Intravascular Ultrasound Imaging for Assessing Regression and Progression in Coronary Artery Disease




New imaging techniques have been used as surrogate markers of atherosclerotic burden to determine the effects of pharmacologic intervention. The aim of this study was to better determine potential utility and limitations of intravascular ultrasound (IVUS) imaging for assessing regression and progression in coronary artery disease. Medline was searched for randomized trials using IVUS for assessing regression and progression in coronary artery disease (through September 2009). A comparison of IVUS studies with large trials evaluating the same issue with clinical end points was performed. A total of 26 relevant reports (8,631 patients randomized [median 207.5], 5,794 patients analyzed [median 152], duration 2 weeks to 3.4 years [median 12 months]) were identified. Three frequently used IVUS variables were the focus of the analysis: (1) nominal change in plaque volume, (2) percentage change in plaque volume, and (3) nominal change in percentage plaque volume. These variables were presented in 21, 12, and 11 studies, respectively. The variables were the primary end points in 4, 5, and 4 studies, respectively. Large variance with a relatively small difference was noticed in all 3 variables. Fewer than half of the variables showed statistically significant differences in comparing groups. Comparison of IVUS studies with large trials evaluating the same issue with clinical end points showed consistent and inconsistent results. In conclusion, the current method of calculating plaque volume using IVUS seems logical, and some clinical outcomes trials have yielded some evidence. Future studies are needed to determine which IVUS variable is the best surrogate to determine the effects of pharmacologic intervention in patients with coronary artery disease.


The availability of several imaging techniques for use as surrogate markers of atherosclerotic burden has enabled the effects of pharmacologic intervention to be examined at the vascular level. These imaging modalities, which include angiography, B-mode ultrasonography, intravascular ultrasound (IVUS), magnetic resonance imaging, and computed tomography, differ in terms of method of assessment, sensitivity, and ease of use; these differences influence the applicability of the techniques to the assessment of atherosclerotic burden in clinical trial populations. In this review, we discuss the potential utility and limitations of IVUS imaging for assessing regression and progression in coronary artery disease (CAD). In addition, comparison of IVUS studies with large trials evaluating the same issue with clinical end points was performed.


Methods


We identified relevant English-language reports pertaining to IVUS studies for assessing regression and progression in CAD by searching the PubMed databases (through September 2009). The following search terms were used to identify primary reports: (1) reduce* or reduci* or reduct* or regres* or progress* or atheroma and (2) IVUS or “intravascular ultrasound” or “intravascular ultrasonography”. We used a highly sensitive search strategy for identifying all randomized controlled trials in Medline. Potentially relevant studies were retrieved and evaluated by 2 reviewers.


We included only peer-reviewed reports and did not search for unpublished data. Inclusion criteria for retrieved studies were IVUS volume analyses in native coronary arteries at baseline and follow-up. We excluded studies involving cardiac transplantation, peripheral arteries, bypass graft, and treated or adjacent (<5 mm) reference segments after percutaneous coronary intervention (PCI). Large-scale randomized controlled trials of the same interventions were identified by a Medline search using appropriate keywords.




Results


PubMed queries permitted the retrieval of 710 citations. On the basis of screening of titles and abstracts, 654 reports were excluded because of nonrandomization (n = 547), comparison of PCI devices or techniques such as drug-eluting stents (n = 75), transplantation-associated arteriosclerosis (n = 13), only study design (n = 10), duplicate study (n = 4), bypass graft (n = 2), IVUS not used (n = 2), and not human study (n = 1). After evaluation of full text of 56 reports, 29 were excluded because only treated or adjacent (<5 mm) reference segments after PCI were examined. One study was not included, because no volume analyses were reported. Finally, 26 published studies were selected.


Tables 1 to 3 summarize the 26 studies that met the inclusion criteria for this review. A total of 8,631 patients were randomized (median 207.5, range 26 to 1,240). A total of 5,794 patients were analyzed (median 152, range 20 to 910, median 78% of randomized patients). Study duration ranged from 2 weeks to 3.4 years (median 12 months). In all studies, patients underwent initial coronary angiography on the basis of clinical indication. Most studies included segments with <50% angiographic stenosis to eliminate patients in whom coronary surgery or intervention was likely within the follow-up period. In some studies, patients underwent PCI, and segments located >5 mm proximal or distal to the PCI site or in another artery were analyzed. Definition of the analyzed segment varied from study to study. Whereas analyzed segments were chosen at baseline in some studies, analyzed segments were selected after baseline and follow-up IVUS images were reviewed together on a display in other studies. IVUS examinations were analyzed at core laboratories in 15 studies.



Table 1

Included study characteristics























































































































































































































































Study Year Randomized Number Duration (years) Age (years) Men (%) Patients Used Drug
GAIN 2001 131 1 60 85 PCI, LDL-C >160/130 mg/dl Atorvastatin
CART-1 2003 305 0.5 59 81 PCI Probucol/AGI-1067
Nissen et al 2003 57 5/52 57 62 ACS, CAG Apo A-I Milano
REVERSAL 2004 654 1.5 56 72 CAG, LDL-C 125–210 mg/dl Pravastatin/atorvastatin
ESTABLISH 2004 70 0.5 61 86 ACS, PCI, LDL-C >150 mg/dl Atorvastatin
NORMALISE , ⁎ 2004 431 2 58 74 CAG, diastolic BP <100 mm Hg Amlodipine/enalapril
A-PLUS 2004 639 2 58 81 CAG, LDL-C <125 mg/dl Avasimibe
Petronio et al 2005 71 1 62 75 PCI, LDL-C <130 mg/dl Simvastatin
Kawasaki et al 2005 57 0.5 66 75 SAP, PCI, TC >220 mg/dl Pravastatin/atorvastatin
Yokoyama et al 2005 50 0.5 63 90 SAP, PCI, TC 170–230 mg/dl Atorvastatin
Tani et al 2005 82 0.5 63 76 SAP, PCI Pravastatin
ACTIVATE 2006 534 1.5 59 69 CAG Pactimibe
ILLUSTRATE 2007 1,188 2 57 71 CAG Torcetrapib
ERASE 2007 183 7/52 58 83 ACS, CAG Reconstituted HDL
PERSPECTIVE , ⁎ 2007 244 3 57 81 SAP, CAG Perindopril
REACH 2007 69 1 67 72 CAG, LDL-C 100–140 mg/dl Atorvastatin
CART-2 23 2008 1,240 † 1 61 80 PCI AGI-1067
STRADIVARIUS 2008 839 1.5 58 65 CAG, MS, or current smoker Rimonabant
PERISCOPE 2008 543 1.5 60 67 CAG, HbA 1c 6%–10% Pioglitazone
IBIS-2 2008 330 1 58 82 CAG Darapladib
Ogasawara et al 2009 54 0.5 68 65 SAP, PCI, DM Pioglitazone
ENCORE II 2009 272 ‡ 2 58 82 CAG Nifedipine
Hong et al 2009 100 ‡ 1 59 77 CAG? Simvastatin/rosuvastatin
JAPAN-ACS 2009 307 1 62 82 ACS, PCI, TC >220 mg/dl or LDL-C >140 mg/dl Atorvastatin/pitavastatin
Toi et al 2009 160 ‡ 3/52 62 76 ACS, PCI Atorvastatin/pitavastatin
PIGEON 2010 26 0.5 65 80 SAP, PCI, DM or IGT Pioglitazone

ACS = acute coronary syndromes; ACTIVATE = ACAT Intravascular Atherosclerosis Treatment Evaluation; A-PLUS = Avasimibe and Progression of Lesions on Ultrasound; Apo = apolipoprotein; CAG = coronary angiography; CART = Canadian Antioxidant Restenosis Trial; DM = diabetes mellitus; ENCORE = Evaluation of Nifedipine and Cerivastatin on Recovery of Coronary Endothelial Function; ERASE = Effect of rHDL on Atherosclerosis—Safety and Efficacy; ESTABLISH = Early Statin Treatment in Patients With Acute Coronary Syndrome: Demonstration of the Beneficial Effect on Atherosclerotic Lesions by Serial Volumetric Intravascular Ultra-Sound Analysis During Half a Year After Coronary Event; GAIN = German Atorvastatin Intravascular Ultrasound Study Investigators; HbA 1c = glycosylated hemoglobin; IBIS = Integrated Biomarker and Imaging Study; IGT = impaired glucose tolerance; JAPAN-ACS = Japan Assessment of Pitavastatin and Atorvastatin in Acute Coronary Syndrome; LDL-C = low-density lipoprotein cholesterol; MS = metabolic syndrome; NORMALISE = Norvasc for Regression of Manifest Atherosclerotic Lesions by Intravascular Sonographic Evaluation; PERISCOPE = Pioglitazone Effect on Regression of Intravascular Sonographic Coronary Obstruction Prospective Evaluation; PERSPECTIVE = Perindopril’s Prospective Effect on Coronary Atherosclerosis by Angiography and Intravascular Ultrasound Evaluation; PIGEON = Effects of Pioglitazone on Coronary Atherosclerotic Plaques of Patients With Impaired Glucose Tolerance or Type 2 Diabetes Mellitus: A Randomized, Open Labeled, Prospective Study; REACH = Randomized Evaluation of Atorvastatin in Patients With Coronary Heart Disease; REVERSAL = Reversal of Atherosclerosis With Aggressive Lipid Lowering; rHDL = reconstituted high-density lipoprotein; SAP = stable angina pectoris; STRADIVARIUS = Strategy to Reduce Atherosclerosis Development Involving Administration of Rimonabant: The Intravascular Ultrasound Study; TC = total cholesterol.

⁎ IVUS substudy.


† Study was modified.


‡ Unclear (only analyzed number reported).



Table 2

Included study characteristics
















































































































Study Lesion Analyzed Length (mm)
GAIN DS <50%; >10 mm proximal to the PCI site or another artery; plaque thickness >0.3 mm 11.7 ± 6.5
CART-1 Most normal looking cross section 5–12 mm proximal to the PCI site 5
Nissen et al 20% <DS <50% 49.4 (30–80)
REVERSAL 20% <DS <50% >30
ESTABLISH Non-PCI site (>5 mm proximal or distal to the PCI site) 8.63 ± 1.97
NORMALISE , ⁎ 20% <DS <50% >30
A-PLUS 20% <DS <50% 30
Petronio et al LA >4.0 mm 2 , >1 cm in length, >1 cm far from stent edges, and absence of calcifications covering >90% >10
Kawasaki et al Mild or moderate stenosis, >20 mm from the intervention site or another coronary artery 18
Yokoyama et al DS <50%; plaques within the arterial segment 10 mm proximal of the PCI-targeted area were excluded 10
Tani et al Insignificantly narrowed side branches >10 mm from the angioplasty site C 6.8 ± 4.3; P 6.5 ± 3.6
ACTIVATE 20% <DS <50%; vessel could not have undergone revascularization >30
ILLUSTRATE 20% <DS <50% >40
ERASE DS >20% 30
PERSPECTIVE , ⁎ Non-infarct-related or percutaneously treated vessel C 31 ± 15; A 31 ± 14
REACH DS <50%; plaque thickness >0.5 mm C 10.0 ± 6.0; A 10.8 ± 6.4
CART-2 DS <50%; proximal 4 cm of that non-PCI target artery; reference >2.5 mm; without thrombus 30
STRADIVARIUS 20% <DS <50% >30
PERISCOPE 20% <DS <50% >40
IBIS-2 DS <50% >40
Ogasawara et al Focal site (25%–75% stenosis) of PCI-related vessel; >10 mm away from the PCI target area C 10.3 ± 5.0; P 9.5 ± 4.5
ENCORE II LCA; <40% area stenosis and no vasodilation on acetylcholine infusion NA
Hong et al DS <50%; plaque burden <0.75, 1-mm interval centered on the minimal LA 10
JAPAN-ACS Non-PCI site (>5 mm proximal or distal to the PCI site) A 7.3 ± 3.1; P 6.1 ± 2.8
Toi et al <50%; RVD >3 mm; 5–15 mm; distance from the PCI site >5 mm 7.7 ± 2.1
PIGEON DS <50%; >10 mm proximal/distal to the PCI site; echolucent plaques 10

A = atorvastatin; C = control; DS = diameter stenosis; LA = luminal area; LCA = left coronary artery; RVD = reference vessel diameter; P = pravastatin, pioglitazone, or pitavastatin. Other abbreviations as in Table 1 .

⁎ IVUS substudy.



Table 3

Included study characteristics






































































































































































Study Design Blind Primary EP Primary EP Met
GAIN M Open label Absolute and percentage changes in plaque volume and plaque echogenicity Partially met †
CART-1 M Double Minimal LA Met †
Nissen et al M Double Serial change in percent atheroma volume in combined ETC-216 group Met †
REVERSAL M Double Percentage change in total atheroma volume Met
ESTABLISH S Open label Percent change in plaque volume Met
NORMALISE , ⁎ M Double Cardiovascular events for amlodipine versus placebo Unmet †
A-PLUS M Double Change in plaque volume Unmet
Petronio et al S Open label QCA variables; neointima within stent Unmet †
Kawasaki et al S Open label Not defined
Yokoyama et al S Open label Not defined
Tani et al S Open label Not defined
ACTIVATE M Double Change in percentage atheroma volume Unmet
ILLUSTRATE M Double Change in percentage atheroma volume Unmet
ERASE M Double Percentage change in atheroma volume Unmet
PERSPECTIVE , ⁎ M Double QCA variables Unmet †
REACH M Open label Absolute changes in plaque volume Met
CART-2 M Double Change in plaque volume (initially restenosis) Unmet
STRADIVARIUS M Double Change in percentage atheroma volume Unmet
PERISCOPE M Double Change in percentage atheroma volume Met
IBIS-2 M Double Coronary atheroma deformability and C-reactive protein Unmet †
Ogasawara et al S Open label Adiponectin; VH-IVUS parameters Partially met †
ENCORE II M Double Acetylcholine-induced coronary vascular response Met †
Hong et al S Open label Not defined
JAPAN-ACS M Open label Percentage change in coronary plaque volume Met ‡
Toi et al S Open label Not defined
PIGEON S Open label Not defined

EP = end point; M = multicenter; QCA = quantitative coronary angiographic; S = single center; VH = virtual histology. Other abbreviations as in Table 1 .

⁎ IVUS substudy.


† Not IVUS variables examined in this study.


‡ Noninferiority.



Eleven studies examined statins (of these, 5 compared 2 different statins), 3 antihypertensive drugs, 3 antidiabetic drugs, 3 drugs modifying high-density lipoprotein, 2 lipid-lowering drugs other than statins, 2 antioxidants, 1 antiobesity drugs, and 1 other drugs. Except for 1 noninferiority trial, superiority design was used in these trials. Two studies were substudies of larger studies. Of 26 studies, 13 studies were funded by for-profit organizations such as pharmaceutical companies. In most studies, mechanically rotating transducers were used, except in 5 studies in which electronically switched multiple-element array systems were used.


We focused on 3 frequently used IVUS variables: (1) absolute or nominal change in plaque or atheroma volume, (2) percentage change in plaque or atheroma volume, and (3) absolute or nominal change in percentage plaque or atheroma volume. These variables were presented in 21, 12, and 11 studies (or could be calculated in 2, 0, and 2), respectively ( Tables 4 and 5 ). In 4, 5, and 4 studies, the variables were the primary end points. Percentage plaque or atheroma volume was defined as (external elastic membrane (EEM) volume − luminal volume)/EEM volume. In 5 studies, normalized plaque or atheroma volume was used to standardize for different analyzed length, and absolute or nominal change in plaque or atheroma volume in the most diseased 10-mm subsegment was examined.



Table 4

Intravascular ultrasound variables





















































































































































































































































































































































































































































































































































































































































































Study Treatment Randomized Number Analyzed Number Absolute Change in PV/TAV (mm 3 ) p Value Percentage Change in PV/TAV p Value # Change in Percentage PV/TAV p Value ⁎⁎
GAIN Excluding atorvastatin 66 51 9.6 ± 28.1 ‡ 11.8 ± 31.0 ‡
Atorvastatin 20 to 80 mg 65 48 1.2 ± 30.4 0.19 2.5 ± 24.9 0.14
CART-1 8 Placebo 61 42 −2.7 ± 14.4
Probucol 60 48 −2.2 ± 14.8
AGI-1067 70 mg 59 41 −2.5 ± 14.6
AGI-1067 140 mg 64 38 −7.3 ± 14.5 0.14
AGI-1067 280 mg 61 42 −3.1 ± 17.2 0.08
Nissen et al Placebo 12 11 −2.9 ± 23.3 0.14 ± 3.09
ETC-216 15 mg/kg 23 21 −15.1 ± 50.6 −1.29 ± 3.48
ETC-216 45 mg/kg 22 15 −12.6 ± 15.3 −0.73 ± 2.75
Combined 45 36 −14.1 ± 39.5 0.18 −1.06 ± 3.17 0.29
REVERSAL Pravastatin 40 mg 329 249 5.1 ± 31 5.4 ± 20 ‡ 1.9 ± 4.9
Atorvastatin 80 mg 328 253 −0.4 ± 32 0.02 4.1 ± 30 0.02 0.6 ± 5.1 0.001
ESTABLISH Control 35 24 4.2 ± 8.6 8.7 ± 14.9 ‡
Atorvastatin 20 mg 35 24 −8.3 ± 9.0 0.0001 −13.1 ± 12.8 0.0001
NORMALISE Placebo 144 95 1.3 ± 4.4
Amlodipine 5 mg 141 91 0.5 ± 3.9 0.12
Enalapril 10 mg 146 88 0.8 ± 3.7 0.32
A-PLUS Placebo 154 109 −2.5 ± 26.6 ‡ −0.1 ± 12.7 0.3 ± 3.4
Avasimibe 50 mg 157 108 5.1 ± 30.0 0.17 3.6 ± 16.1 0.16 0.7 ± 3.6 0.47
Avasimibe 250 mg 164 98 1.2 ± 24.2 0.37 1.2 ± 12.8 0.56 0.7 ± 3.7 0.47
Avasimibe 750 mg 164 117 1.9 ± 33.1 0.37 1.0 ± 14.7 0.56 1.0 ± 3.7 0.47
Combined 485 323 2.8 ± 29.5 1.9 ± 14.6 0.8 ± 3.6
Petronio et al Control 35 26 9 ± 9
Simvastatin 20 mg 36 30 −10 ± 8 0.001
Kawasaki et al Control 18 17 0 † 0 1.6 †
Pravastatin 20 mg 19 17 −1.6 † NA −1 NA 0.2 † NA
Atorvastatin 20 mg 20 18 −3.8 † NA −2 NA −3.2 † NA
Yokoyama et al Control 25 22 −2 †
Atorvastatin 10 mg 25 20 −3.9 † NA −3.2 NA
Tani et al Control 28 23 0.5 ± 2.1 1.1 ± 4.6
Pravastatin 5 to 20 mg 54 52 −7.8 ± 13 0.01 −14 ± 23 0.05
ACTIVATE Placebo 268 202 −5.6 (1.47) 0.59 (0.25) ‡
Pactimibe 100 mg 266 206 −1.3 (1.47) 0.03 0.69 (0.25) 0.77
ILLUSTRATE Atorvastatin 10 to 80 mg + placebo 597 446 −6.3 ± 22.2 0.19 ± 2.83 ‡
Atorvastatin + torcetrapib 60 mg 591 464 −9.4 ± 21 0.02 0.12 ± 2.99 0.72
ERASE Placebo 60 47 −2.33 (−9.41 to 3.31) −1.62 (−5.95 to 1.94) ‡
CSL-111 40 mg/kg ⁎ 111 89 −5.34 (−9.11 to 2.25) 0.39 −3.41 (−6.55 to 1.88) 0.48
PERSPECTIVE Placebo 117 69 −4 ± 37
Perindopril 8 mg 127 75 −2 ± 55 NS
REACH Control 36 32 7.6 ± 10.3 ‡ 3 †
Atorvastatin 10 to 20 mg 33 26 −1.4 ± 11.6 0.01 −2 † NA
CART-2 Placebo 312 49 −0.6 ± 13.4 ‡ −0.4 ± 7.0 0.5 ± 2.5
Combined ∥ 928 183 −3.4 ± 14.5 0.12 −1.5 ± 8.2 0.32 0.5 ± 2.3 0.73
STRADIVARIUS Placebo 417 341 0.88 (0.97) 0.51 (0.15) ‡
Rimonabant 20 mg 422 335 −2.2 (0.98) 0.03 0.25 (0.15) 0.22
PERISCOPE Glimepiride 2 to 4 mg 273 181 −1.5 (−4.50 to 1.54) 0.73 (0.33 to 1.12) ‡
Pioglitazone 30 to 45 mg 274 179 −5.5 (−8.67 to −2.38) 0.06 −0.16 (−0.57 to 0.25) 0.002
IBIS-2 Placebo 155 143 −4.9 ± 32.7
Darapladib 160 mg 175 118 −5.0 ± 28.0 0.95
Ogasawara et al Control 27 24 1.2 ± 19.8 −0.2 ± 5.8
Pioglitazone 15 mg 27 22 3.9 ± 30.4 0.63 1.7 ± 6.6 0.14
ENCORE II Placebo 132 96 § −0.5 (−7.3 to 6.4) 0.84 3.2 (−1.9 to 8.3)
Nifedipine GITS 30 to 60 mg 140 97 § 0.5 (−6.5 to 7.5) 0.84 5.0 (−1.3 to 11.2) 0.66
Hong et al Simvastatin 20 mg 50 50 § −1.8 ± 5.7
Rosuvastatin 10 mg 50 50 § −3.6 ± 7.2 0.16
JAPAN-ACS Atorvastatin 20 mg 154 127 −10.6 ± 10.6 −18.1 ± 14.2 ‡ −6.3 ± 6.1
Pitavastatin 4 mg 153 125 −8.2 ± 8.9 0.05 −16.9 ± 13.9 0.50 −5.7 ± 6.3 0.50
Toi et al Atorvastatin 10 mg 80 80 § 0.2 ± 8.9
Pitavastatin 2 mg 80 80 § −2.6 ± 9.3 0.107
PIGEON Control 13 12 2.3 ± 6.2 2.8 ± 6.9
Pioglitazone 15 to 30 mg 13 8 −6.7 ± 5.9 0.0003 −7.2 ± 6.3 0.0002

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Dec 22, 2016 | Posted by in CARDIOLOGY | Comments Off on Intravascular Ultrasound Imaging for Assessing Regression and Progression in Coronary Artery Disease

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