Author + information
- Received April 24, 2018
- Revision received August 17, 2018
- Accepted August 20, 2018
- Published online October 15, 2018.
- Anne-Sophie Schuurman, MSca,b,
- Maxime M. Vroegindewey, MSca,b,
- Isabella Kardys, MD, PhDa,b,
- Rohit M. Oemrawsingh, MDa,b,c,
- Hector M. Garcia-Garcia, MD, PhDd,
- Robert-Jan van Geuns, MD, PhDa,b,e,
- Evelyn Regar, MD, PhDa,b,f,
- Nicolas M. Van Mieghem, MD, PhDa,b,
- Jurgen Ligthart, RTa,
- Patrick W. Serruys, MD, PhDa,g,
- Eric Boersma, PhDa,b and
- K. Martijn Akkerhuis, MD, PhDa,b,∗ (, )@ErasmusMC
- aDepartment of Cardiology, Erasmus Medical Center, University Medical Center, Rotterdam, the Netherlands
- bCardiovascular Research School COEUR, Erasmus MC University Medical Center, Rotterdam, the Netherlands
- cDepartment of Cardiology, Amphia Hospital, Breda, the Netherlands
- dInterventional Cardiology, MedStar Washington Hospital Center, Washington, DC
- eDepartment of Cardiology, Radboud University Medical Center, Nijmegen, the Netherlands
- fDepartment of Cardiovascular Surgery, University Hospital Zurich, Zurich, Switzerland
- gImperial College, London, United Kingdom
- ↵∗Address for correspondence:
Dr. K. Martijn Akkerhuis, Erasmus Medical Center, Department of Cardiology, Rg-427, ‘s Gravendijkwal 230, 3015 CE Rotterdam, the Netherlands.
Background It has been shown that intravascular ultrasound (IVUS) and radiofrequency (RF-)IVUS can detect high-risk coronary plaque characteristics.
Objectives The authors studied the long-term prognostic value of (RF-)IVUS-derived plaque characteristics in patients with coronary artery disease (CAD) undergoing coronary angiography.
Methods From 2008 to 2011, (RF-)IVUS was performed in 1 nonstenotic segment of a nonculprit coronary artery in 581 patients undergoing coronary angiography for acute coronary syndrome (ACS) or stable angina. The pre-defined primary endpoint was major adverse cardiovascular events (MACE), defined as the composite of all-cause death, nonfatal ACS, or unplanned revascularization. Hazard ratios (HRs) were adjusted for age, sex, and clinical risk factors.
Results During a median follow-up of 4.7 years, 152 patients (26.2%) had MACE. The presence of a lesion with a minimal luminal area ≤4.0 mm2 was independently associated with MACE (HR: 1.49; 95% CI: 1.07 to 2.08; p = 0.020), whereas the presence of a thin-cap fibroatheroma lesion or a lesion with a plaque burden ≥70% on its own were not. Results were comparable when the composite endpoint included cardiac death instead of all-cause death. The presence of a lesion with a plaque burden of ≥70% was independently associated with the composite endpoint of cardiac death, nonfatal ACS, or unplanned revascularization after exclusion of culprit lesion-related events (HR: 1.66; 95% CI: 1.06 to 2.58; p = 0.026). Likewise, each 10-U increase in segmental plaque burden was independently associated with a 26% increase in risk of this composite endpoint (HR: 1.26 per 10-U increase; 95% CI: 1.03 to 1.52; p = 0.022).
Conclusions IVUS-derived small luminal area and large plaque burden, and not RF-IVUS–derived compositional plaque features on their own, predict adverse cardiovascular outcome during long-term follow-up in patients with CAD. (The European Collaborative Project on Inflammation and Vascular Wall Remodeling in Atherosclerosis–Intravascular Ultrasound Study [AtheroRemoIVUS]; NCT01789411)
- atherosclerotic burden
- cardiovascular outcome
- coronary plaque characteristics
- intravascular ultrasound
Patients with coronary artery disease (CAD) are at increased risk of recurrent adverse cardiovascular events, such as acute coronary syndromes (ACS) (1,2). Whereas coronary angiography (CAG) only yields a 2-dimensional silhouette of the lumen (3), grayscale intravascular ultrasound (IVUS) and radiofrequency (RF-)IVUS have shown to be able to identify high-risk coronary plaque characteristics within the coronary artery wall (4–7). Therefore, (RF-)IVUS may be useful to identify patients who are at increased risk of future adverse cardiovascular events (6–8). Autopsy studies suggest that an ACS is often caused by rupture or fissure of a thin-cap fibroatheroma (TCFA), a vulnerable coronary plaque containing a large lipid-rich necrotic core overlaid by a thin inflamed fibrous cap (9–12). Identification of this vulnerable coronary plaque phenotype by invasive imaging may therefore improve risk stratification and management of CAD patients.
To date, a few studies have investigated the prognostic value of (RF-)IVUS for adverse cardiovascular outcome (13,14). The PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) study demonstrated that (RF-)IVUS–derived high-risk plaque characteristics in the 3 major coronary arteries predict adverse cardiac events in patients admitted with ACS during long-term follow-up (13). However, patients with stable angina pectoris (SAP) were not included in the PROSPECT trial, and the number of endpoint events in that study was primarily driven by rehospitalizations. Our ATHEROREMO-IVUS (European Collaborative Project on Inflammation and Vascular Wall Remodeling in Atherosclerosis–Intravascular Ultrasound) study demonstrated that high-risk plaque characteristics, as derived by (RF-)IVUS in 1 nonstenotic segment of a nonculprit coronary artery, were predictive of adverse cardiovascular events in a broad spectrum of patients with CAD, including SAP, at 1-year follow-up (15). We now report the long-term (median 4.7 years) follow-up data.
Study design and population
The design of the ATHEROREMO-IVUS study has been described in detail elsewhere (15,16). Briefly, between 2008 and 2011, 581 patients undergoing diagnostic CAG or percutaneous coronary intervention (PCI) for ACS or SAP underwent (RF-)IVUS imaging of a nonculprit coronary artery in the Erasmus MC, Rotterdam, the Netherlands (15,16). Baseline (RF-)IVUS images were analyzed offline and were not used for patient care. Thereafter, patients were followed-up on adverse cardiovascular outcome.
The ATHEROREMO-IVUS study was approved by the medical ethics committee of the Erasmus MC and was performed in accordance with the Declaration of Helsinki. All patients provided written informed consent, which included approval for long-term follow-up. The ATHEROREMO-IVUS study was registered at ClinicalTrials.gov (NCT01789411).
Subsequent to the standard index CAG, (RF-)IVUS imaging was performed in a nonstenotic segment of a nonculprit coronary artery. The target segment in this nonculprit coronary artery was required to be at least 40 mm in length and without significant luminal narrowing (<50% stenosis) as assessed by online angiography. The order of preference for selection of the nonculprit vessel was: 1) left anterior descending artery; 2) right coronary artery; and 3) left circumflex artery (15,16). IVUS images were acquired by the Volcano s5/s5i Imaging system, including a Volcano Eagle Eye Gold IVUS catheter (20 MHz) that was automatically pulled back at a standard speed of 0.5 mm/s (Volcano Corp., San Diego, California). Grayscale- and RF-IVUS data were analyzed offline by an independent core laboratory (Cardialysis, Rotterdam, the Netherlands) using the pcVH 2.1 and qVH software (Volcano Corp., San Diego, California). The core laboratory was blinded to all other patient characteristics and outcome data.
Grayscale IVUS measurements included segmental plaque volume and plaque burden. The external elastic membrane and luminal borders were contoured for each frame (median interslice distance, 0.40 mm). Segmental plaque burden was defined as the plaque and media cross-sectional area divided by the external elastic membrane cross-sectional area. A coronary lesion was defined as a segment with a plaque burden of >40% in at least 3 consecutive frames. Using RF-IVUS analyses, compositional features of coronary lesions were classified as fibrous, fibro-fatty, necrotic core, or dense calcium (5,15,16). Confluent necrotic core or dense calcium, or the contact of necrotic core with the lumen, were assessed by visual examination performed independently by 3 investigators blinded to outcome data. Coronary lesions were further classified into 8 different lesion types (7,15,16). The mentioned criteria should be present in 3 consecutive frames for a lesion to be considered of a particular category. Three lesions, as identified by (RF-)IVUS, were considered as lesions associated with a high risk for subsequent adverse cardiac events: 1) TCFA lesion, defined as a lesion with the presence of >10% confluent necrotic core in direct contact with the lumen; 2) lesion with a plaque burden ≥70%; and 3) lesion with a minimal luminal area ≤4.0 mm2 (15).
Follow-up was reported by January 2015. The vital status of the patients was obtained from municipal civil registries. Subsequently, as a first screening method, follow-up questionnaires were sent to all living patients for identifying possible adverse events. Thereafter, hospital discharge letters were obtained if any hospitalization or possible event was reported. In patients who did not return the questionnaire, the local hospital records were investigated for possible events. Cause of death was obtained from hospital records, autopsy reports, or general practitioner notes.
The pre-defined primary endpoint consisted of major adverse cardiovascular events (MACE), defined as the composite of all-cause death, nonfatal ACS, or unplanned revascularization during long-term follow-up. In accordance with our previous studies on the prognostic value of (RF-)IVUS and near-infrared spectroscopy (NIRS) in this study population, we also performed a pre-defined analysis on the composite endpoint of cardiac death, nonfatal ACS, or unplanned revascularization. This analysis was performed based on the pathophysiological concept that (RF-)IVUS-derived plaque characteristics would hypothetically be more likely associated with (atherosclerotic-driven) cardiovascular events and not with definite noncardiac events (such as death because of malignancy). Similarly, an additional analysis was performed on this endpoint after exclusion of definite culprit lesion–related events. This exploratory analysis aimed to determine whether the atherosclerotic burden, as assessed in a single, nonculprit coronary artery segment, would reflect vulnerability of the entire coronary tree.
In accordance with the guidelines of the European Society of Cardiology, nonfatal ACS was defined as the clinical diagnosis of ST-segment or non–ST-segment elevation myocardial infarction or unstable angina (17,18). Unplanned coronary revascularization was defined as urgent revascularization for ACS or unplanned (i.e., not part of pre-planned multistage PCI) elective revascularization for progressive angina pectoris. Cardiac death was defined as any death due to proximate cardiac cause, unwitnessed death, or death of unknown cause.
Based on original source data of available coronary angiography and hospital records at the time of the event, the clinical event committee adjudicated (blinded to IVUS data) whether the event was related to the coronary site that had been treated during the index procedure (culprit lesion–related event) or as related to a coronary site that had not been treated during the index procedure (nonculprit lesion–related event). Events that were related to both the culprit lesion and a nonculprit site (e.g., revascularization of multiple vessels with coronary artery bypass grafting) were classified into both categories. When information was not sufficient to classify an event as either culprit lesion related or nonculprit lesion related, the event was classified as indeterminate (15).
Normally distributed continuous variables were reported as mean ± SD. Nonnormally-distributed variables were reported as median (interquartile range [IQR]). Categorical variables were reported as numbers and percentages.
Cumulative event rates were estimated by the Kaplan-Meier method, and differences between groups were evaluated by the log-rank test. Patients that were lost to follow-up were censored at the date of last contact. In case a patient had multiple events, the first event was counted for the composite endpoint.
The associations between (RF-)IVUS characteristics and study endpoints were further analyzed by Cox proportional hazard regression analysis. We applied multivariable Cox regression, with adjustment for age, sex, diabetes mellitus, hypertension, dyslipidemia, indication for CAG (ACS or SAP), history of myocardial infarction, history of PCI, history of coronary artery bypass grafting, history of peripheral artery disease, and PCI performed at index procedure. These potential confounders were chosen based on clinical relevance or their significant association with MACE in univariable Cox regression analysis. Hazard ratios (HRs) were reported with 95% confidence intervals (CIs).
In case the composite endpoint was defined with exclusion of culprit lesion–related events, the occurrence of a culprit lesion–related event as a first event during follow-up was not counted and the patient was not censored, as this patient is considered to be still at risk of a nonculprit lesion–related or indeterminate event during further follow-up. When the composite endpoint was based on nonculprit lesion–related or indeterminate events, patients were only censored in case a nonculprit lesion–related or indeterminate event occurred, if they were lost-to-follow-up, or if they died.
All statistical tests were 2-tailed, and p values <0.05 were considered statistically significant. Statistical analyses were performed using IBM SPSS statistics version 21.0 (IBM Corp., Armonk, New York).
The mean age of the patients was 61.6 ± 11.3 years; 75.6% were men, and 54.7% presented with an ACS (Table 1). Median segmental plaque burden was 39.1% (IQR: 30.0% to 46.4%), and plaque volume was 222.7 mm3 (IQR: 136.1 to 326.6 mm3). On the basis of (RF-)IVUS, 724 lesions were identified in 508 (87.4%) patients that had at least 1 lesion in the imaged segment, including 127 (17.5%) lesions with a plaque burden ≥70% in 124 (21.3%) patients, 206 (28.5%) lesions with a minimal luminal area ≤4.0 mm2 in 182 (31.3%) patients, and 74 (10.2%) lesions with both plaque characteristics in 74 (12.7%) patients. On the basis of RF-IVUS, 271 (37.4%) TCFA lesions were identified in 242 (41.7%) patients, including 71 (9.8%) TCFA lesions with a plaque burden ≥70% in 69 patients (11.9%), 61 (8.4%) TCFA lesions with a minimal luminal area ≤4.0 mm2 in 61 (10.5%) patients, and 35 (4.8%) TCFA lesions with both plaque characteristics in 35 (6.0%) patients.
Incidence of study endpoints
Median follow-up time was 4.7 years (IQR: 4.2 to 5.6 years). Follow-up questionnaires were sent to all 528 (90.9%) living patients and were completed by 86%. The pre-defined composite endpoint of all-cause death, nonfatal ACS, or unplanned revascularization occurred in 152 patients (26.2%) (Table 2). A total of 27 events were classified as definite culprit lesion–related, 72 as nonculprit lesion–related, and 53 as indeterminate events (Table 2). The composite endpoint of cardiac death, nonfatal ACS, or unplanned revascularization occurred in 125 patients (21.5%) (Table 2). The composite endpoint of cardiac death, nonfatal ACS, or unplanned revascularization after exclusion of definite culprit lesion–related events occurred in 98 patients (16.9%) (Table 2).
Association between (RF-)IVUS and MACE
The presence of a lesion with a minimal luminal area ≤4.0 mm2 was significantly and independently associated with MACE (cumulative MACE incidence when present: 33.9% vs. 22.2% when absent; adjusted HR: 1.49; 95% CI: 1.07 to 2.08; p = 0.020) (Table 3⇓). Furthermore, the presence of a TCFA lesion with a plaque burden ≥70% was significantly associated with MACE (cumulative MACE incidence when present: 37.7% vs. 24.6% when absent; adjusted HR: 1.73; 95% CI: 1.12 to 2.66; p = 0.013), while the presence of a TCFA lesion or a lesion with a plaque burden ≥70% itself was not independently associated with MACE (Table 3). After multivariable adjustment, segmental plaque burden and plaque volume remained no longer independently associated with MACE (Table 3). The results were essentially similar when definite culprit lesion–related events were excluded. Cox regression analysis with follow-up duration as a time-dependent variable showed that both the presence of a TCFA lesion and a lesion with a plaque burden ≥70% were strong predictors of MACE for the first year of follow-up, but not beyond 1-year follow-up. On the contrary, a lesion with a minimal luminal area ≤4.0 mm2 itself was not an independent predictor in the first year of follow-up (adjusted HR: 1.40; 95% CI: 0.83 to 2.34; p = 0.21), but did predict MACE beyond 1-year of follow-up (1-year to 5-year follow-up adjusted HR: 1.58; 95% CI: 1.04 to 2.40; p = 0.032). Results remained essentially similar when we performed an exploratory multivariable analysis applying the model used for the 1-year follow-up data (which comprised 6 variables instead of the 11 variables used in the model for the current analyses) (Table 4).
Association between (RF-)IVUS and the composite endpoint of cardiac death, nonfatal ACS, or unplanned revascularization
The presence of a lesion with a minimal luminal area ≤4.0 mm2 was also significantly and independently associated with a higher rate of the composite endpoint of cardiac death, nonfatal ACS, or unplanned revascularization (cumulative incidence of composite endpoint when present: 30.6% vs. 16.9% when absent; adjusted HR: 1.82; 95% CI: 1.26 to 2.64; p = 0.001) (Figure 1, Table 3). The same was true for TCFA lesions with a plaque burden ≥70% or a minimal luminal area ≤4.0 mm2 (Table 3). The highest risk, in terms of adjusted HRs, was among patients who had a TCFA lesion with both a plaque burden ≥70% and a minimal luminal area ≤4.0 mm2 (cumulative incidence of composite endpoint when present: 34.3% vs. 20.7% when absent; adjusted HR: 2.09; 95% CI: 1.12 to 3.89; p = 0.020) (Table 3).
These associations remained essentially unchanged after exclusion of culprit lesion–related events (Central Illustration, Table 3). In addition, a significant association was observed for the presence of a lesion with a plaque burden ≥70%, or its combination with a minimal luminal area ≤4.0 mm2, as well as for segmental plaque burden with each 10-U increase in segmental plaque burden resulting in a 26% increase in risk for occurrence of the composite endpoint of cardiac death, nonfatal ACS, or unplanned revascularization after exclusion of culprit lesion-related events (adjusted HR: 1.26 per 10-U increase; 95% CI: 1.03 to 1.52; p =0.022) (Central Illustration, Table 3).
This 4.7-year follow-up of the ATHEROREMO-IVUS study demonstrated that a small luminal area and a large plaque burden, but not RF-IVUS–derived compositional plaque features on their own, are independent determinants of (nonculprit lesion–related) adverse cardiac events in patients with CAD. The increased risk associated with a minimal luminal area ≤4.0 mm2 was not observed at 1-year follow-up (15), whereas the prognostic value of plaque burden ≥70% was confirmed, although statistical significance was not consistently present for all different composite endpoints. In contrast, the independent association between a TCFA lesion as an isolated characteristic and adverse outcome at 1 year did not persist during long-term follow-up. Still, patients with a TCFA lesion with a large plaque burden and/or a small luminal area were at increased risk.
In line with the PROSPECT study, we found that a lesion with a large plaque burden, small luminal area, or their combination with a TCFA lesion predicted adverse cardiovascular events in patients with CAD during long-term follow-up. In contrast to the PROSPECT and VIVA (Virtual histology Intravascular ultrasound in Vulnerable Atherosclerosis) studies, we did not find such an independent association for a TCFA lesion on its own (13,14). However, the results of our study and the PROSPECT study cannot be directly compared, because different definitions of study endpoints were used. In addition, PROSPECT only included patients admitted with ACS, and the study endpoint was primarily driven by rehospitalizations (13). Furthermore, in the VIVA study, only univariable regression analysis was performed due to the small number of endpoints (14). Importantly, in both the PROSPECT and VIVA studies, (RF-)IVUS was applied in all 3 major coronary arteries, whereas in our study only 1 single nonstenotic, nonculprit coronary artery segment was investigated (13,14).
We consider several possible explanations for the inconsistent association between the presence of a TCFA lesion as an isolated characteristic and the risk of adverse cardiac events during short-term versus long-term follow-up. First, controversy exists about the ability of RF-IVUS to correctly discern and identify the thin-cap and necrotic core as individual components of a TCFA lesion, due to the limitations with respect to spatial resolution (4,19). Second, the dynamic nature of TCFA lesions over time should be appreciated, because it has been described that particularly (proximal) TCFA lesions with a large plaque burden heal less often and might have a greater tendency to rupture (20). This may explain our finding that the presence of a TCFA lesion with a large plaque burden was associated with an increased risk for adverse cardiac events over 4.7-years of follow-up, whereas a TCFA lesion in itself was not. Third, previous studies have demonstrated that a lesion with a large plaque burden is a consistent and prevalent predictor for adverse cardiac outcome. However, whereas the atherosclerotic disease burden has been shown as a consistent and strong predictor of adverse cardiovascular events, no study has yet demonstrated that a TCFA lesion by itself independently predicts adverse cardiovascular outcome after adjustment for plaque burden and other potential confounders (13,14,21,22).
Our current study suggests that an RF-IVUS–derived TFCA lesion only has long-term prognostic value if accompanied with other high-risk plaque features. Therefore, this study further adds to the discussion of whether RF-IVUS offers incremental prognostic value to grayscale IVUS in terms of identification of high-risk coronary plaque phenotypes based on compositional features. In addition, our current study demonstrates for the first time that (RF-)IVUS plaque characteristics, as assessed in 1 nonstenotic segment of a nonculprit coronary artery, predicts adverse cardiovascular events in patients with CAD during long-term follow-up. A post hoc analysis did not show heterogeneity in the HR estimates in patients with ACS versus SAP. Moreover, the large number of endpoints allowed for a separate analysis with exclusion of culprit lesion-related endpoint events, with results that remained essentially unchanged. This indicates that (RF-)IVUS-derived plaque characteristics, as identified in 1 nonculprit coronary artery segment, may reflect atherosclerotic vulnerability of the entire coronary tree.
Recently, we have demonstrated that the lipid core burden index, as assessed by NIRS in a single nonculprit coronary artery segment, predicts adverse cardiovascular outcome, independent of clinical characteristics and IVUS-derived segmental plaque burden, over 4 years in CAD patients referred for CAG (23). In this context, a combined NIRS-IVUS catheter may improve the (long-term) prognostic value of intravascular imaging in patients with CAD (24).
First, the number of TCFA lesions might be overestimated by RF-IVUS because of the limited spatial resolution with respect to the identification of the thin cap of a TCFA lesion. Second, IVUS imaging was not repeated during follow-up. Therefore, we could not account for the potential dynamic nature of coronary lesions. It should also be noted that this study does not provide insight into how the individual lesion correlates to the adverse event. Third, the follow-up questionnaire was completed by 86% of the patients. Although, for the majority of the remaining patients, follow-up information was retrieved from our local hospital records, we cannot fully exclude the possibility that loss to follow-up was in part selective. However, our study reflects daily clinical practice, because patients admitted with both ACS and SAP were included. Besides, the current study represents a long-term study investigating the association between (RF-)IVUS-derived plaque characteristics and adverse cardiovascular outcome during 4.7-years of follow-up in patients with ACS or SAP, which represents the longest follow-up reported so far.
This study demonstrates that a small luminal area and a large plaque burden, and not RF-IVUS–derived compositional plaque features on their own, as assessed by (RF-)IVUS in 1 single nonstenotic segment of a nonculprit coronary artery, predict (nonculprit lesion–related) adverse cardiovascular outcomes during long-term follow-up over 4.7 years in patients with CAD. In contrast, this study did not show a single isolated imaging parameter as derived by RF-IVUS to be of long-term independent prognostic value.
COMPETENCY IN MEDICAL KNOWLEDGE: Greyscale and radiofrequency IVUS imaging can identify high-risk coronary atherosclerotic lesions responsible for acute ischemic events.
TRANSLATIONAL OUTLOOK: Future studies should define the proper role of invasive IVUS imaging in risk stratification and management of patients at risk of coronary events.
This work was supported by the European Commission, Seventh Framework Programme (FP7-HEALTH-2007-2.4.2-1). Dr. Ligthart has served as a consultant/speaker for Boston Scientific, Philips Volcano, and Abbott (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
- acute coronary syndrome
- coronary artery disease
- coronary angiography
- intravascular ultrasound
- major adverse cardiovascular events
- near-infrared spectroscopy
- percutaneous coronary intervention
- stable angina pectoris
- thin-cap fibroatheroma
- Received April 24, 2018.
- Revision received August 17, 2018.
- Accepted August 20, 2018.
- 2018 American College of Cardiology Foundation
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