
Dr. Bon-Kwon Koo, Department of Internal Medicine and Cardiovascular Center, Seoul National University Hospital, 101 Daehang-ro, Chongno-gu, Seoul 110-744, Korea.
Background Although the presence of ischemia is a key prognostic factor in patients with coronary artery disease, the presence of high-risk plaque characteristics (HRPC) is also associated with increased risk of cardiovascular events. Limited data exist regarding the prognostic implications of combined information on physiological stenosis severity assessed by fractional flow reserve (FFR) and plaque vulnerability by coronary computed tomography angiography (CTA)–defined HRPC.
Objectives The current study aimed to evaluate the: 1) association between physiological stenosis severity and coronary CTA-defined HRPC; and 2) prognostic implications of coronary CTA-defined HRPC according to physiological stenosis severity in patients with coronary artery disease.
Methods A total of 772 vessels (299 patients) evaluated by both coronary CTA and FFR were analyzed. The presence and number of HRPC (minimum lumen area <4 mm2, plaque burden ≥70%, low attenuating plaque, positive remodeling, napkin-ring sign, or spotty calcification) were assessed using coronary CTA images. The risk of vessel-oriented composite outcome (VOCO) (a composite of vessel-related ischemia-driven revascularization, vessel-related myocardial infarction, or cardiac death) at 5 years was compared according to the number of HRPC and FFR categories.
Results The proportion of lesions with ≥3 HRPC was significantly decreased according to the increase in FFR values (58.6%, 46.5%, 36.8%, 15.7%, and 3.5% for FFR ≤0.60, 0.61 to ≤0.70, 0.71 to ≤0.80, 0.81 to ≤0.90, and >0.90, respectively; overall p value <0.001). Both FFR and number of HRPC showed significant association with the estimated risk of VOCO (p = 0.008 and p = 0.023, respectively). In the FFR >0.80 group, lesions with ≥3 HRPC showed significantly higher risk of VOCO than those with <3 HRPC (15.0% vs. 4.3%; hazard ratio: 3.964; 95% confidence interval: 1.451 to 10.828; p = 0.007). However, there was no significant difference in the risk of VOCO according to HRPC in the FFR ≤0.80 group. By multivariable analysis, the presence of ≥3 HRPC was independently associated with the risk of VOCO in the FFR >0.80 group.
Conclusions Physiological stenosis severity and the number of HRPC were closely related, and both components had significant association with the risk of clinical events. However, the prognostic implication of HRPC was different according to FFR. Integration of both physiological stenosis severity and plaque vulnerability would provide better prognostic stratification of patients than either individual component alone, especially in patients with FFR >0.80. (Clinical Implication of 3-vessel Fractional Flow Reserve [3V FFR-FRIENDS study]; NCT01621438)
Invasive treatment for ischemic heart disease has been focused on the identification and revascularization of obstructive coronary artery disease (CAD). However, it is well-known that a discrepancy exists between angiographic stenosis severity and the presence of myocardial ischemia (1). As the presence of ischemia is a prerequisite for the improvement of clinical outcomes with percutaneous coronary intervention (PCI), the decision to perform revascularization should be guided by evidence of myocardial ischemia. Fractional flow reserve (FFR), one of the pressure-derived physiological indexes, is regarded as a standard invasive method to evaluate the functional significance or physiological severity of epicardial coronary artery stenosis in patients with CAD (2). The clinical outcomes of FFR-guided PCI were reported to be better than those of angiography-guided PCI or medical treatment (3,4). However, clinical events still occur in patients with FFR >0.80 (4,5).
Previous evidence from postmortem studies provided insights into the morphology of atherosclerotic plaque prone to rupture and spawned the development of numerous noninvasive and invasive imaging techniques to detect high-risk plaque (6). Invasive imaging studies consistently showed that the assessment of plaque burden or composition could predict the risk of cardiovascular events (7–9). In addition, noninvasive imaging studies based on coronary computed tomography angiography (CTA) also showed the additive value of coronary CTA-defined high-risk plaque characteristics (HRPC) in the prediction of future cardiovascular events (10–12).
Although both FFR and HRPC are associated with clinical outcomes as individual prognostic indicators, their association and differential prognostic implications have not been well-defined. The current study sought to evaluate the: 1) association between physiological stenosis severity assessed by FFR and plaque vulnerability assessed by coronary CTA-defined HRPC; and 2) prognostic implications of coronary CTA-defined HRPC according to FFR in patients with CAD.
Study design and patient population
The study population was derived from the 3V FFR-FRIENDS study (3-Vessel Fractional Flow Reserve for the Assessment of Total Stenosis Burden and Its Clinical Impact in Patients With Coronary Artery Disease) (NCT01621438) which was designed to investigate the clinical relevance of total stenosis burden assessed by 3-vessel FFR measurement (1). Briefly, 1,136 patients (3,298 vessels) who had >30% stenosis by visual estimation in major epicardial coronary arteries and underwent successful FFR measurement in all 3 major coronary arteries were included in this study. Patients with depressed left ventricular systolic function (ejection fraction <35%), acute ST-segment elevation myocardial infarction (MI) within 72 h, previous coronary artery bypass graft surgery (CABG), chronic renal disease, abnormal epicardial coronary flow (Thrombolysis In Myocardial Infarction flow <3) or planned CABG after diagnostic angiography were excluded.
Among the total population, 299 patients (772 vessels) who underwent coronary CTA within 90 days of FFR measurement and available pre-PCI FFR were included in the current study (Online Figure 1). Coronary CTA was performed as part of routine clinical practice for patients with suspected coronary artery disease, and the decision to perform coronary CTA before invasive angiography was at the discretion of the physicians in charge. The enrolled patients were not taking part in conflicting studies. The study protocol was approved by the Institutional Review Board or Ethics Committee at each participating center, and all patients provided written informed consent.
Coronary CTA and analysis of high-risk plaque characteristics
Coronary CTA images were obtained in accordance with the Society of Cardiovascular Computed Tomography guidelines on performance of coronary CTA, with 64 or higher detector row scanner platforms (13). The coronary CTA images were analyzed at a core laboratory (Severance Cardiovascular Hospital, Seoul, Korea) in a blinded fashion. In addition to quantitative analysis of target stenosis and vessels including minimum lumen area (MLA), plaque burden, area stenosis, total aggregated plaque volume (TAPV), and percent TAPV (percent TAPV = TAPV/total vessel volume × 100), qualitative analysis for plaque characteristics was performed according to the definitions from previous studies (10,14,15). Briefly, plaque density was assessed semi-automatically using a dedicated cardiac workstation (Intellispace Portal, Philips Healthcare, Cleveland, Ohio) (15). The presence of the following high-risk characteristics was analyzed in a core laboratory: 1) low-attenuation plaque (average density ≤30 HU from 3 random region-of-interest measurements with approximately 0.5 to 1.0 mm2 in noncalcified low CT attenuation portion of the plaque); 2) positive remodeling (remodeling index ≥1.1); 3) napkin-ring sign (ring-like attenuation pattern with peripheral high attenuation tissue surrounding a central lower attenuation portion); and 4) spotty calcification (average density >130 HU, diameter <3 mm in any direction, length of the calcium <1.5× the vessel diameter, and width of the calcification less than two-thirds of the vessel diameter). Combining both quantitative and qualitative parameters, the following characteristics were defined as HRPC in our study: MLA <4 mm2, plaque burden ≥70%, low-attenuation plaque, positive remodeling, napkin-ring sign, or spotty calcification. The definition of HRPC was pre-specified based on previous studies before the current analysis (7,8,10,11). The reproducibility and reliability of quantitative analysis of coronary CTA in the core laboratory was evaluated in a recent study, which showed consistency in the analysis for 2 paired coronary CTA scans (16).
Angiographic analysis and quantitative coronary angiography
Coronary angiography was performed using standard techniques. Angiographic views were obtained after administration of intracoronary nitrate (100 or 200 μg). All angiograms were analyzed at a core laboratory (Seoul National University Hospital, Seoul, Korea) in a blinded fashion. Quantitative coronary angiography (QCA) was performed in optimal projections with validated software (CAAS II, Pie Medical System, Maastricht, the Netherlands). Minimum lumen diameter, reference vessel size, percent diameter stenosis (% DS), and lesion length were measured. Angiographic disease severity was also assessed by SYNTAX score.
Coronary physiological measurements
All coronary physiological measurements were obtained after diagnostic angiography as previously described (1). Briefly, a 5- to 7-F guide catheter was used to engage the coronary artery. The pressure-temperature sensor guidewire (Abbott Vascular, Santa Clara, California) was zeroed and equalized to aortic pressure, and then was positioned at the distal segment of a target vessel. Intracoronary nitrate (100 or 200 μg) was administered before each set of physiological measurements. Continuous intravenous infusion of adenosine was used to induce hyperemia for FFR measurement. Hyperemic proximal aortic pressure and distal arterial pressure were obtained, and FFR was calculated as the lowest average of 3 consecutive beats during adenosine infusion. All pressure readings were collected and validated at the core laboratory in a blinded fashion.
Patient follow-up, outcome measurements, and adjudication of clinical events
Clinical data were obtained at outpatient clinic visits or by telephone contact when needed. An independent clinical event committee whose members were unaware of clinical, angiographic, and physiological data adjudicated all events. All patients were followed until February 6, 2018, with a window period of 30 days. The primary outcome was vessel-oriented composite outcome (VOCO), which included vessel-related ischemia-driven target vessel revascularization, vessel-related myocardial infarction (MI), and cardiac death (17,18). All events records were independently reviewed to assess vessel-related clinical events. All clinical outcomes were defined according to the Academic Research Consortium, including the addendum to the definition of MI. All deaths were considered cardiac in nature unless an undisputable noncardiac cause was present. Cardiac death in patients with multivessel interrogation was assigned to each of the interrogated vessels. MI was defined as third universal definition of MI with a combination of criteria with mandated elevation of a cardiac biomarker, preferably high-sensitivity cardiac troponin, and at least 1 of the following: symptoms of ischemia, significant ST- to T-wave changes, pathological Q waves, imaging evidence of new regional wall motion abnormality, or intracoronary thrombus. Periprocedural MI was not included as a clinical outcome (19). Ischemia-driven revascularization was defined as a revascularization procedure with at least 1 of the following: 1) recurrence of angina; 2) positive noninvasive test; and 3) positive invasive physiological test.
Categorical variables were presented as numbers and relative frequencies (percentages), and continuous variables as means and SDs or median with interquartile range (Q1 to Q3) according to their distribution, which was checked by the Kolmogorov-Smirnov test. Linear regression analysis was used to estimate the correlation coefficient between quantitative variables.
Data were analyzed on a per-patient basis for clinical characteristics and on a per-vessel basis for comparison of lesion characteristics, physiological indexes, and vessel-specific clinical outcomes. For per-vessel analyses, a generalized estimating equation was used to adjust for intrasubject variability among vessels from the same patient. Estimated mean ± SD are presented as summary statistics. No post hoc adjustment was performed. In comparisons of clinical outcomes among groups, event rates were calculated on the basis of Kaplan-Meier censoring estimates and presented with the cumulative incidence at 5 years, and the log-rank test or the Breslow test was used to compare survival curves between groups. In addition, marginal Cox proportional hazard regression was used to calculate hazard ratio (HR) and 95% confidence interval (CI) to compare between-group differences for a per-vessel comparison of cumulative incidence of target vessel–related events. The assumption of proportionality was assessed graphically by log-minus-log plot, and Cox proportional hazard models for all clinical outcomes satisfied the proportional hazards assumption. To select the best cut-off value of number of HRPC to discriminate the occurrence of VOCO, a method using maximally selected log-rank statistics was used.
A multivariable marginal Cox model was used to identify independent predictors of VOCO among deferred vessels. The covariates with clinical relevance or a univariate relationship with outcome (p < 0.10) were entered into the model. To avoid overfitting of the predictive model, a Firth penalized model was used (20). The discrimination ability of predictive model was presented with Harrell’s c-index. All probability values were 2-sided, and p values <0.05 were considered statistically significant.
Characteristics of patients and lesions
Online Table 1 shows general characteristics of the study population, and Online Table 2 shows the target vessel characteristics. Most patients (80.6%) presented with stable angina, and mean angiographic %DS and FFR were 43.1 ± 17.5% and 0.87 ± 0.12, respectively. FFR was low (≤0.80) in 197 vessels (25.5%). Among the total 772 vessels, 154 vessels were revascularized after FFR measurements and 618 were deferred revascularization. Among the deferred vessels, 65 vessels showed FFR ≤0.80. In these vessels, PCI was deferred due to insignificant angiographic stenosis (39 vessels, 60.0%), diffuse disease (11 vessels, 16.9%), no angiographic progression since previous angiography (1 vessel, 1.5%), negative results of noninvasive tests (5 vessels, 7.7%), small myocardial territory (1 vessel, 1.5%), and other reasons (8 vessels, 12.3%). There were significant but modest correlations between FFR and quantitative coronary CTA parameters (MLA, plaque burden, area stenosis, and percent TAPV) (Online Figure 2).
Association between HRPC and FFR
Table 1 and Figure 1 show coronary CTA-measured characteristics of target vessels according to FFR. The vessels with FFR ≤0.80 showed a higher proportion of MLA <4 mm2, plaque burden ≥70%, low attenuation plaque, and napkin-ring sign than those with FFR >0.80 (Table 1). When the number of HRPC was compared according to FFR, there were significant differences in the number of HRPC among different FFR categories (overall p value <0.001). The proportions of lesions with ≥3 HRPC were 58.6%, 46.5%, 36.8%, 15.7%, and 3.5% in FFR ≤0.60, 0.61 to ≤0.70, 0.71 to ≤0.80, 0.81 to ≤0.90, and >0.90 categories, respectively (Figure 1). The number of HRPC also showed significant association with per-vessel FFR (Online Figure 3). When comparing the vessel characteristics between <3 and ≥3 HRPC in the FFR >0.80 group, lesions with ≥3 HRPC showed low FFR; higher stenosis severity and plaque burden; and higher prevalence of low attenuating plaque, positive remodeling, and spotty calcification. The difference between <3 and ≥3 HRPC among lesions with FFR ≤0.80 was also similar (Table 2). Among the individual components of HRPC, low attenuating plaque, MLA, and plaque burden were independently associated with per-vessel FFR (Online Table 3).
Clinical outcomes according to HRPC and FFR
Both FFR and number of HRPC showed significant association with the cumulative incidence of VOCO at 5 years among deferred vessels (p values 0.008 and 0.023 for FFR and number of HRPC, respectively) (Figure 2). A similar association was also observed in the entire population (p < 0.001 and p = 0.002 for FFR and number of HRPC, respectively) (Online Figure 4). When the predictability of individual component of HRPC was compared with combined criteria of HRPC, the number of HRPC showed a higher c-index than the individual component of HRPC (0.517 [95% CI: 0.423 to 0.589] for low-attenuating plaque, 0.590 [95% CI: 0.479 to 0.700] for positive remodeling, 0.513 [95% CI: 0.480 to 0.551] for napkin-ring sign, 0.529 [95% CI: 0.476 to 0.583] for spotty calcification, 0.687 [95% CI: 0.499 to 0.875] for MLA <4 mm2, 0.764 [95% CI: 0.615 to 0.913] for plaque burden ≥70%, and 0.795 [95% CI: 0.645 to 0.944] for number of HRPC). Among vessels with an FFR >0.80, the mean FFR values in those with and without subsequent ischemia-driven revascularization were 0.90 ± 0.05 and 0.93 ± 0.05, respectively (p = 0.037).
By maximally selected log-rank statistics, the presence of 3 or more HRPC showed the best discrimination ability for the occurrence of VOCO at 5 years. When all deferred lesions were classified into 2 groups by the best cut-off value, the lesions with ≥3 HRPC showed a significantly higher risk of VOCO compared with those with <3 HRPC in the FFR >0.80 group (15.0% vs. 4.3%; HR: 3.964; 95% CI: 1.451 to 10.828; p = 0.007) (Figure 3, Table 3). However, there was no significant difference in the risk of VOCO between ≥3 HRPC versus <3 HRPC in the FFR ≤0.80 group (17.2% vs. 17.0%; HR: 1.257; 95% CI: 0.300 to 5.270; p = 0.754) (Table 3, Online Figure 5). The different risk of VOCO between ≥3 and <3 HRPC, according to FFR levels, showed significant interaction (interaction p value = 0.031) (Table 3).
The cumulative incidence of VOCO at 5 years was 4.3%, 15.0%, and 10.7% among the deferred vessels with FFR >0.80 and <3 HRPC, deferred vessels with FFR >0.80 and ≥3 HRPC, and stented vessels with FFR ≤0.80, respectively. Both stented vessels with FFR ≤0.80 and deferred vessels with FFR >0.80 and ≥3 HRPC showed significantly higher risk of VOCO compared with deferred vessels with FFR >0.80 and <3 HRPC (Figure 4).
Among 21 cases of ischemia-driven revascularization, 8 cases were due to acute coronary syndrome, 5 cases to recurrent angina with low FFR, 2 cases to recurrent angina and positive noninvasive tests, 3 cases to positive noninvasive tests without angina, and 3 cases to recurrent angina and definite progression of target lesions. Among the cases of ischemia-driven revascularization, 4 cases showed FFR ≤0.80 at the index procedure.
Independent predictors of VOCO
A multivariable marginal Cox model revealed that FFR, ≥3 HRPC, and diabetes mellitus were independently associated with the occurrence of VOCO (Table 4). The results were similar when the number of HRPC was included as an ordinal variable (Online Table 4). The presence of ≥3 HRPC was independently associated with the occurrence of VOCO in the FFR >0.80 group (HR: 3.975; 95% CI: 1.351 to 11.696; p = 0.012) but not in the FFR ≤0.80 group (HR: 0.929; 95% CI: 0.187 to 4.624; p = 0.929).
The current study evaluated the association between per-vessel physiological disease burden (FFR) and quantitative and qualitative plaque characteristics (coronary CTA-defined HRPC) and their prognostic implications (Central Illustration). The main findings are as follows. First, there was a significant difference in the number of HRPC among the different ranges of FFR. The number of HRPC increased with decrease in FFR, and vice versa. Second, both FFR and number of HRPC showed a significant association with the cumulative incidence of VOCO at 5 years and both were independent predictors for the risk of VOCO among deferred vessels. Third, the lesions with ≥3 HRPC showed significantly higher risk of VOCO compared with those with <3 HRPC in the FFR >0.80 group. By multivariable analysis, the presence of ≥3 HRPC was independently associated with the risk of VOCO in the FFR >0.80 group, but not in the FFR ≤0.80 group. Last, deferred vessels with FFR >0.80 and ≥3 HRPC showed similar risk of VOCO with stented vessels with FFR ≤0.80. The estimated risk of VOCO in both groups was significantly higher than deferred vessels with FFR >0.80 and 0 to 2 HRPC.
Association among anatomic stenosis severity, plaque characteristics, and physiological stenosis severity in patients with CAD
Previous studies have indicated that the prevalence of adverse plaque characteristics increases according to the increase in stenosis severity (21) or plaque burden (7–9). Furthermore, degree of luminal stenosis (22,23) as well as amount of plaque (plaque burden, plaque volume, or TAPV) (7–9,24) were linked with the risk of plaque-related clinical events. In the PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) study, clinical events occurred in only 0.3% of lesions with MLA >4.0 mm2, plaque burden <70%, and no thin-cap fibroatheroma (TCFA) during a median follow-up period of 3.4 years (7). Conversely, the MACE rate originated from lesions that included 1, 2, or all 3 of MLA ≤4.0 mm2, plaque burden ≥70%, or TCFA were 4.8%, 10.5%, and 18.2%, respectively (7). These results imply that both quantitative and qualitative components need to be considered to define HRPC for the prediction of future adverse events and the clinical relevance of the number of HRPC. Previous published data demonstrated the clinical relevance of 4 adverse plaque characteristics derived from coronary CTA (positive remodeling, low-attenuation plaque, napkin-ring sign, and spotty calcification). Based on those study results, we combined coronary CTA-derived qualitative and quantitative parameters to define HRPC in our study (12). In the current study, MLA and plaque burden showed higher predictive values for 5 years risk of VOCO than qualitative parameters. This result is in line with the previous ATHEROREMO-IVUS (European Collaborative Project on Inflammation and Vascular Wall Remodeling in Atherosclerosis–Intravascular Ultrasound) study (8), which showed a lack of prognostic impact in patients with TCFA without a significant amount of plaque burden (<70%), or the CONFIRM (COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter Registry), which showed prognostic importance of anatomic stenosis severity and extent measured by coronary CTA (25).
Recent studies have presented the association of both qualitative and quantitative plaque characteristics with per-vessel physiological stenosis severity. In a study by Driessen et al. (26), both qualitative and quantitative plaque characteristics were associated with the decrease in myocardial blood flow and FFR. Ahmadi et al. (27) also reported that both stenosis severity and necrotic core volume were the predictors of per-vessel FFR. In our study, lesions with FFR >0.90 showed about 11× lower probability to have ≥3 HRPC than those with FFR ≤0.80. Similarly, only 7.3% of lesions without HRPC were functionally significant (FFR ≤0.80) and conversely, 64.8% of lesions with ≥3 HRPC showed FFR ≤0.80. These results suggest a link between anatomic and physiological stenosis severity and plaque characteristics. However, further studies are needed to clarify whether significant anatomic or physiological stenoses induce the adverse transformation of plaque characteristics (12,15,28), or adverse plaque characteristics produce a higher pressure gradient across the stenosis, thereby influencing physiological stenosis severity (27).
Multifactorial influence of anatomic stenosis severity, plaque characteristics, and physiological stenosis severity to prognosis of patients with CAD
Previous studies showed that there are associations among quantitative lesion severity, qualitative plaque characteristics, and physiological lesion severity (7–9,21,26,27). However, those relationships can differ in each patient/lesion due to numerous patient- or lesion-specific parameters such as plaque contents, presence of positive or negative remodeling, lesion location, or variation in coronary flow and microvascular function.
It is well-known that both FFR (1,4,29) and HRPC (10,11,30) are associated with clinical outcomes as individual parameters. Nevertheless, their differential prognostic implications have not been well defined. The relevant question might be whether the presence of HRPC would pose additional risk for lesions with FFR ≤0.80, or more importantly, whether deferred lesion(s) with FFR >0.80 but with HRPC would pose excess risk of adverse clinical events. These questions are important, as the goal of revascularization or guideline-directed medical treatment is to reduce patient risk, and not merely alleviating the coronary stenosis (31,32).
In our study, there was no significant difference in the risk of VOCO according to number of HRPC among deferred lesions with FFR ≤0.80. Conversely, in deferred vessels with FFR >0.80, those with ≥3 HRPC showed a significantly higher risk of VOCO compared with those with <3 HRPC. Although several previous studies showed the safety of deferral of lesions with FFR >0.80, clinical events still occur in deferred vessels with FFR >0.80, and the FAME 2 (Fractional Flow Reserve versus Angiography for Multivessel Evaluation 2) study reported that the rate of primary endpoint was 15.7% in their registry cohort (FFR >0.80 and deferred revascularization) at 5-year follow-up (4). In our study, the risk of VOCO in deferred lesions with FFR >0.80 but ≥3 HRPC showed similar risk of VOCO with stented vessels with FFR ≤0.80, and it was significantly higher than that in deferred lesions with FFR >0.80 and <3 HRPC. These results are in line with previous trials in which a large number of events were caused by nonobstructive lesions (33), and suggest that the integration of HRPC into the current FFR-guided decision strategy would provide better risk stratification of patients, especially in deferred vessels based on FFR (Online Figure 6).
Whether revascularization for lesions with FFR >0.80 but with vulnerable plaque characteristics would reduce the risk of clinical events has not been clarified and the results of currently ongoing clinical studies (PROSPECT II [NCT02171065], PREVENT [Preventive Coronary Intervention on Stenosis With Functionally Insignificant Vulnerable Plaque] [NCT02316886], and FLAVOUR [Fractional FLow Reserve And IVUS for Clinical OUtcomes in Patients With InteRmediate Stenosis] [NCT02673424] ) may provide further insights into this issue. However, considering the relatively low incidence of lesions with ≥3 HRPC among deferred vessels with FFR >0.80 (39 of 553, 7.1%), the strategy of preventive revascularization based on plaque characteristics assessed by invasive imaging modalities should be considered in the context of procedure-related risk as well as cost-effectiveness in daily clinical practice. It will be interesting to see whether the adoption of CT-derived FFR and other hemodynamic parameters, such as wall shear stress and plaque stress, in addition to coronary CTA-derived plaque characteristics will produce the same results (12,35).
It is evident that neither functional significance nor HRPC alone could fully explain the risk of adverse clinical events in an individual lesion or patient. The current study results support the importance of comprehensive assessment of anatomic/physiological stenosis severity and plaque characteristics to better stratify patients with high risk of future clinical events.
This was a post hoc analysis of 3V-FFR-FRIENDS study, and the influence of potential selection bias could not be completely excluded. The number of vessels with FFR ≤0.80 was relatively small, and the primary outcome, VOCO, was not pre-specified initially as this was a post hoc analysis of a main study. However, all the events were independently adjudicated by the event adjudication committee. Second, investigators were not blinded to initial per-vessel FFR values. However, all events were adjudicated by an independent event adjudication committee, and most events were associated with objective evidence of disease progression. Third, the decision to perform PCI was at the discretion of the operators. Therefore, there is the possibility of selection bias, especially for deferred lesions with an FFR ≤0.80. In addition, the relatively small number of deferred lesions with FFR ≤0.80 precluded proper interpretation of the results for this subgroup. Fourth, intravascular imaging, such as intravascular ultrasound or optical coherence tomography, was not systematically performed. Fifth, as the current study included patients with relatively low-grade stenosis and relatively low SYNTAX score, further study is warranted to clarify whether the main results of the current study would be applied to the population with higher anatomical disease burden. Sixth, the difference of vessel-related events was mainly driven by ischemia-driven revascularization. As the current study included lesions with relatively low-grade stenosis, the rate of death or MI was relatively low, like previous studies with deferred lesions (4). Seventh, the current study did not include the quantification of coronary CTA plaque components such as necrotic core volume, or fibrous volume.
Physiological stenosis severity and the number of HRPC were closely related, and both components had significant association with the risk of clinical events. However, the prognostic implication of HRPC was different according to FFR. Integration of both physiological stenosis severity and plaque vulnerability would provide better prognostic stratification of patients than either of the individual components alone, especially in patients with FFR >0.80.
COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: Measurement of FFR and HRPC identified by coronary CTA are both useful prognostic indicators in patients undergoing percutaneous coronary interventions.
TRANSLATIONAL OUTLOOK: Further studies are needed to assess whether integration of physiological stenosis severity with features indicative of plaque vulnerability enhances prognostic stratification of patients compared with either component alone.
This study was supported by an unrestricted research grant from St. Jude Medical. The company had no role in study design, conduct, data analysis, or manuscript preparation. Dr. Joo Myung Lee has received a research grant from St. Jude Medical (Abbott Vascular) and Philips Volcano. Dr. Bon-Kwon Koo has received an institutional research grant from St. Jude Medical (Abbott Vascular) and Philips Volcano. All other authors have reported they have no relationships relevant to the contents of this paper to disclose.
Listen to this manuscript's audio summary by Editor-in-Chief Dr. Valentin Fuster on JACC.org.
- Abbreviations and Acronyms
- coronary artery disease
- computed tomography angiography
- fractional flow reserve
- hazard ratio
- high-risk plaque characteristics
- minimum lumen area
- percutaneous coronary intervention
- total aggregated plaque volume
- vessel-oriented composite outcome
- Received December 31, 2018.
- Revision received January 25, 2019.
- Accepted February 18, 2019.
- 2019 American College of Cardiology Foundation
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