- Email: [email protected]
Usefulness of Coronary Atheroma Burden to Predict Cardiovascular Events in Patients Presenting With Acute Coronary Syndromes (from the PROSPECT Study)
Usefulness of Coronary Atheroma Burden to Predict Cardiovascular Events in Patients Presenting With Acute Coronary Syndromes (from the PROSPECT Study) Peiren Shan, MDa,b,c, Gary S. Mintz, MDa, John A. McPherson, MDd, Bernard De Bruyne, MD, PhDe, Naim Z. Farhat, MDf, Steven P. Marso, MDg, Patrick W. Serruys, MD, PhDh, Gregg W. Stone, MDa,b, and Akiko Maehara, MDa,b,* We investigated the relation between overall atheroma burden and clinical events in the Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) study. In PROSPECT, 660 patients (3,229 nonculprit lesions with a plaque burden ‡40% and complete intravascular ultrasound data) were divided into tertiles according to baseline percent atheroma volume (PAV: total plaque/vessel volume). Patients were followed for 3.4 years (median); major adverse cardiac events (MACE: death from cardiac causes, cardiac arrest, myocardial infarction, or rehospitalization because of unstable or progressive angina) were adjudicated to either culprit or nonculprit lesions. Compared with patients in low or intermediate PAV tertiles, patients in the high PAV tertile had the greatest prevalence of plaque rupture and radiofrequency thin-cap fibroatheroma (VH-TCFA) and the highest percentage of necrotic core volume; they were also more likely to have high-risk lesion characteristics: ‡1 lesion with minimal luminal area £4 mm2, plaque burden >70%, and/or VH-TCFA. Three-year cumulative nonculprit lesion-related MACE was greater in the intermediate and high tertiles than in the low tertile (6.3% vs 14.7% vs 15.1%, low vs intermediate vs high tertiles, p [ 0.009). On Cox multivariable analysis, insulin-dependent diabetes (hazard ratio [HR] 3.98, p [ 0.002), PAV (HR 1.06, p [ 0.03), and the presence of ‡1 VH-TCFA (HR 1.80, p [ 0.02) were independent predictors of nonculprit MACE. In conclusion, increasing baseline overall atheroma burden was associated with more advanced, complex, and vulnerable intravascular ultrasound lesion morphology and independently predicted nonculprit lesion-related MACE in patients with acute coronary syndromes after successful culprit lesion intervention. Ó 2015 Elsevier Inc. All rights reserved. (Am J Cardiol 2015;-:-e-)
Previous intravascular ultrasound (IVUS) studies showed that baseline coronary atheroma burden was independently associated with subsequent adverse cardiovascular events in patients enrolled in progression/regression studies.1e3 The Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) study was a prospective, multicenter natural history study that used
3-vessel angiography and grayscale and radiofrequency (VH)-IVUS to characterize the coronary tree and the relation between specific atherosclerotic lesion characteristics and long-term follow-up events.4 Therefore, we performed a secondary, patient-level analysis using the data from PROSPECT to investigate the clinical impact of overall atheroma burden on clinical events, specifically in patients with acute coronary syndromes (ACS).
a Clinical Trials Center, Cardiovascular Research Foundation, New York, New York; bCenter for Interventional Vascular Therapy, Division of Cardiology, NewYork-Presbyterian Hospital/Columbia University Medical Center, New York, New York; cDepartment of Cardiology, The Key Laboratory of Cardiovascular Disease of Wenzhou, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang, China; dDivision of Cardiovascular Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee; eCardiovascular Center Aalst, OLV-Clinic, Aalst, Belgium; fNorth Ohio Heart Center/Elyria Memorial Hospital Regional Medical Center, Elyria, Ohio; gInterventional Cardiology Program, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; and hDepartment of Interventional Cardiology, Erasmus Medical Center, Rotterdam, The Netherlands. Manuscript received July 23, 2015; revised manuscript received and accepted August 20, 2015. See page 6 for disclosure information. *Corresponding author: Tel: (646) 434-4569; fax: (646) 434-4464. E-mail address: [email protected] (A. Maehara).
Methods
0002-9149/15/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2015.08.038
The design, major inclusion and exclusion criteria, end points, and definitions of the PROSPECT study have been described in detail.4e11 In brief, 697 patients with ACS underwent grayscale and VH-IVUS examination of the proximal 6 to 8 cm of the all 3 major epicardial coronary vessels after successful percutaneous coronary intervention of all lesions responsible for ACS events and any other planned interventions. Imaging was performed with a synthetic aperture array, 20-MHz, 3.2 Fr catheter (Eagle Eye; Volcano Corporation, Rancho Cordova, California) and motorized catheter pullback (0.5 mm/s). The study was approved by the institutional review board at each participating center, and all patients gave written informed consent. All baseline angiograms and IVUS images were prospectively analyzed at independent core laboratories www.ajconline.org
2
The American Journal of Cardiology (www.ajconline.org)
Table 1 Baseline characteristics Variable
Age (years) Men Body mass index (kg/m2) Any diabetes mellitus Insulin dependent Hypertension Hypercholesterolemia Current cigarette use Renal insufficiency* Family history of coronary artery disease Prior myocardial infarction Prior cardiac intervention Metabolic syndrome Framingham score Clinical presentation ST-segment elevation myocardial infarction Non-ST-segment elevation myocardial infarction Unstable angina Total cholesterol (mg/dL) High-density lipoprotein Low-density lipoprotein Triglycerides Fasting plasma glucose (mg/dL) Hemoglobin A1c (%) C-reactive protein (mg/L) Day 30 Day 180 Statin use Discharge 3 Years Aspirin use Discharge 3 Years Thienopyridine use Discharge
Tertile
p Value
Low (n ¼ 220)
Intermediate (n ¼ 220)
High (n ¼ 220)
56.9 (50.2, 65.2) 75.5% (166) 28.1 (25.6, 31.3) 14.2% (31) 2.3% (5) 47.0% (103/219) 41.5% (80/193) 44.2% (96/217) 6.8% (14/207) 45.5% (90) 9.7% (21) 7.7% (17) 45.3% (97/214) 7.0 (5.0, 9.0)
57.7 (50.0, 67.5) 74.1% (163) 28.4 (25.2, 31.6) 18.3% (40) 2.7% (6) 44.2% (96/217) 44.6% (90/202) 52.3% (114/218) 10.0% (21/210) 45.5% (90) 9.1% (20) 9.1% (20) 49.5% (105/212) 7.0 (5.0, 9.0)
60.4 (52.5, 67.9) 81.4% (179) 27.6 (24.8, 31.0) 19.1% (42) 3.2% (7) 48.6% (106/218) 48.5% (100/206) 46.8% (101/216) 12.6% (26/206) 44.9% (84/187) 13.2% (29) 15.5% (34) 50.0% (106/212) 7.0 (5.0, 9.0)
0.052 0.16 0.29 0.35 0.85 0.65 0.36 0.23 0.13 0.99 0.33 0.02 0.57 0.25
30.5% (67) 66.4% (146) 3.2% (7) 166.0 (138.5, 201.0) 38.6 (33.0, 45.0) 97.8 (79.0, 127.0) 119.0 (88.6, 169.0) 102.0 (90.0, 120.0) 5.7 (5.3, 6.1)
32.3% (71) 63.2% (139) 4.5% (10) 176.0 (153.8, 204.0) 38.6 (34.5, 46.0) 101.4 (82.2, 130.2) 127.0 (90.0, 177.1) 98.5 (90.0, 113.0) 5.8 (5.4, 6.2)
27.3% (60) 69.1% (152) 3.6% (8) 167.0(152.0, 197.0) 38.6(33.0, 48.0) 103.2 (78.6, 127.2) 125.0 (88.6, 177.1) 102.0 (90.0, 120.0) 5.8 (5.4, 6.2)
0.51 0.42 0.75 0.28 0.46 0.70 0.54 0.39 0.37
1.6 (0.7, 3.2) 1.3 (0.7, 2.5)
2.0 (0.8, 4.7) 1.8 (0.8, 3.6)
1.7 (0.9, 3.9) 1.4 (0.8, 2.7)
0.29 0.17
83.5% (182/218) 84.8% (145/171)
85.5% (188) 83.3% (155/186)
90.0% (198) 86.4% (165/191)
0.13 0.71
97.3% (214) 95.9% (165/172)
97.3% (214) 88.2% (164/186)
95.9% (211) 91.1% (174/191)
0.64 0.03
97.3% (214)
97.3% (214)
96.8% (213)
0.95
Values are median (interquartile range) or % (n/N). * Baseline estimated creatinine clearance 60 mL/min.
(Cardiovascular Research Foundation, New York, New York) without knowledge of future events. Angiographic quantitative and qualitative coronary angiography measures were performed using proprietary methodology modified from standard CMS software (version 7.0; Medis, Leiden, The Netherlands). Analyses included the major epicardial coronary arteries and all side branches >1.5 mm in diameter. As described previously, IVUS and VH-IVUS analyses were conducted using QCU-CMS software (Medis) for contouring, pcVH 2.1 software (Volcano Corporation) for contouring and data output, and proprietary software (qVH; Cardiovascular Research Foundation) for segmental qualitative and quantitative output.4e11 An IVUS nonculprit lesion was defined as plaque burden (PB) 40% involving 3 consecutive frames. Lesions were considered separate if there was a 5-mm-long segment with <40% PB between them. For every nonculprit lesion, the external elastic membrane (EEM) and lumen borders were detected at
w0.4-mm intervals and used to determine the EEM, lumen, and plaque þ media (EEM minus lumen) cross-sectional area (CSA) and volumes.12 The slice with the minimal lumen area (MLA) within each nonculprit lesion was identified and assessed. All nonculprit lesions were summed to generate the patient-level IVUS calculation of percent atheroma volume (PAV)1e3: P ðEEM area lumen areaÞ P PAV ¼ 100: EEM area A plaque rupture was defined as an intraplaque cavity that communicated with the lumen with an overlying residual fibrous cap fragment. Echolucent plaque contained an intraplaque zone of absent or low echogenicity surrounded by tissue of greater echodensity.13 VH-IVUS plaque components were color coded as dense calcium (white), necrotic core (red), fibrofatty (light green), or fibrous tissue (dark green) and reported as percentages of total
Coronary Artery Disease/Atheroma Burden Predicts CV Events
3
Table 2 Univariable and multivariable linear regression analysis for predictors of percent atheroma volume Variable
Univariable
b Coefficient (95% Confidence Interval) Men Age Prior cardiac intervention Insulin-dependent diabetes Hypercholesterolemia Hypertension High density lipoprotein Body mass index Metabolic syndrome
0.52 0.05 1.74 0.81 0.73 0.43 0.01 -0.06 0.51
(-0.25e1.28) (0.02e0.08) (0.71e2.77) (-1.17e2.78) (0.05e1.41) (-0.23e1.08) (-0.02e0.03) (-0.12e0.003) (-0.15e1.17)
Multivariable p Value
b Coefficient (95% Confidence Interval)
p Value
0.19 0.0007 0.001 0.43 0.04 0.20 0.63 0.04 0.13
0.79 (0.01e1.56) 0.05 (0.02e0.08) 1.51 (0.48e2.54)
0.046 0.0006 0.004
Table 3 Patient-level angiography and grayscale and VH-IVUS findings Variable
Tertile Low (n ¼ 220)
Quantitative coronary angiography Total length of angio non-culprit lesions (mm) Angiographic non-culprit lesions 3-vessel coronary artery disease Grayscale IVUS Echolucent plaque Plaque rupture Total length of IVUS non-culprit lesion (mm) Average EEM CSA (mm2) Average lumen CSA (mm2) Average plaqueþmedia CSA (mm2) Percent atheroma volume (%) VH-IVUS VH-TCFA lesions FA lesions Necrotic core volume (%) Dense calcium volume (%) Fibrous tissue volume (%) Fibrofatty volume (%) High-risk IVUS non-culprit characteristics per patient 1 lesion with MLA 4 mm2 1 lesion with MLA 4 mm2 and PB 70% 1 lesion with MLA 4 mm2 and VH-TCFA 1 lesion with PB 70% and VH-TCFA
15.9 (5.2, 28.7) 2.0 (1.0, 3.0) 20.7% (44/213) 5.9% (13) 7.7% (17) 54.8 (31.9, 82.2) 16.2 (13.8, 18.6) 8.9 (7.6, 10.2) 7.2 (6.2, 8.3) 45.7 (44.1, 46.7) n ¼ 212 0.0 (0.0, 1.0) 2.0 (1.0, 3.0) 10.0 (6.2, 15.7) 4.1 (2.2, 7.2) 60.2 (56.2, 64.7) 21.8 (15.3, 28.7) 36.4% (80) 3.2% (7) 16.4% (36) 3.25% (7)
Intermediate (n ¼ 220) 19.1 (8.1, 39.0) 2.0 (1.0, 4.0) 31.6% (68/215) 15.9% (35) 12.3% (27) 77.3 (46.2, 107.3) 16.1 (13.9, 18.5) 8.2 (7.0, 9.5) 7.8 (6.9, 9.2) 49.2 (48.4, 50.0) n ¼ 199 1.0 (0.0, 2.0) 3.0 (2.0, 4.0) 12.4 (7.7, 17.7) 5.2 (2.7, 8.8) 60.0 (55.8, 63.9) 20.0 (14.8, 25.8) 58.2% (128) 23.2% (51) 32.3% (71) 19.5% (43)
p Value High (n ¼ 220) 26.9 (12.3, 48.5) 3.0 (1.5, 5.0) 39.3% (86/219) 28.2% (62) 22.3% (49) 84.7 (59.8, 114.9) 16.1 (13.9, 18.6) 7.3 (6.3, 8.6) 8.7 (7.5, 10.1) 53.5 (52.1, 55.4) n ¼ 198 1.0 (0.0, 2.0) 3.0 (2.0, 4.0) 14.4 (9.2, 18.2) 6.2 (3.5, 9.8) 58.8 (53.6, 62.4) 18.4 (14.2, 25.1) 71.8% (158) 50.5% (111) 39.1% (86) 33.6% (74)
<0.0001 <0.0001 0.0001 <0.0001 <0.0001 <0.0001 0.91 <0.0001 <0.0001 <0.0001 0.001 <0.0001 <0.0001 <0.0001 0.01 0.01 <0.0001 <0.0001 <0.0001 <0.0001
Values are median (interquartile range) or % (n). CSA ¼ cross-sectional area; EEM ¼ external elastic membrane; FA ¼ fibroatheroma; IVUS ¼ intravascular ultrasound; MLA ¼ minimal luminal area; PB ¼ plaque burden; VH-TCFA ¼ virtual histology thin-cap fibroatheroma.
plaque volumes.11,14 Each lesion was further classified by VH-IVUS phenotype as previously reported. A fibroatheroma had >10% confluent necrotic core. If >30 of the necrotic core abutted the lumen in 3 consecutive frames, the fibroatheroma was classified as thin-cap fibroatheroma (VH-TCFA). All volumes were calculated using Simpson’s rule. The primary end point of the PROSPECT study was nonculprit lesion-related major adverse cardiac events (MACE): the composite of death from cardiac causes, cardiac arrest, myocardial infarction (MI), or rehospitalization because of unstable or progressive angina according to the Braunwald Unstable Angina Classification and the
Canadian Cardiovascular Society Angina Classification. Cardiac death was defined as death due to immediate cardiac cause and included unwitnessed death and death of unknown cause. An independent clinical events committee adjudicated all clinical events occurring during follow-up as because of recurrence at the original treated segments (“culprit” lesion), at a previously untreated coronary segments (“nonculprit” lesions), or at an undetermined segment location (“indeterminate” lesion) if follow-up angiography was not performed. Categorical variables were presented as number (%) and compared by the chi-square statistics or Fisher’s exact test
4
The American Journal of Cardiology (www.ajconline.org)
Table 4 Three-year non-culprit lesion-related major adverse cardiac events Variable
Composite major adverse cardiac events Cardiac death, arrest, or myocardial infarction Cardiac death Cardiac arrest Myocardial infarction Rehospitalization Due to unstable angina Due to progressive angina Revascularization
Tertile
p Value
Low Intermediate (n ¼ 220) (n ¼ 220)
High (n ¼ 220)
6.3% (12)
14.7% (30)
15.1% (31) 0.009
0.5% (1)
1.6% (3)
1.0% (2)
0.63
0 0 0.5% (1) 5.8% (11) 3.2% (6)
0 0 1.6% (3) 13.1% (27) 3.4% (7)
0 — 0 — 1.0% (2) 0.63 14.6% (30) 0.01 3.9% (8) 0.91
3.1% (6)
10.7% (22)
12.2% (25) 0.003
5.8% (11)
13.3% (27)
14.1% (29) 0.01
Events rate are shown as Kaplan-Meier estimate percentage (number of events).
Figure 1. Kaplan-Meier time-to-event curves for nonculprit lesion-related MACE in 660 patients with acute coronary syndromes. MACE included cardiac death, cardiac arrest, MI, or rehospitalization for unstable or progressive angina. The 3-year cumulative nonculprit lesion-related MACE rates are shown (Kaplan-Meier estimates).
(if there was an expected cell value <5). Continuous variables were reported as median with interquartile range and compared by Wilcoxon rank-sum tests. A multivariable linear regression analysis was conducted to identify independent predictors for PAV. Univariable predictors of PAV with p values <0.2 were entered into the multivariable model. Independent predictors and their regression coefficients were calculated. Outcomes were summarized as Kaplan-Meier percentages and numbers of events and compared using the log-rank tests. Multivariable Cox regression models were used to determine the independent predictor of MACE. The following variables were considered for the multivariable model using stepwise selection: age, male gender, total nonculprit lesion length, history of cardiac intervention, insulin-dependent diabetes, PAV, necrotic core volume, patients with 1 lesions with MLA
4 mm2, and those with 1 VH-TCFAs. The discriminatory capability of the PAV to identify patients who had cumulative 3-year events was assessed using the area under the receiver-operating characteristics curve. All statistical analyses were performed using SAS, version 9.2 (SAS Institute Inc., Cary, North Carolina). A p value <0.05 was considered to indicate statistical significance. Results Overall, 660 patients and 3,229 nonculprit lesions with complete grayscale IVUS data were identified and included in this study. Of these, 609 patients with 2,874 lesions had complete 3-vessel VH-IVUS data. The median PAV of the total cohort of 660 patients was 49.2% (interquartile range 46.7% to 52.1%). We divided the study patients into tertiles according to their baseline PAV: low tertile, PAV <47.7% (n ¼ 220); intermediate tertile 47.7% to <50.9% (n ¼ 220); and high tertile 50.9% (n ¼ 220). The baseline characteristics of the subjects are listed in Table 1. The highest PAV tertile group patients were likely to be older (56.9 years [50.2, 65.2] vs 57.7 years [50.0, 67.5] vs 60.4 years [52.5, 67.9], low vs intermediate vs high tertiles, p ¼ 0.052) and more likely to have had previous cardiac intervention (7.7% vs 9.1% vs 15.5%, p ¼ 0.02). The profiles of plasma glucose and lipids and the prevalence of cardiovascular risk factors, such as diabetes mellitus, hypertension, hypercholesterolemia, and current smoking, did not differ among these tertiles. Clinical presentations and Framingham risk scores were also similar. As listed in Table 2, by multivariable linear analysis, male gender (p ¼ 0.046), patient age (p ¼ 0.0006), and a history of previous cardiac intervention (p ¼ 0.004) were independently associated with baseline PAV. Angiographic and IVUS findings are presented in Table 3. By coronary angiography, patients with a larger PAV had a longer total length of nonculprit lesions, more nonculprit lesions, and a higher percentage of 3-vessel coronary artery disease. By grayscale IVUS analysis, patients in the highest tertile of PAV had a greater number of echolucent and ruptured plaques, a larger average plaque þ media CSA, and a smaller average lumen CSA (8.9 [7.6, 10.2] vs 8.2 [7.0, 9.5] vs 7.3 [6.3, 8.6] mm2, p <0.0001). By VH-IVUS analysis, patients with a larger PAV had more VH-TCFA lesions, fibroatheromas, and larger percentages of necrotic core and dense calcium volume but smaller percentages of fibrous and fibrofatty volume. The highest tertile PAV group patients were more likely to have high-risk IVUS characteristics, such as 1 lesion with an MLA 4 mm2 and a PB 70%, 1 lesion with an MLA 4 mm2 and a VH-TCFA, and 1 lesion with a PB 70% and a VH-TCFA. As listed in Table 4, 6.3% of low tertile, 14.7% of intermediate tertile, and 15.1% of high tertile patients experienced 3-year cumulative nonculprit lesion-related MACE (p ¼ 0.009) with most MACE driven by rehospitalization and coronary revascularization. The Kaplan-Meier analysis of the 3-year cumulative nonculprit lesion-related MACE rates, shown in the Figure 1, demonstrates that patients in the intermediate and high PAV tertiles were
Coronary Artery Disease/Atheroma Burden Predicts CV Events
5
Table 5 Cox hazard model analysis for non-culprit lesion-related major adverse cardiac events Variable
Univariable Hazard Ratio (95% Confidence Interval)
Men Age per year Prior cardiac intervention Insulin-dependent diabetes Total IVUS non-culprit lesion length (mm) Patient with plaque rupture Necrotic core volume (%) Patient with at least 1 lesion with minimum lumen area 4 mm2 Atheroma volume (%) Patient with at least 1 virtual histology thin-cap fibroatheroma
similar but had more MACE events compared with those in the low PAV tertile. The results of univariable and multivariable Cox hazard analyses for nonculprit lesion-related MACE are summarized in Table 5. After adjustment for gender, age, and variables with p <0.2 on univariable analysis, only insulindependent diabetes mellitus (hazard ratio [HR] 3.98; 95% confidence interval [CI] 1.58 to 10.04, p ¼ 0.002), PAV (HR 1.06; 95% CI 1.00 to 1.11, p ¼ 0.03), and the presence of 1 VH-TCFA (HR 1.80; 95% CI 1.08 to 2.99, p ¼ 0.02) were independent predictors of 3-year cumulative MACE. By receiver-operating characteristic analysis, baseline PAV predicted 3-year cumulative nonculprit lesion-related MACE moderately with a cut-off value 47.5% (area under the curve 0.61, 95% CI 0.57 to 0.65, p ¼ 0.0009). Discussion The main findings of this PROSPECT substudy were the following: (1) male gender, patient age, and a history of cardiac intervention were most likely to be associated with a greater baseline PAV; (2) increasing total coronary PAV was associated with more advanced and more complex grayscale and VH-IVUS lesion morphology; and (3) total coronary PAV was an independent predictor for future adverse clinical events in patients with ACS treated initially with primary percutaneous coronary intervention and subsequently with modern medical therapy. Rishi et al3 showed that male gender, hypertension, diabetes mellitus, and increasing patient age were associated with a larger baseline PAV, whereas baseline use of antiplatelet medications, greater body mass index, and higher high-density lipoprotein cholesterol were associated with a lower baseline PAV. The present study enrolled only patients presenting with ACS (and almost exclusively patients with ST-segment elevation myocardial infarction [STEMI] and without STEMI as listed in Table 1) who required primary percutaneous coronary intervention, whereas the study by Rishi et al included mostly stable angina patients. Not surprisingly and irrespective of the different inclusion criteria, these 2 studies showed that known coronary risk factors predicted quantitative measurements of coronary atherosclerosis. The finding in our present study that total coronary PAV was an independent predictor for future adverse clinical
0.77 1.00 1.94 3.46 1.01 1.33 1.04 1.61 1.08 1.71
(0.46e1.29) (0.98e1.02) (1.06e3.53) (1.40e8.58) (1.00e1.01) (0.73e2.42) (1.00e1.07) (0.99e2.61) (1.03e1.13) (1.03e2.84)
Multivariable p Value 0.32 0.90 0.03 0.004 0.02 0.35 0.03 0.053 0.003 0.04
Hazard Ratio (95% Confidence Interval)
p Value
1.74 (0.92e3.29) 3.98 (1.58e10.04)
0.09 0.002
1.06 (1.00e1.11) 1.80 (1.08e2.99)
0.03 0.02
events driven by coronary revascularization is consistent with previous studies.1e3,15 A pooled analysis from 6 clinical trials (4,137 patients) demonstrated that each SD increase in baseline PAV was associated with a 1.34-fold increase in the risk for MI, a 1.31-fold greater risk for coronary revascularization, and a 1.32-fold greater risk for MACE (death, MI, and coronary revascularization).1 A post hoc analysis of the Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin Versus Atorvastatin (SATURN) study using serial IVUS to measure coronary atheroma volume in 1,039 patients showed that baseline PAV predicted 2-year follow-up MACE (death, MI, stroke, coronary revascularization, hospitalization for unstable angina) despite achieving very low on-treatment low-density lipoprotein cholesterol levels with maximally intensive statin therapy.3 An analysis of 340 patients from 7 clinical trials showed that a greater baseline PAV of the left main segment was associated with future clinical events (death, MI, hospital stay for unstable angina, and coronary revascularization).2 Similar to the present report, the Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry study showed that extent and severity of coronary artery disease by coronary computed tomography angiography was associated with allcause mortality. Importantly, individuals without evident coronary artery disease had a very low mortality.15 There are some differences between these studies and the present study. In the earlier mentioned first 3 studies, only 1 mildly diseased vessel was selected for IVUS interrogation, whereas in the present PROSPECT study all imaged nonculprit lesions with PB 40% in the 3 major epicardial arteries were analyzed. Furthermore, the earlier mentioned 3 studies included mostly stable patients, whereas the present PROSPECT study included only unstable patients and they mostly were with and without STEMI. Finally, Puri et al16 showed that patients with ACS with a greater baseline PB had greater plaque regression even in the setting of intensive statin therapy. The major reason that total PAV predicts MACE is that a larger atheroma burden is associated with more high-risk lesions. Previous studies linked lesion PB to high-risk lesion-specific characteristics. One study of the relation between angiographic coronary stenosis and vulnerable plaque by optical coherence tomography showed that the
6
The American Journal of Cardiology (www.ajconline.org)
prevalence of a TCFA was twice as high in plaques with angiographic stenosis >70% compared with mild or moderate stenosis; moreover, TCFAs in patients with severe lesions had greater IVUS PB and more features of vulnerability, including microvessels, cholesterol crystals, thin fibrous cap, and positive remodeling.17 Another previous autopsy study demonstrated that healed ruptures were found in 61% of 142 hearts of men who sustained sudden coronary death, and multiple healed rupture sites with layering were frequently found in segments with acute and healed rupture,18 suggesting that silent plaque rupture is a form of wound healing that results in progression of atherosclerosis and luminal narrowing. The present study extends these observations by linking patient-specific overall atheroma burden to high-risk lesion-specific characteristics. Our present study was a cross-sectional analysis of plaques and not a serial IVUS imaging study. Although IVUS examination of the proximal 6 to 8 cm of the all 3 major epicardial coronary vessels was conducted and nonculprit lesions with PB 40% were analyzed, very distal lesions, mild lesions with PB <40%, and many side branches were not included in the present study. MACE rates in the present study were largely driven by the need for repeat coronary revascularization rather than “hard” clinical events, such as death and MI. Disclosures PROSPECT was funded by Abbott Vascular (Santa Clara, California) and Volcano Corporation (San Diego, California); Dr. Shan: Research grant from Boston Scientific (Marlborough, Massachusetts); Dr. Mintz has received consultant fees from ACIST (Eden Prairie, Minnesota), Boston Scientific, InfraReDx (Burlington, Massachusetts), and Volcano Corporation; Dr. McPherson has received consultant fees from Cardiox, Inc. (Redwood City, California), Healthwise, Inc. (Boise, Idaho), and Velomedix Inc. (Menlo Park, California); Dr. Maehara has received grant support from Boston Scientific and consultant fees from ACIST, Boston Scientific, and St. Jude Medical. All other authors have no conflicts of interest to declare. 1. Nicholls SJ, Hsu A, Wolski K, Hu B, Bayturan O, Lavoie A, Uno K, Tuzcu EM, Nissen SE. Intravascular ultrasound-derived measures of coronary atherosclerotic plaque burden and clinical outcome. J Am Coll Cardiol 2010;55:2399e2407. 2. Puri R, Wolski K, Uno K, Kataoka Y, King KL, Crowe TD, Kapadia SR, Tuzcu EM, Nissen SE, Nicholls SJ. Left main coronary atherosclerosis progression, constrictive remodeling, and clinical events. JACC Cardiovasc Interv 2013;6:29e35. 3. Puri R, Nissen SE, Shao M, Ballantyne CM, Barter PJ, Chapman MJ, Erbel R, Libby P, Raichlen JS, Uno K, Kataoka Y, Nicholls SJ. Coronary atheroma volume and cardiovascular events during maximally intensive statin therapy. Eur Heart J 2013;34:3182e3190. 4. Stone GW, Maehara A, Lansky AJ, de Bruyne B, Cristea E, Mintz GS, Mehran R, McPherson J, Farhat N, Marso SP, Parise H, Templin B, White R, Zhang Z, Serruys PW; PROSPECT Investigators. A prospective natural-history study of coronary atherosclerosis. N Engl J Med 2011;364:226e235. 5. Yun KH, Mintz GS, Farhat N, Marso SP, Taglieri N, Verheye S, Foster MC, Margolis MP, Templin B, Xu K, Dressler O, Mehran R, Stone GW, Maehara A. Relation between angiographic lesion severity, vulnerable plaque morphology and future adverse cardiac events (from the Providing Regional Observations to Study Predictors of Events in the Coronary Tree study). Am J Cardiol 2012;110:471e477.
6. Xu Y, Mintz GS, Tam A, McPherson JA, Iñiguez A, Fajadet J, Fahy M, Weisz G, De Bruyne B, Serruys PW, Stone GW, Maehara A. Prevalence, distribution, predictors, and outcomes of patients with calcified nodules in native coronary arteries: a 3-vessel intravascular ultrasound analysis from Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT). Circulation 2012;126:537e545. 7. Dohi T, Mintz GS, McPherson JA, de Bruyne B, Farhat NZ, Lansky AJ, Mehran R, Weisz G, Xu K, Stone GW, Maehara A. Non-fibroatheroma lesion phenotype and long-term clinical outcomes: a substudy analysis from the PROSPECT study. JACC Cardiovasc Imaging 2013;6:908e916. 8. Bourantas CV, Garcia-Garcia HM, Farooq V, Maehara A, Xu K, Généreux P, Diletti R, Muramatsu T, Fahy M, Weisz G, Stone GW, Serruys PW. Clinical and angiographic characteristics of patients likely to have vulnerable plaques: analysis from the PROSPECT study. JACC Cardiovasc Imaging 2013;6:1263e1272. 9. Inaba S, Mintz GS, Farhat NZ, Fajadet J, Dudek D, Marzocchi A, Templin B, Weisz G, Xu K, de Bruyne B, Serruys PW, Stone GW, Maehara A. Impact of positive and negative lesion site remodeling on clinical outcomes: insights from PROSPECT. JACC Cardiovasc Imaging 2014;7:70e78. 10. Xie Y, Mintz GS, Yang J, Doi H, Iñiguez A, Dangas GD, Serruys PW, McPherson JA, Wennerblom B, Xu K, Weisz G, Stone GW, Maehara A. Clinical outcome of nonculprit plaque ruptures in patients with acute coronary syndrome in the PROSPECT study. JACC Cardiovasc Imaging 2014;7:397e405. 11. Maehara A, Cristea E, Mintz GS, Lansky AJ, Dressler O, Biro S, Templin B, Virmani R, de Bruyne B, Serruys PW, Stone GW. Definitions and methodology for the grayscale and radiofrequency intravascular ultrasound and coronary angiographic analyses. JACC Cardiovasc Imaging 2012;5:S1eS9. 12. Mintz GS, Nissen SE, Anderson WD, Bailey SR, Erbel R, Fitzgerald PJ, Pinto FJ, Rosenfield K, Siegel RJ, Tuzcu EM, Yock PG. American College of Cardiology Clinical Expert Consensus Document on standards for acquisition, measurement and reporting of intravascular ultrasound studies (IVUS). A report of the American college of Cardiology Task Force on clinical Expert Consensus Documents. J Am Coll Cardiol 2001;37:1478e1492. 13. Pu J, Mintz GS, Biro S, Lee JB, Sum ST, Madden SP, Burke AP, Zhang P, He B, Goldstein JA, Stone GW, Muller JE, Virmani R, Maehara A. Insights into echo-attenuated plaques, echolucent plaques, and plaques with spotty calcification: novel findings from comparisons among intravascular ultrasound, near-infrared spectroscopy, and pathological histology in 2,294 human coronary artery segments. J Am Coll Cardiol 2014;63:2220e2233. 14. García-García HM, Mintz GS, Lerman A, Vince DG, Margolis MP, van Es GA, Morel MA, Nair A, Virmani R, Burke AP, Stone GW, Serruys PW. Tissue characterisation using intravascular radiofrequency data analysis: recommendations for acquisition, analysis, interpretation and reporting. EuroIntervention 2009;5:177e189. 15. Min JK, Dunning A, Lin FY, Achenbach S, Al-Mallah M, Budoff MJ, Cademartiri F, Callister TQ, Chang HJ, Cheng V, Chinnaiyan K, Chow BJ, Delago A, Hadamitzky M, Hausleiter J, Kaufmann P, Maffei E, Raff G, Shaw LJ, Villines T, Berman DS; CONFIRM Investigators. Age- and sex-related differences in all-cause mortality risk based on coronary computed tomography angiography findings results from the International Multicenter CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: an International Multicenter Registry) of 23,854 patients without known coronary artery disease. J Am Coll Cardiol 2011;58:849e860. 16. Puri R, Nissen SE, Shao M, Ballantyne CM, Barter PJ, Chapman MJ, Erbel R, Libby P, Raichlen JS, Uno K, Kataoka Y, Nicholls SJ. Antiatherosclerotic effects of long-term maximally intensive statin therapy after acute coronary syndrome: insights from Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin versus Atorvastatin. Arterioscler Thromb Vasc Biol 2014;34:2465e2472. 17. Tian J, Dauerman H, Toma C, Samady H, Itoh T, Kuramitsu S, Domei T, Jia H, Vergallo R, Soeda T, Hu S, Minami Y, Lee H, Yu B, Jang IK. Prevalence and characteristics of TCFA and degree of coronary artery stenosis: an OCT, IVUS, and angiographic study. J Am Coll Cardiol 2014;64:672e680. 18. Burke AP, Kolodgie FD, Farb A, Weber DK, Malcom GT, Smialek J, Virmani R. Healed plaque ruptures and sudden coronary death: evidence that subclinical rupture has a role in plaque progression. Circulation 2001;103:934e940.
Previous intravascular ultrasound (IVUS) studies showed that baseline coronary atheroma burden was independently associated with subsequent adverse cardiovascular events in patients enrolled in progression/regression studies.1e3 The Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) study was a prospective, multicenter natural history study that used
3-vessel angiography and grayscale and radiofrequency (VH)-IVUS to characterize the coronary tree and the relation between specific atherosclerotic lesion characteristics and long-term follow-up events.4 Therefore, we performed a secondary, patient-level analysis using the data from PROSPECT to investigate the clinical impact of overall atheroma burden on clinical events, specifically in patients with acute coronary syndromes (ACS).
a Clinical Trials Center, Cardiovascular Research Foundation, New York, New York; bCenter for Interventional Vascular Therapy, Division of Cardiology, NewYork-Presbyterian Hospital/Columbia University Medical Center, New York, New York; cDepartment of Cardiology, The Key Laboratory of Cardiovascular Disease of Wenzhou, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang, China; dDivision of Cardiovascular Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee; eCardiovascular Center Aalst, OLV-Clinic, Aalst, Belgium; fNorth Ohio Heart Center/Elyria Memorial Hospital Regional Medical Center, Elyria, Ohio; gInterventional Cardiology Program, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; and hDepartment of Interventional Cardiology, Erasmus Medical Center, Rotterdam, The Netherlands. Manuscript received July 23, 2015; revised manuscript received and accepted August 20, 2015. See page 6 for disclosure information. *Corresponding author: Tel: (646) 434-4569; fax: (646) 434-4464. E-mail address: [email protected] (A. Maehara).
Methods
0002-9149/15/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2015.08.038
The design, major inclusion and exclusion criteria, end points, and definitions of the PROSPECT study have been described in detail.4e11 In brief, 697 patients with ACS underwent grayscale and VH-IVUS examination of the proximal 6 to 8 cm of the all 3 major epicardial coronary vessels after successful percutaneous coronary intervention of all lesions responsible for ACS events and any other planned interventions. Imaging was performed with a synthetic aperture array, 20-MHz, 3.2 Fr catheter (Eagle Eye; Volcano Corporation, Rancho Cordova, California) and motorized catheter pullback (0.5 mm/s). The study was approved by the institutional review board at each participating center, and all patients gave written informed consent. All baseline angiograms and IVUS images were prospectively analyzed at independent core laboratories www.ajconline.org
2
The American Journal of Cardiology (www.ajconline.org)
Table 1 Baseline characteristics Variable
Age (years) Men Body mass index (kg/m2) Any diabetes mellitus Insulin dependent Hypertension Hypercholesterolemia Current cigarette use Renal insufficiency* Family history of coronary artery disease Prior myocardial infarction Prior cardiac intervention Metabolic syndrome Framingham score Clinical presentation ST-segment elevation myocardial infarction Non-ST-segment elevation myocardial infarction Unstable angina Total cholesterol (mg/dL) High-density lipoprotein Low-density lipoprotein Triglycerides Fasting plasma glucose (mg/dL) Hemoglobin A1c (%) C-reactive protein (mg/L) Day 30 Day 180 Statin use Discharge 3 Years Aspirin use Discharge 3 Years Thienopyridine use Discharge
Tertile
p Value
Low (n ¼ 220)
Intermediate (n ¼ 220)
High (n ¼ 220)
56.9 (50.2, 65.2) 75.5% (166) 28.1 (25.6, 31.3) 14.2% (31) 2.3% (5) 47.0% (103/219) 41.5% (80/193) 44.2% (96/217) 6.8% (14/207) 45.5% (90) 9.7% (21) 7.7% (17) 45.3% (97/214) 7.0 (5.0, 9.0)
57.7 (50.0, 67.5) 74.1% (163) 28.4 (25.2, 31.6) 18.3% (40) 2.7% (6) 44.2% (96/217) 44.6% (90/202) 52.3% (114/218) 10.0% (21/210) 45.5% (90) 9.1% (20) 9.1% (20) 49.5% (105/212) 7.0 (5.0, 9.0)
60.4 (52.5, 67.9) 81.4% (179) 27.6 (24.8, 31.0) 19.1% (42) 3.2% (7) 48.6% (106/218) 48.5% (100/206) 46.8% (101/216) 12.6% (26/206) 44.9% (84/187) 13.2% (29) 15.5% (34) 50.0% (106/212) 7.0 (5.0, 9.0)
0.052 0.16 0.29 0.35 0.85 0.65 0.36 0.23 0.13 0.99 0.33 0.02 0.57 0.25
30.5% (67) 66.4% (146) 3.2% (7) 166.0 (138.5, 201.0) 38.6 (33.0, 45.0) 97.8 (79.0, 127.0) 119.0 (88.6, 169.0) 102.0 (90.0, 120.0) 5.7 (5.3, 6.1)
32.3% (71) 63.2% (139) 4.5% (10) 176.0 (153.8, 204.0) 38.6 (34.5, 46.0) 101.4 (82.2, 130.2) 127.0 (90.0, 177.1) 98.5 (90.0, 113.0) 5.8 (5.4, 6.2)
27.3% (60) 69.1% (152) 3.6% (8) 167.0(152.0, 197.0) 38.6(33.0, 48.0) 103.2 (78.6, 127.2) 125.0 (88.6, 177.1) 102.0 (90.0, 120.0) 5.8 (5.4, 6.2)
0.51 0.42 0.75 0.28 0.46 0.70 0.54 0.39 0.37
1.6 (0.7, 3.2) 1.3 (0.7, 2.5)
2.0 (0.8, 4.7) 1.8 (0.8, 3.6)
1.7 (0.9, 3.9) 1.4 (0.8, 2.7)
0.29 0.17
83.5% (182/218) 84.8% (145/171)
85.5% (188) 83.3% (155/186)
90.0% (198) 86.4% (165/191)
0.13 0.71
97.3% (214) 95.9% (165/172)
97.3% (214) 88.2% (164/186)
95.9% (211) 91.1% (174/191)
0.64 0.03
97.3% (214)
97.3% (214)
96.8% (213)
0.95
Values are median (interquartile range) or % (n/N). * Baseline estimated creatinine clearance 60 mL/min.
(Cardiovascular Research Foundation, New York, New York) without knowledge of future events. Angiographic quantitative and qualitative coronary angiography measures were performed using proprietary methodology modified from standard CMS software (version 7.0; Medis, Leiden, The Netherlands). Analyses included the major epicardial coronary arteries and all side branches >1.5 mm in diameter. As described previously, IVUS and VH-IVUS analyses were conducted using QCU-CMS software (Medis) for contouring, pcVH 2.1 software (Volcano Corporation) for contouring and data output, and proprietary software (qVH; Cardiovascular Research Foundation) for segmental qualitative and quantitative output.4e11 An IVUS nonculprit lesion was defined as plaque burden (PB) 40% involving 3 consecutive frames. Lesions were considered separate if there was a 5-mm-long segment with <40% PB between them. For every nonculprit lesion, the external elastic membrane (EEM) and lumen borders were detected at
w0.4-mm intervals and used to determine the EEM, lumen, and plaque þ media (EEM minus lumen) cross-sectional area (CSA) and volumes.12 The slice with the minimal lumen area (MLA) within each nonculprit lesion was identified and assessed. All nonculprit lesions were summed to generate the patient-level IVUS calculation of percent atheroma volume (PAV)1e3: P ðEEM area lumen areaÞ P PAV ¼ 100: EEM area A plaque rupture was defined as an intraplaque cavity that communicated with the lumen with an overlying residual fibrous cap fragment. Echolucent plaque contained an intraplaque zone of absent or low echogenicity surrounded by tissue of greater echodensity.13 VH-IVUS plaque components were color coded as dense calcium (white), necrotic core (red), fibrofatty (light green), or fibrous tissue (dark green) and reported as percentages of total
Coronary Artery Disease/Atheroma Burden Predicts CV Events
3
Table 2 Univariable and multivariable linear regression analysis for predictors of percent atheroma volume Variable
Univariable
b Coefficient (95% Confidence Interval) Men Age Prior cardiac intervention Insulin-dependent diabetes Hypercholesterolemia Hypertension High density lipoprotein Body mass index Metabolic syndrome
0.52 0.05 1.74 0.81 0.73 0.43 0.01 -0.06 0.51
(-0.25e1.28) (0.02e0.08) (0.71e2.77) (-1.17e2.78) (0.05e1.41) (-0.23e1.08) (-0.02e0.03) (-0.12e0.003) (-0.15e1.17)
Multivariable p Value
b Coefficient (95% Confidence Interval)
p Value
0.19 0.0007 0.001 0.43 0.04 0.20 0.63 0.04 0.13
0.79 (0.01e1.56) 0.05 (0.02e0.08) 1.51 (0.48e2.54)
0.046 0.0006 0.004
Table 3 Patient-level angiography and grayscale and VH-IVUS findings Variable
Tertile Low (n ¼ 220)
Quantitative coronary angiography Total length of angio non-culprit lesions (mm) Angiographic non-culprit lesions 3-vessel coronary artery disease Grayscale IVUS Echolucent plaque Plaque rupture Total length of IVUS non-culprit lesion (mm) Average EEM CSA (mm2) Average lumen CSA (mm2) Average plaqueþmedia CSA (mm2) Percent atheroma volume (%) VH-IVUS VH-TCFA lesions FA lesions Necrotic core volume (%) Dense calcium volume (%) Fibrous tissue volume (%) Fibrofatty volume (%) High-risk IVUS non-culprit characteristics per patient 1 lesion with MLA 4 mm2 1 lesion with MLA 4 mm2 and PB 70% 1 lesion with MLA 4 mm2 and VH-TCFA 1 lesion with PB 70% and VH-TCFA
15.9 (5.2, 28.7) 2.0 (1.0, 3.0) 20.7% (44/213) 5.9% (13) 7.7% (17) 54.8 (31.9, 82.2) 16.2 (13.8, 18.6) 8.9 (7.6, 10.2) 7.2 (6.2, 8.3) 45.7 (44.1, 46.7) n ¼ 212 0.0 (0.0, 1.0) 2.0 (1.0, 3.0) 10.0 (6.2, 15.7) 4.1 (2.2, 7.2) 60.2 (56.2, 64.7) 21.8 (15.3, 28.7) 36.4% (80) 3.2% (7) 16.4% (36) 3.25% (7)
Intermediate (n ¼ 220) 19.1 (8.1, 39.0) 2.0 (1.0, 4.0) 31.6% (68/215) 15.9% (35) 12.3% (27) 77.3 (46.2, 107.3) 16.1 (13.9, 18.5) 8.2 (7.0, 9.5) 7.8 (6.9, 9.2) 49.2 (48.4, 50.0) n ¼ 199 1.0 (0.0, 2.0) 3.0 (2.0, 4.0) 12.4 (7.7, 17.7) 5.2 (2.7, 8.8) 60.0 (55.8, 63.9) 20.0 (14.8, 25.8) 58.2% (128) 23.2% (51) 32.3% (71) 19.5% (43)
p Value High (n ¼ 220) 26.9 (12.3, 48.5) 3.0 (1.5, 5.0) 39.3% (86/219) 28.2% (62) 22.3% (49) 84.7 (59.8, 114.9) 16.1 (13.9, 18.6) 7.3 (6.3, 8.6) 8.7 (7.5, 10.1) 53.5 (52.1, 55.4) n ¼ 198 1.0 (0.0, 2.0) 3.0 (2.0, 4.0) 14.4 (9.2, 18.2) 6.2 (3.5, 9.8) 58.8 (53.6, 62.4) 18.4 (14.2, 25.1) 71.8% (158) 50.5% (111) 39.1% (86) 33.6% (74)
<0.0001 <0.0001 0.0001 <0.0001 <0.0001 <0.0001 0.91 <0.0001 <0.0001 <0.0001 0.001 <0.0001 <0.0001 <0.0001 0.01 0.01 <0.0001 <0.0001 <0.0001 <0.0001
Values are median (interquartile range) or % (n). CSA ¼ cross-sectional area; EEM ¼ external elastic membrane; FA ¼ fibroatheroma; IVUS ¼ intravascular ultrasound; MLA ¼ minimal luminal area; PB ¼ plaque burden; VH-TCFA ¼ virtual histology thin-cap fibroatheroma.
plaque volumes.11,14 Each lesion was further classified by VH-IVUS phenotype as previously reported. A fibroatheroma had >10% confluent necrotic core. If >30 of the necrotic core abutted the lumen in 3 consecutive frames, the fibroatheroma was classified as thin-cap fibroatheroma (VH-TCFA). All volumes were calculated using Simpson’s rule. The primary end point of the PROSPECT study was nonculprit lesion-related major adverse cardiac events (MACE): the composite of death from cardiac causes, cardiac arrest, myocardial infarction (MI), or rehospitalization because of unstable or progressive angina according to the Braunwald Unstable Angina Classification and the
Canadian Cardiovascular Society Angina Classification. Cardiac death was defined as death due to immediate cardiac cause and included unwitnessed death and death of unknown cause. An independent clinical events committee adjudicated all clinical events occurring during follow-up as because of recurrence at the original treated segments (“culprit” lesion), at a previously untreated coronary segments (“nonculprit” lesions), or at an undetermined segment location (“indeterminate” lesion) if follow-up angiography was not performed. Categorical variables were presented as number (%) and compared by the chi-square statistics or Fisher’s exact test
4
The American Journal of Cardiology (www.ajconline.org)
Table 4 Three-year non-culprit lesion-related major adverse cardiac events Variable
Composite major adverse cardiac events Cardiac death, arrest, or myocardial infarction Cardiac death Cardiac arrest Myocardial infarction Rehospitalization Due to unstable angina Due to progressive angina Revascularization
Tertile
p Value
Low Intermediate (n ¼ 220) (n ¼ 220)
High (n ¼ 220)
6.3% (12)
14.7% (30)
15.1% (31) 0.009
0.5% (1)
1.6% (3)
1.0% (2)
0.63
0 0 0.5% (1) 5.8% (11) 3.2% (6)
0 0 1.6% (3) 13.1% (27) 3.4% (7)
0 — 0 — 1.0% (2) 0.63 14.6% (30) 0.01 3.9% (8) 0.91
3.1% (6)
10.7% (22)
12.2% (25) 0.003
5.8% (11)
13.3% (27)
14.1% (29) 0.01
Events rate are shown as Kaplan-Meier estimate percentage (number of events).
Figure 1. Kaplan-Meier time-to-event curves for nonculprit lesion-related MACE in 660 patients with acute coronary syndromes. MACE included cardiac death, cardiac arrest, MI, or rehospitalization for unstable or progressive angina. The 3-year cumulative nonculprit lesion-related MACE rates are shown (Kaplan-Meier estimates).
(if there was an expected cell value <5). Continuous variables were reported as median with interquartile range and compared by Wilcoxon rank-sum tests. A multivariable linear regression analysis was conducted to identify independent predictors for PAV. Univariable predictors of PAV with p values <0.2 were entered into the multivariable model. Independent predictors and their regression coefficients were calculated. Outcomes were summarized as Kaplan-Meier percentages and numbers of events and compared using the log-rank tests. Multivariable Cox regression models were used to determine the independent predictor of MACE. The following variables were considered for the multivariable model using stepwise selection: age, male gender, total nonculprit lesion length, history of cardiac intervention, insulin-dependent diabetes, PAV, necrotic core volume, patients with 1 lesions with MLA
4 mm2, and those with 1 VH-TCFAs. The discriminatory capability of the PAV to identify patients who had cumulative 3-year events was assessed using the area under the receiver-operating characteristics curve. All statistical analyses were performed using SAS, version 9.2 (SAS Institute Inc., Cary, North Carolina). A p value <0.05 was considered to indicate statistical significance. Results Overall, 660 patients and 3,229 nonculprit lesions with complete grayscale IVUS data were identified and included in this study. Of these, 609 patients with 2,874 lesions had complete 3-vessel VH-IVUS data. The median PAV of the total cohort of 660 patients was 49.2% (interquartile range 46.7% to 52.1%). We divided the study patients into tertiles according to their baseline PAV: low tertile, PAV <47.7% (n ¼ 220); intermediate tertile 47.7% to <50.9% (n ¼ 220); and high tertile 50.9% (n ¼ 220). The baseline characteristics of the subjects are listed in Table 1. The highest PAV tertile group patients were likely to be older (56.9 years [50.2, 65.2] vs 57.7 years [50.0, 67.5] vs 60.4 years [52.5, 67.9], low vs intermediate vs high tertiles, p ¼ 0.052) and more likely to have had previous cardiac intervention (7.7% vs 9.1% vs 15.5%, p ¼ 0.02). The profiles of plasma glucose and lipids and the prevalence of cardiovascular risk factors, such as diabetes mellitus, hypertension, hypercholesterolemia, and current smoking, did not differ among these tertiles. Clinical presentations and Framingham risk scores were also similar. As listed in Table 2, by multivariable linear analysis, male gender (p ¼ 0.046), patient age (p ¼ 0.0006), and a history of previous cardiac intervention (p ¼ 0.004) were independently associated with baseline PAV. Angiographic and IVUS findings are presented in Table 3. By coronary angiography, patients with a larger PAV had a longer total length of nonculprit lesions, more nonculprit lesions, and a higher percentage of 3-vessel coronary artery disease. By grayscale IVUS analysis, patients in the highest tertile of PAV had a greater number of echolucent and ruptured plaques, a larger average plaque þ media CSA, and a smaller average lumen CSA (8.9 [7.6, 10.2] vs 8.2 [7.0, 9.5] vs 7.3 [6.3, 8.6] mm2, p <0.0001). By VH-IVUS analysis, patients with a larger PAV had more VH-TCFA lesions, fibroatheromas, and larger percentages of necrotic core and dense calcium volume but smaller percentages of fibrous and fibrofatty volume. The highest tertile PAV group patients were more likely to have high-risk IVUS characteristics, such as 1 lesion with an MLA 4 mm2 and a PB 70%, 1 lesion with an MLA 4 mm2 and a VH-TCFA, and 1 lesion with a PB 70% and a VH-TCFA. As listed in Table 4, 6.3% of low tertile, 14.7% of intermediate tertile, and 15.1% of high tertile patients experienced 3-year cumulative nonculprit lesion-related MACE (p ¼ 0.009) with most MACE driven by rehospitalization and coronary revascularization. The Kaplan-Meier analysis of the 3-year cumulative nonculprit lesion-related MACE rates, shown in the Figure 1, demonstrates that patients in the intermediate and high PAV tertiles were
Coronary Artery Disease/Atheroma Burden Predicts CV Events
5
Table 5 Cox hazard model analysis for non-culprit lesion-related major adverse cardiac events Variable
Univariable Hazard Ratio (95% Confidence Interval)
Men Age per year Prior cardiac intervention Insulin-dependent diabetes Total IVUS non-culprit lesion length (mm) Patient with plaque rupture Necrotic core volume (%) Patient with at least 1 lesion with minimum lumen area 4 mm2 Atheroma volume (%) Patient with at least 1 virtual histology thin-cap fibroatheroma
similar but had more MACE events compared with those in the low PAV tertile. The results of univariable and multivariable Cox hazard analyses for nonculprit lesion-related MACE are summarized in Table 5. After adjustment for gender, age, and variables with p <0.2 on univariable analysis, only insulindependent diabetes mellitus (hazard ratio [HR] 3.98; 95% confidence interval [CI] 1.58 to 10.04, p ¼ 0.002), PAV (HR 1.06; 95% CI 1.00 to 1.11, p ¼ 0.03), and the presence of 1 VH-TCFA (HR 1.80; 95% CI 1.08 to 2.99, p ¼ 0.02) were independent predictors of 3-year cumulative MACE. By receiver-operating characteristic analysis, baseline PAV predicted 3-year cumulative nonculprit lesion-related MACE moderately with a cut-off value 47.5% (area under the curve 0.61, 95% CI 0.57 to 0.65, p ¼ 0.0009). Discussion The main findings of this PROSPECT substudy were the following: (1) male gender, patient age, and a history of cardiac intervention were most likely to be associated with a greater baseline PAV; (2) increasing total coronary PAV was associated with more advanced and more complex grayscale and VH-IVUS lesion morphology; and (3) total coronary PAV was an independent predictor for future adverse clinical events in patients with ACS treated initially with primary percutaneous coronary intervention and subsequently with modern medical therapy. Rishi et al3 showed that male gender, hypertension, diabetes mellitus, and increasing patient age were associated with a larger baseline PAV, whereas baseline use of antiplatelet medications, greater body mass index, and higher high-density lipoprotein cholesterol were associated with a lower baseline PAV. The present study enrolled only patients presenting with ACS (and almost exclusively patients with ST-segment elevation myocardial infarction [STEMI] and without STEMI as listed in Table 1) who required primary percutaneous coronary intervention, whereas the study by Rishi et al included mostly stable angina patients. Not surprisingly and irrespective of the different inclusion criteria, these 2 studies showed that known coronary risk factors predicted quantitative measurements of coronary atherosclerosis. The finding in our present study that total coronary PAV was an independent predictor for future adverse clinical
0.77 1.00 1.94 3.46 1.01 1.33 1.04 1.61 1.08 1.71
(0.46e1.29) (0.98e1.02) (1.06e3.53) (1.40e8.58) (1.00e1.01) (0.73e2.42) (1.00e1.07) (0.99e2.61) (1.03e1.13) (1.03e2.84)
Multivariable p Value 0.32 0.90 0.03 0.004 0.02 0.35 0.03 0.053 0.003 0.04
Hazard Ratio (95% Confidence Interval)
p Value
1.74 (0.92e3.29) 3.98 (1.58e10.04)
0.09 0.002
1.06 (1.00e1.11) 1.80 (1.08e2.99)
0.03 0.02
events driven by coronary revascularization is consistent with previous studies.1e3,15 A pooled analysis from 6 clinical trials (4,137 patients) demonstrated that each SD increase in baseline PAV was associated with a 1.34-fold increase in the risk for MI, a 1.31-fold greater risk for coronary revascularization, and a 1.32-fold greater risk for MACE (death, MI, and coronary revascularization).1 A post hoc analysis of the Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin Versus Atorvastatin (SATURN) study using serial IVUS to measure coronary atheroma volume in 1,039 patients showed that baseline PAV predicted 2-year follow-up MACE (death, MI, stroke, coronary revascularization, hospitalization for unstable angina) despite achieving very low on-treatment low-density lipoprotein cholesterol levels with maximally intensive statin therapy.3 An analysis of 340 patients from 7 clinical trials showed that a greater baseline PAV of the left main segment was associated with future clinical events (death, MI, hospital stay for unstable angina, and coronary revascularization).2 Similar to the present report, the Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry study showed that extent and severity of coronary artery disease by coronary computed tomography angiography was associated with allcause mortality. Importantly, individuals without evident coronary artery disease had a very low mortality.15 There are some differences between these studies and the present study. In the earlier mentioned first 3 studies, only 1 mildly diseased vessel was selected for IVUS interrogation, whereas in the present PROSPECT study all imaged nonculprit lesions with PB 40% in the 3 major epicardial arteries were analyzed. Furthermore, the earlier mentioned 3 studies included mostly stable patients, whereas the present PROSPECT study included only unstable patients and they mostly were with and without STEMI. Finally, Puri et al16 showed that patients with ACS with a greater baseline PB had greater plaque regression even in the setting of intensive statin therapy. The major reason that total PAV predicts MACE is that a larger atheroma burden is associated with more high-risk lesions. Previous studies linked lesion PB to high-risk lesion-specific characteristics. One study of the relation between angiographic coronary stenosis and vulnerable plaque by optical coherence tomography showed that the
6
The American Journal of Cardiology (www.ajconline.org)
prevalence of a TCFA was twice as high in plaques with angiographic stenosis >70% compared with mild or moderate stenosis; moreover, TCFAs in patients with severe lesions had greater IVUS PB and more features of vulnerability, including microvessels, cholesterol crystals, thin fibrous cap, and positive remodeling.17 Another previous autopsy study demonstrated that healed ruptures were found in 61% of 142 hearts of men who sustained sudden coronary death, and multiple healed rupture sites with layering were frequently found in segments with acute and healed rupture,18 suggesting that silent plaque rupture is a form of wound healing that results in progression of atherosclerosis and luminal narrowing. The present study extends these observations by linking patient-specific overall atheroma burden to high-risk lesion-specific characteristics. Our present study was a cross-sectional analysis of plaques and not a serial IVUS imaging study. Although IVUS examination of the proximal 6 to 8 cm of the all 3 major epicardial coronary vessels was conducted and nonculprit lesions with PB 40% were analyzed, very distal lesions, mild lesions with PB <40%, and many side branches were not included in the present study. MACE rates in the present study were largely driven by the need for repeat coronary revascularization rather than “hard” clinical events, such as death and MI. Disclosures PROSPECT was funded by Abbott Vascular (Santa Clara, California) and Volcano Corporation (San Diego, California); Dr. Shan: Research grant from Boston Scientific (Marlborough, Massachusetts); Dr. Mintz has received consultant fees from ACIST (Eden Prairie, Minnesota), Boston Scientific, InfraReDx (Burlington, Massachusetts), and Volcano Corporation; Dr. McPherson has received consultant fees from Cardiox, Inc. (Redwood City, California), Healthwise, Inc. (Boise, Idaho), and Velomedix Inc. (Menlo Park, California); Dr. Maehara has received grant support from Boston Scientific and consultant fees from ACIST, Boston Scientific, and St. Jude Medical. All other authors have no conflicts of interest to declare. 1. Nicholls SJ, Hsu A, Wolski K, Hu B, Bayturan O, Lavoie A, Uno K, Tuzcu EM, Nissen SE. Intravascular ultrasound-derived measures of coronary atherosclerotic plaque burden and clinical outcome. J Am Coll Cardiol 2010;55:2399e2407. 2. Puri R, Wolski K, Uno K, Kataoka Y, King KL, Crowe TD, Kapadia SR, Tuzcu EM, Nissen SE, Nicholls SJ. Left main coronary atherosclerosis progression, constrictive remodeling, and clinical events. JACC Cardiovasc Interv 2013;6:29e35. 3. Puri R, Nissen SE, Shao M, Ballantyne CM, Barter PJ, Chapman MJ, Erbel R, Libby P, Raichlen JS, Uno K, Kataoka Y, Nicholls SJ. Coronary atheroma volume and cardiovascular events during maximally intensive statin therapy. Eur Heart J 2013;34:3182e3190. 4. Stone GW, Maehara A, Lansky AJ, de Bruyne B, Cristea E, Mintz GS, Mehran R, McPherson J, Farhat N, Marso SP, Parise H, Templin B, White R, Zhang Z, Serruys PW; PROSPECT Investigators. A prospective natural-history study of coronary atherosclerosis. N Engl J Med 2011;364:226e235. 5. Yun KH, Mintz GS, Farhat N, Marso SP, Taglieri N, Verheye S, Foster MC, Margolis MP, Templin B, Xu K, Dressler O, Mehran R, Stone GW, Maehara A. Relation between angiographic lesion severity, vulnerable plaque morphology and future adverse cardiac events (from the Providing Regional Observations to Study Predictors of Events in the Coronary Tree study). Am J Cardiol 2012;110:471e477.
6. Xu Y, Mintz GS, Tam A, McPherson JA, Iñiguez A, Fajadet J, Fahy M, Weisz G, De Bruyne B, Serruys PW, Stone GW, Maehara A. Prevalence, distribution, predictors, and outcomes of patients with calcified nodules in native coronary arteries: a 3-vessel intravascular ultrasound analysis from Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT). Circulation 2012;126:537e545. 7. Dohi T, Mintz GS, McPherson JA, de Bruyne B, Farhat NZ, Lansky AJ, Mehran R, Weisz G, Xu K, Stone GW, Maehara A. Non-fibroatheroma lesion phenotype and long-term clinical outcomes: a substudy analysis from the PROSPECT study. JACC Cardiovasc Imaging 2013;6:908e916. 8. Bourantas CV, Garcia-Garcia HM, Farooq V, Maehara A, Xu K, Généreux P, Diletti R, Muramatsu T, Fahy M, Weisz G, Stone GW, Serruys PW. Clinical and angiographic characteristics of patients likely to have vulnerable plaques: analysis from the PROSPECT study. JACC Cardiovasc Imaging 2013;6:1263e1272. 9. Inaba S, Mintz GS, Farhat NZ, Fajadet J, Dudek D, Marzocchi A, Templin B, Weisz G, Xu K, de Bruyne B, Serruys PW, Stone GW, Maehara A. Impact of positive and negative lesion site remodeling on clinical outcomes: insights from PROSPECT. JACC Cardiovasc Imaging 2014;7:70e78. 10. Xie Y, Mintz GS, Yang J, Doi H, Iñiguez A, Dangas GD, Serruys PW, McPherson JA, Wennerblom B, Xu K, Weisz G, Stone GW, Maehara A. Clinical outcome of nonculprit plaque ruptures in patients with acute coronary syndrome in the PROSPECT study. JACC Cardiovasc Imaging 2014;7:397e405. 11. Maehara A, Cristea E, Mintz GS, Lansky AJ, Dressler O, Biro S, Templin B, Virmani R, de Bruyne B, Serruys PW, Stone GW. Definitions and methodology for the grayscale and radiofrequency intravascular ultrasound and coronary angiographic analyses. JACC Cardiovasc Imaging 2012;5:S1eS9. 12. Mintz GS, Nissen SE, Anderson WD, Bailey SR, Erbel R, Fitzgerald PJ, Pinto FJ, Rosenfield K, Siegel RJ, Tuzcu EM, Yock PG. American College of Cardiology Clinical Expert Consensus Document on standards for acquisition, measurement and reporting of intravascular ultrasound studies (IVUS). A report of the American college of Cardiology Task Force on clinical Expert Consensus Documents. J Am Coll Cardiol 2001;37:1478e1492. 13. Pu J, Mintz GS, Biro S, Lee JB, Sum ST, Madden SP, Burke AP, Zhang P, He B, Goldstein JA, Stone GW, Muller JE, Virmani R, Maehara A. Insights into echo-attenuated plaques, echolucent plaques, and plaques with spotty calcification: novel findings from comparisons among intravascular ultrasound, near-infrared spectroscopy, and pathological histology in 2,294 human coronary artery segments. J Am Coll Cardiol 2014;63:2220e2233. 14. García-García HM, Mintz GS, Lerman A, Vince DG, Margolis MP, van Es GA, Morel MA, Nair A, Virmani R, Burke AP, Stone GW, Serruys PW. Tissue characterisation using intravascular radiofrequency data analysis: recommendations for acquisition, analysis, interpretation and reporting. EuroIntervention 2009;5:177e189. 15. Min JK, Dunning A, Lin FY, Achenbach S, Al-Mallah M, Budoff MJ, Cademartiri F, Callister TQ, Chang HJ, Cheng V, Chinnaiyan K, Chow BJ, Delago A, Hadamitzky M, Hausleiter J, Kaufmann P, Maffei E, Raff G, Shaw LJ, Villines T, Berman DS; CONFIRM Investigators. Age- and sex-related differences in all-cause mortality risk based on coronary computed tomography angiography findings results from the International Multicenter CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: an International Multicenter Registry) of 23,854 patients without known coronary artery disease. J Am Coll Cardiol 2011;58:849e860. 16. Puri R, Nissen SE, Shao M, Ballantyne CM, Barter PJ, Chapman MJ, Erbel R, Libby P, Raichlen JS, Uno K, Kataoka Y, Nicholls SJ. Antiatherosclerotic effects of long-term maximally intensive statin therapy after acute coronary syndrome: insights from Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin versus Atorvastatin. Arterioscler Thromb Vasc Biol 2014;34:2465e2472. 17. Tian J, Dauerman H, Toma C, Samady H, Itoh T, Kuramitsu S, Domei T, Jia H, Vergallo R, Soeda T, Hu S, Minami Y, Lee H, Yu B, Jang IK. Prevalence and characteristics of TCFA and degree of coronary artery stenosis: an OCT, IVUS, and angiographic study. J Am Coll Cardiol 2014;64:672e680. 18. Burke AP, Kolodgie FD, Farb A, Weber DK, Malcom GT, Smialek J, Virmani R. Healed plaque ruptures and sudden coronary death: evidence that subclinical rupture has a role in plaque progression. Circulation 2001;103:934e940.