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Table of Contents
EDITORIAL REVIEW
Year : 2018  |  Volume : 1  |  Issue : 2  |  Page : 95-123

Intravascular ultrasound and optical coherence tomography for the assessment of coronary artery disease and percutaneous coronary intervention optimization: Specific lesion subsets


1 Institute of Cardiovascular Diseases, The Madras Medical Mission, Chennai, India
2 CardioVascular Clinics, St Andrews War Memorial Hospital, Cardiology Program, The Prince Charles Hospital, and University of Queensland, Queensland, Australia

Date of Web Publication13-Dec-2018

Correspondence Address:
Dr. Vijayakumar Subban
Institute of Cardiovascular Diseases, The Madras Medical Mission, 4A, Dr. J. Jayalalitha Nagar, Mogappair, Chennai 600037, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IHJI.IHJI_33_18

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  Abstract 

In contemporary practice, the legacy of coronary angiography as the “one technique” to answer all questions in interventional cardiology has been proven inaccurate. Intravascular imaging techniques have advanced from the framework of research to clinical decision-making in daily practice. Regardless of its routine use, angiography has several limitations that restrict the ability to accurately predict lesion architecture and hemodynamic significance. Intravascular ultrasound (IVUS) and optical coherence tomography (OCT) images with far superior spatial resolution compared with angiography result in more precise characterization of lesion length, eccentricity, calcification, thrombus, necrotic cores, dissections, and stent apposition. Due to the technical complexity and potential prognostic implications, revascularization of specific subsets such as acute coronary syndrome, left main coronary artery, bifurcation, and chronic total occlusions poses additional challenges; therefore, it requires careful lesion preparation and cautiously optimized stenting for successful outcomes. Intravascular imaging has now become a mandatory procedural step in the therapeutic, interventional approach to treat these subsets and has been shown to improve stenting technique, procedure results, and consequently, patient outcomes. Stent malapposition, underexpansion, geographical miss, and significant stent edge dissection are all possible stent-related complications easily detectable by intravascular imaging. In this article, we present the salient features of evaluation and treatment of high-risk coronary interventions by IVUS and OCT.

Keywords: Intravascular ultrasound, optical coherence tomography, acute coronary syndrome, stent failure


How to cite this article:
Subban V, Raffel OC, Vasu N, Victor SM, Ajit Sankardas M. Intravascular ultrasound and optical coherence tomography for the assessment of coronary artery disease and percutaneous coronary intervention optimization: Specific lesion subsets. Indian Heart J Interv 2018;1:95-123

How to cite this URL:
Subban V, Raffel OC, Vasu N, Victor SM, Ajit Sankardas M. Intravascular ultrasound and optical coherence tomography for the assessment of coronary artery disease and percutaneous coronary intervention optimization: Specific lesion subsets. Indian Heart J Interv [serial online] 2018 [cited 2019 Nov 14];1:95-123. Available from: http://www.ihji.org/text.asp?2018/1/2/95/247453




  Introduction Top


Angiography-based treatment of coronary artery disease (CAD) is imprecise and has been shown to be associated with inferior outcomes, particularly in complex lesion subsets.[1] Introduction of intravascular ultrasound (IVUS), and recently, optical coherence tomography (OCT) has improved our understanding of the disease process and stent–vessel wall interactions. This enabled interventionist to deliver precise and optimal treatment for CAD, which in turn improved procedure success and patient outcomes. The first review covered the basic aspects of IVUS and OCT imaging, including qualitative and quantitative analysis, stent optimization, and clinical evidence.[2] This article focuses on the role of intravascular imaging (IVI) in the evaluation and treatment of specific lesion subsets. Although we described essential aspects of both imaging modalities, preference is given to more relevant imaging modality for the particular lesion subset.


  Acute Coronary Syndrome Top


Prompt restoration of coronary artery flow with percutaneous coronary intervention (PCI) improves outcomes in patients with acute coronary syndrome (ACS). The presence of thrombus and plaque with large thrombogenic lipid/necrotic cores may result in significant distal embolization during balloon and stent inflation and this can mitigate the success of PCI in patients with ACS. In addition, ACS results from a spectrum of pathological processes that may require individualized treatment. Further, it is an important predictor of drug-eluting stent (DES) failure.[3]

IVI plays an important role in the management of patients with ACS. Although both IVUS and OCT are useful in the evaluation of these patients, OCT is better suited for this purpose because of its superior resolution. The various roles of IVI in patients with ACS are as follows: (1) it clearly identifies the culprit lesion in patients with ACS as it is not uncommon for these patients to have more than one stenoses; (2) it precisely categorizes the underlying pathology that permits the selection of an appropriate treatment strategy; (3) it provides an estimation of thrombus burden and the need for thrombus aspiration and also its effectiveness; (4) it characterizes the underlying plaque morphology that predicts the risk of no-reflow; (5) it accurately estimates the vessel dimensions and extent of disease for stent sizing; and (6) after stenting, it helps in stent optimization and the identification of any acute complications from stenting. The following discussion focuses mainly on the IVI-guided intervention to prevent no-reflow, pathology-targeted management of ACS, and spontaneous coronary dissection (SCAD).

IVI-guided intervention to prevent no-reflow

No-reflow during PCI has been associated with poor acute and long-term outcomes. In patients with ACS, distal embolization is one of the major predictors of no-reflow. Although embolic protection devices reduce the incidence of distal embolization, the routine use of distal protection devices during primary PCI has not been shown to reduce the incidence of no-reflow.[4],[5] As discussed in the first review, there are various IVUS (attenuated plaque, positive remodeling) and OCT (thin-cap fibroatheroma [TCFA], large lipid core, and thrombus) predictors of no-reflow following PCI in patients with ACS.[2] This gives an opportunity to selectively intervene on the patients with high-risk features noted on IVI. The Vacuum Aspiration Thrombus Removal 3 (VAMPIRE 3) trial randomly assigned 200 patients with ACS related to native coronary lesions and IVUS-detected attenuated plaque with a longitudinal length of ≥5mm either to PCI with distal filter protection (Filtrap; Nipro, Tokyo, Japan) or to standard treatment. Thrombus aspiration was recommended in patients presenting with ST-segment elevation myocardial infarction (STEMI) for primary PCI in both groups and immediately after stenting in the distal protection group. The primary end point of no-reflow occurred less often in the distal protection group (26.5% vs. 41.7%; P = 0.026). In addition, the distal protection group also had fewer corrected thrombolysis in myocardial infarction (TIMI) frame count (23.0 vs. 30.5; P = 0.0003) and lower incidence of in-hospital adverse events. However, there was no difference in the myocardial blush grade or cardiac enzyme elevation between the groups. Although this approach is promising, we need more evidence before implementing it in routine practice related to both hard outcomes and cost-effectiveness.[6]

ACS pathology and response to treatment

Coronary thrombosis during ACS results from three basic mechanisms. Plaque rupture (PR) is the most frequent pathology and accounts for 65% of all cases with ACS. It results from disruption of the thin fibrous cap overlaying the large necrotic core in a TCFA. This results in exposure of highly thrombogenic necrotic core directly to the circulating elements promoting thrombosis. Plaque erosion (PE) is the second prevalent cause and constitutes up to 30% of cases with ACS. It results from damage to the endothelial layer covering the plaque. In contrast to PR, it occurs in an early atherosclerotic plaque and the fibrous cap is intact. Calcified nodule (CN) accounts for the remaining cases. Disruption of the fibrous cap by protruding nodular calcification causes thrombosis in CN.[7]

Two recent studies evaluated the morphological characteristics of culprit plaques with PR, PE, and CN and compared their postprocedure outcomes.

Saia et al.[8] analyzed 140 patients with STEMI who underwent OCT evaluation before PCI, after everolimus-eluting stent implantation, and 9 months after the procedure as part of the Optical Coherence Tomography Assessment of Gender Diversity in Primary Angioplasty (OCTAVIA) trial. In addition, thrombus aspirates were analyzed with histopathology and immunohistochemistry, and serum biomarkers were measured at baseline. A total of 43 patients were excluded due to image quality not fulfilling the prespecified criteria (n = 12), indeterminate culprit morphology because of large residual thrombus burden (n = 22), or possible thrombectomy-induced dissections (n = 9). Culprit lesion morphology was clearly identified in the remaining 97 patients: 63 (64.9%) PR, 32 (33.0%) PE, and 2 (2.1%) SCAD. There were no differences in the clinical characteristics and the levels of the inflammatory and platelet biomarkers between patients with PR and PE. Patients with PE presented more often with a patent infarct-related artery (IRA; 56.2% vs. 34.9%; P = 0.047) and had lower peak creatinine kinase–myocardial band (66.6 vs. 149.8 IU/L; P = 0.025). In addition, PE patients had smaller volumes of both red (0.41 vs. 1.52mm3; P = 0.001) and white (0 vs. 0.29mm3; P = 0.001) thrombi before PCI, more fibrotic areas (25.0% vs. 0.0%; P = 0.005) and fewer lipid areas (75% vs. 100%; P < 0.001) at the lesion site, less number of TCFA along the IRA (46.9% vs. 93.7%; P < 0.001), and similar lumen areas (mean 1.27 vs. 1.17mm2; P = 0.91). There was no difference in the mean stent area (PE vs. PR: 7.04 vs. 7.19mm2; P = 0.82), stent expansion index (82.8 vs. 83.0; P = 0.68), malapposition area (0.07 vs. 0.09mm2; P = 0.62), and volume of tissue protrusion (7.4% vs. 9.1%; P = 0.07) at the time of index procedure and strut coverage (92.5% vs. 91.2%; P = 0.15) and percentage volume obstruction (12.6% vs. 10.2%; P = 0.27) at 9-month follow-up. The clinical outcomes were similar between the groups up to 2-year follow-up.

In a similar study, Higuma et al.[9] evaluated 112 STEMI patients with both IVUS and OCT imaging following thrombus aspiration. Culprit lesion morphology was PR in 72 (64.3%) patients, PE in 30 (26.8%), CN in 9 (8.0%), and SCAD in 1(0.9%). IVUS identified only 17 (23.6%) PR of 72 with OCT. Compared with PR, the prevalence of fibrous plaque was higher (P < 0.001 and P < 0.001) and of lipid plaque (P < 0.001 and P < 0.001) and TCFA (P < 0.001 and P < 0.001) was lower in both PE and CN. In the lipid plaques of PE and CN, the lipid burden was smaller than PR. Microchannels were observed less often with PE compared to PR (P < 0.001). Although the prevalence and arc of calcium were similar between the groups, they are located deeper in PE (P < 0.001). The calcium was more superficial and the arc was larger in CN compared to other two groups (both P < 0.001). Compared with PR, PE was associated with smaller plaque burden (PB; P = 0.003), larger lumen cross-sectional area (P = 0.005), and greater eccentricity index (P < 0.001). Positive remodeling was observed more often with PR and negative remodeling with CN. The incidence of no-reflow was lower with PE compared to PR (13.3% vs. 38.9%; P = 0.011).

Pathology-targeted therapy in ACS

PR is the most common and most studied mechanism of ACS, and all the therapeutic strategies in the management of ACS have been focused on the pathophysiology of PR. It is associated with gross alteration of the vessel architecture in the form of large PB, positive remodeling, TCFA, fibrous cap disruption, intraplaque cavity, and a small residual lumen area. In addition, the thrombus burden is large and there is persistent stimulus for thrombus formation from the necrotic core elements at the lesion site. Importantly, it was associated with high incidence of reocclusion in the thrombolytic trials. This mandates stent implantation along with antithrombotic therapy in the management of ACS with PR. Thus, DES implantation and potent antiplatelet therapies improved outcomes in this group of patients.[10],[11]

In contrast, in patients with PE, vessel wall architecture is preserved and once the thrombus is treated, a plaque with low vulnerability (pathological intimal thickening or early fibroatheroma) remains and that is mostly non-flow-limiting. In addition, the stimulus for formation of thrombus is limited (no necrotic elements) to the disrupted endothelium, and this can be easily controlled with antithrombotic treatment. Thus, in a large proportion of patients with PE, treatment can be based on antithrombotic and secondary prevention strategies without the need for PCI. Given the risk of in-stent restenosis (ISR), stent thrombosis (ST), and bleeding with dual antiplatelet therapy (DAPT), this approach may improve the long-term outcome of these patients [Figure 1]. This novel strategy was evaluated in two small retrospective and one prospective registries.
Figure 1: OCT imaging guided treatment in Acute coronary syndrome (ACS). (A) Coronary angiography showing a hazy lesion in proximal Left anterior descending artery (LAD). OCT images (B–F) showing large thrombus (red stars) in proximal LAD with adequate lumen dimensions. Patient was treated with six weeks of anticoagulant therapy. Follow-up angiogram (H) showed good thrombus resolution. Follow-up OCT images (I–M) showed no residual thrombus or evidence of plaque rupture. Hence the probable cause of ACS in this patient is plaque erosion. Double headed red arrows show corresponding angiographic and OCT images at the baseline and during follow-up

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Prati et al.[12] treated 31 patients with OCT identified PE either with thrombectomy only (no stent group, n = 12) or thrombectomy followed by stenting (stent group, n = 19). Glycoprotein (GP) IIb/IIIa inhibitor was used in four patients in each group. All patients were kept on DAPT (aspirin + clopidogrel or prasugrel). The median follow-up was 753 days. A patient in the stent group required repeat revascularization, and there was no death, myocardial infarction (MI), or heart failure admission in either group.

Hu et al.[13] retrospectively analyzed the management strategies and clinical outcomes of 141 patients from the Massachusetts General Hospital OCT registry who presented with ACS and were evaluated with preprocedure OCT imaging. The underlying mechanism of ACS was PR in 79 (56%) patients and PE in 62 (44%) patients. Patients with PE were younger (60.3±10.4 vs. 54.8±12.1 years; P = 0.005) and more often presented with non-ST-segment elevation myocardial infarction (NSTEMI) compared to patients with PR (67.7% vs. 41.8%; P = 0.002). PE was associated with larger mean lumen diameter (1.59±0.82 vs. 0.96±0.46mm; P < 0.001), smaller diameter stenosis (DS; 55.8±17.5 vs. 69.22±12.3%; P = 0.001), and lower incidence of multivessel disease (32.3% vs. 69.6%; P < 0.001). Seventy-seven (97.5%) patients with PR and 49 (79%) with erosion underwent stent implantation (P < 0.001). Patients with PR had higher incidence of malapposition (37.5% vs. 7.3%; P < 0.001), thrombus (59.4% vs. 14.6%; P < 0.001), and tissue prolapse (93.8% vs. 73.2%; P = 0.008). PE was associated with lower incidence of no-reflow and distal embolization. The 1-year event rate was similar between the groups and there were no adverse events in patients treated without stenting.

The EROSION (Effective Anti-thrombotic Therapy Without Stenting: Intravascular Optical Coherence Tomography–based Management in Plaque Erosion) study[14] prospectively evaluated the strategy of antithrombotic treatment with aspirin and ticagrelor alone without stent implantation in patients with OCT-diagnosed PE and noncritical angiographic DS (<70%) at the culprit site. Overall 405 patients with ACS (393 STEMI) had analyzable OCT images, and 103 (25.4%) of them were identified with PE. Of 103 patients, 43 were excluded due to either >70% DS (n = 32) or failure of treating physician to identify PE (n = 11). Among the remaining 60 patients, 4 did not meet the inclusion criteria at the core lab (DS > 70%) and 1 died of gastrointestinal bleeding. Eighty-five percent of the patients underwent thrombus aspiration and 63.3% received GP IIb/IIIa inhibitor. The remaining 55 patients completed 1-month OCT follow-up. The primary end point of >50% reduction in thrombus volume at 1 month was met in 47 patients (78.3%; 95% confidence interval [CI]: 65.8–87.9) and there was no visible thrombus in 22 of them. In addition, thrombus volume reduced from 3.7 to 0.2mm3 and minimal flow area improved from 1.7 to 2.1mm2. One patient required repeat PCI and others remained asymptomatic.[14] Fifty-three patients completed 1-year follow-up and 49 of them were evaluated by repeat OCT imaging. There was further reduction in the thrombus volume between 1 month and 1 year (0.3 vs. 0.1mm3; P = 0.001) and there was no residual thrombus in 23 (46.9%) patients. However, there was no change in the minimal effective flow area (2.1 vs. 2.1mm2; P = 0.152). The clinical end point of major adverse cardiovascular event (MACE; a composite of cardiac death, recurrent MI, ischemia-driven target lesion revascularization [TLR], stroke, and major bleeding) occurred in four patients (three revascularizations for exertional angina, one major bleed).[15]

Although pathology-targeted therapy may be the way forward, we need more clarity on some of the aspects of this strategy: (1) PE occurs in up to a third of patients with ACS and a proportion of these still have flow-limiting disease. Hence, only a minority of the patients with ACS is suitable for this conservative strategy. It is impractical to perform OCT imaging in all the patients with ACS to identify this small portion of patients. Whether a selective application of OCT imaging in patients with angiographically non-flow-limiting stenosis is a more pragmatic approach needs further evaluation. (2) Although patients with PE predominantly have white thrombus and respond well to antiplatelet treatment, whether they need additional oral anticoagulant therapy particularly in the presence of primarily red thrombus or a large thrombus burden is not clear. As layering of thrombus followed by healing is one of the proposed mechanisms of plaque growth with luminal narrowing, whether minimizing the amount of thrombus layering will reduce this effect is unknown.[7] Similarly, the type of DAPT regimen whether with aspirin and clopidogrel or aspirin with ticagrelor/prasugrel needs further evaluation. (3) In the EROSION study, the mean effective flow area at the index procedure was only 1.7mm2 and this improved to 2.1mm2 at 1 month with no change at 1 year. This area is similar to OCT cutoff value for nonischemic lesions in patients with chronic stable angina and may understandably be adequate in patients with ACS and some myocardial loss. Whether these patients need additional evaluation with noninvasive stress test or intravascular physiology is yet to be addressed. (4) The present OCT definition of PE is a diagnosis of exclusion based on the absence of PR or CN. This can make the identification of PE difficult in daily clinical practice. (5) The current generation DES has excellent long-term outcomes. So, the advantage of conservative management needs to be compared with this gold standard treatment in randomized trials. (6) Although outcomes are encouraging at 1 year, there is no long-term follow-up data with the antiplatelet-alone treatment.[11],[16]

Calcified nodule

CN is the third and least frequent cause of ACS with a reported prevalence of 2%–8%.[17] The prevalence increased to 30% in ACS lesions with severe calcification.[18] It occurs most commonly in elderly patients and those with renal dysfunction on hemodialysis. CN is proposed to arise from fragmentation of the sheets of calcium due to mechanical stress. Thus, it is commonly observed in the mid-right coronary artery (RCA) lesions—the site of maximum torsion stress.[17],[18] As described earlier, both IVUS and OCT have high sensitivity to detect CN.[2] It appears as a protruding calcific nodular mass with dorsal shadowing. Although it is less prevalent, it may be the most challenging subset to treat with interventions as the nodules occur in the background of severe superficial calcification and tortuosity. The exact treatment strategy for CN has not been studied. In lesions with CN, thrombus burden is usually small and TCFA are less common and the treatment strategy is as with management of other calcified lesions.[11] Lee et al.[18] observed similar stent expansions in patients with or without CNs. They attributed breaks in calcium sheets observed in patients with CNs for this favorable outcome.[18] IVI assists in the treatment of CN by assessing its response to balloon dilatation and debulking strategies and stent expansion. In addition, similar to patients with PE, patients with CN and large flow area may be left alone safely without stenting.[19]

Spontaneous coronary dissection

SCAD denotes dissection of an epicardial coronary artery that is not related to atherosclerosis or trauma. It is increasingly being recognized as an important cause of ACS, especially in young females. It constitutes 1%–4% of all patients with ACS, and correct identification of SCAD is essential as the therapeutic strategy is significantly different from that of atherosclerotic CAD.[20],[21]

Coronary angiography (CAG) remains the initial imaging modality for evaluation of patients suspected with SCAD. Angiographic diagnosis of SCAD depends on the observation of characteristic appearances of vessel opacification and lumen narrowing. In the presence of lumen narrowing, administration of intracoronary nitroglycerine is important to rule out arterial spasm. Saw and colleagues proposed three angiographic patterns of SCAD—type 1: multiple lumens or arterial wall contrast staining; type 2: diffuse (20mm) smooth narrowing, (2A) normal segments proximal and distal to narrowing, (2B) narrowing extending to the tip of the artery; type 3: focal or tubular stenosis (<20mm), atherosclerosis-like.[21]

CAG can be challenging in the diagnosis of SCAD as the classical angiographic appearance of multiple lumens and arterial wall staining (type 1) occurs only in 30% of the patients. Thus, the guidelines recommend adjunctive diagnostic imaging either invasive (IVUS or OCT) or noninvasive (cardiac computed tomographic angiography, CCTA) when there is a high index of clinical suspicion in non–type I cases. Although CCTA imaging seems appealing, its lower spatial and temporal resolution makes the diagnosis difficult in cases without double lumen appearance or when it involves small-caliber vessels (<2.5mm). However, CCTA may play an important role in the follow-up of patients with SCAD involving large-caliber vessels.[21]

Diagnosis of SCAD on IVI depends on the identification of the intimomedial membrane (composed of intima and part of media) with a dual lumen (true and false lumens) or intramural hematoma (IMH; collection of blood in the medial space). Both IVUS and OCT illustrate the aforementioned features in patients with SCAD with subtle differences. OCT with its higher resolution sharply delineates lumen–intima interface and identifies the intimal rupture and intraluminal thrombi clearly. However, its poor depth penetration limits the assessment of the full extent of the false lumen and IMH. Moreover, it requires contrast flush to achieve a blood-free environment for optimal imaging. In contrast, IVUS lacks the resolution of OCT in visualizing the intimal ruptures but with its higher penetration enables assessment of full extent of false lumen and IMH even in large vessels. In addition, it also identifies thrombus in the false lumen. Moreover, it does not require contrast flush and is able to image through thrombus [Figure 2].[22]
Figure 2: IVUS/OCT imaging in SCAD. (A) CAG in a middle aged female showing smooth narrowing (arrow head) of the ostio-proximal LAD. (B–F) Cross-sectional images and (G) longitudinal view of IVUS images showing SCAD, extending from distal left main to mid LAD. (E) Tightest part of the lesion (stars indicate IMH). (F) Site of entry tear in left main (red arrow). (H–L) Cross-sectional and (M) longitudinal view OCT images of the same patient. Though OCT visualized intimo-medial membrane (blue arrows) and intramural hematoma (stars) it could not delineate the true dimension of it. In addition, entry tear was also not shown (might be due to deep guiding catheter position). White thrombus is visualized close to the imaging catheter in all the OCT cross-sections

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In patients with SCAD, instrumentation of the coronary arteries with guide catheter, guide wire and imaging catheter, and contrast flush during OCT imaging may extent the dissection flap or IMH, which may result in hemodynamic compromise. As most of the patients with SCAD are managed conservatively, IVI is recommended only in cases where the diagnosis is not clear with angiography alone or when there is a need to intervene.[22]

In contrast to ACS in patients with atherosclerotic CAD, a conservative approach is recommended in patients with SCAD as spontaneous healing occurs in most of the patients. Revascularization is considered only when there is ongoing ischemia or hemodynamic instability and in patients with severe left main coronary artery (LMCA) involvement. PCI in patients with SCAD is challenging and is associated with low procedural success rate. IVI complements CAG by providing additional information on position of wire in the SCAD segment (true vs. false lumen), the presence of entry and exit tears, true longitudinal extent of the hematoma, severity of the lumen compromise, presence of intraluminal thrombus, involvement of the side branches, and importantly reference vessel luminal dimensions. The management strategy depends on the presence or absence of IMH. When there is only a dissection flap without hematoma, a short stent placed at the maximum point of separation identified on IVI may be adequate to tack down the dissection plane. If there is hematoma, it is important to identify the entry and exit tears. When there is an entry tear, the stenting may be performed in the usual way from distal to proximal, and in case of exit-only tear, it is advisable to stent from proximal to distal. This approach avoids hematoma propagation in the other direction by sealing the way out.[23] In patients with only hematoma without intimal tears, the proximal and distal ends of the hematoma may be stented before tackling the middle part or cutting balloon dilatation may be used to decompress the hematoma.[24] It is preferable to use longer stents extending well beyond the proximal and distal limits of the hematoma and avoid oversizing to prevent hematoma propagation. IVI not only helps in stent optimization but also confirms full lesion coverage.[23]


  Left Main Coronary Artery Disease Top


LMCA is the most important part of the coronary arterial system. It supplies 85% of the left ventricular myocardium in patients with right-dominant circulation and 100% of the left ventricle in patients with left-dominant circulation, and hence significant disease of this segment is associated with detrimental consequences.[25] Assessment of unprotected LMCA (ULMCA) by angiography is limited by vessel foreshortening, overlap, lack of reference segment in case of diffuse disease, and poor ostial visibility from reflux of contrast into the aortic sinus.[26] Further, in contrast to other territories, the interobserver variability in assessing LMCA stenoses is as high as 50%.[27] In addition, angiography guides stent implantations associated with relatively high MACE and ST rates.[28] In contrast, using IVUS to guide LMCA PCI results in significantly reduced event rates.[29]

Assessment of intermediate left main disease

With increasing evidence showing poor correlation between IVUS minimal lumen area (MLA) in non-LMCA disease and functional significance as assessed by fractional flow reserve (FFR), IVUS is no longer recommended for the assessment of intermediate lesions in non-LMCA disease. However, with its limited anatomical variability and relatively constant myocardial mass of supply, there is good correlation between IVUS and FFR in the LMCA segment. In addition, IVUS is an important adjunct to FFR when there is disease involving both the branches of the LMCA [Figure 3].[30]
Figure 3: Intermediate left main ostial stenosis (A) evaluated by IVUS and FFR. Patient had additional downstream borderline disease in Left anterior descending coronary artery (LAD) and a tight stenosis in left circumflex coronary artery (LCX). FFR measured beyond LAD stenosis was 0.74 and LM was 0.82. In view of additional disease in both branches and borderline FFR, the ostial lesion was further evaluated with IVUS (B) which showed an ostial minimal lumen area (MLA) of 4.8 mm2 and average external elastic membrane diameter (EEM D) of 4 mm. Additionally there was 1.8 mm diameter mismatch between ostium and shaft (C) of LM (negative remodeling). Hence patient was referred for coronary artery bypass graft surgery. (D) Long view IVUS showing ostial narrowing (*) and mismatch in the vessel size between ostium and shaft

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Abizaid et al.[31] were the first to relate an IVUS parameter with clinical outcomes. Their study included 122 patients with ULMCA CAD who did not undergo revascularization. All patients underwent assessment of the severity of ULMCA disease both with quantitative coronary angiography (QCA) and IVUS and were followed up for 1 year. The QCA DS was 42% ± 16%. Though moderate correlation was present between the reference diameters measured with QCA (3.91±0.76mm, mean±1 standard deviation [SD]) and IVUS (4.25±0.78mm, r = 0.492; P = 0.0001), the lesion site minimum lumen diameter (MLD, 2.26±0.82mm) by QCA correlated less well with IVUS (2.8±0.82mm, r = 0.364; P = 0.0005). There were 4 deaths, 14 revascularizations, and no MI during the follow-up. The independent predictors of outcomes were diabetes mellitus, an untreated vessel with a DS >50%, and IVUS MLD. A progressive increase in the event rate was observed with worsening MLD: 3% for an MLD >3.0mm, 16% for an MLD 2.5–3.0mm, 24% for an MLD 2.0–2.5, and 60% for an IVUS MLD <2.0mm.

Jasti et al.[32] assessed 55 patients with angiographically intermediate ULMCA lesions with both FFR and IVUS. On regression analysis, strong correlations were observed between FFR and MLD (r = 0.79; P < 0.0001) and between FFR and MLA (r = 0.74; P < 0.0001). An MLD of <2.8mm had the highest sensitivity and specificity (93% and 98%, respectively), followed by an MLA of <5.9mm2 (93% and 95%, respectively), which predicted an FFR of <0.75. Patients underwent revascularization based on FFR value of <0.75. At 36-month follow-up, no mortality was reported in either of the groups, and the event-free survival was 90% in the deferred group (n = 37) and 100% in the revascularization group (n = 14).

Kang et al.[33] examined 55 patients (31 stable and 24 unstable angina [UA]) with isolated intermediate ULMCA stenosis with both IVUS and FFR before intervention. IVUS-measured MLA was the only predictor of an FFR <0.80. An IVUS MLA of <4.8mm2 predicted an FFR of <0.80 with a sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of 89%, 83%, 82%, 89%, and 86%, respectively. Further, an MLA of <6mm2 showed only 42% specificity to predict an FFR of <0.8. The same group reassessed IVUS and FFR correlation in a large cohort of 112 patients with intermediate ULMCA stenosis. An IVUS MLA of <4.5mm2 predicted an FFR of <0.80 with a sensitivity, specificity, PPV, NPV, and accuracy of 77%, 82%, 84%, 75%, and 86%, respectively.[34]

A study from Mayo clinic group assessed the IVUS lumen area in patients with normal-appearing ULMCA on CAG and assigned the mean – 2 SD (7.5mm2) as the cutoff valve for the assessment of intermediate ULMCA disease. On the basis of this cutoff value, treatment was implemented in a cohort of 214 patients. In those with an MLA of ≥7.5mm2, the revascularization was deferred in 114 (89%) of 131 patients and 71 (85.5%) of 83 patients with an MLA of <7.5mm2, who underwent revascularization. At (3.3±2.0)-year follow-up, no difference in the outcomes was observed between the groups.[35]

de la Torre Hernandez et al.[36] proposed a cutoff value for the assessment of intermediate ULMCA stenosis based on the Finet’s law of coronary bifurcation. Assuming a cutoff value of 3mm2 for left anterior descending (LAD) coronary artery and left circumflex (LCX) artery, the law predicted a ULMCA cutoff value of 5.8mm2. Following the encouraging outcomes in their pilot study of 79 patients,[36] this was prospectively evaluated in a multicenter LITRO (estudio de Lesiones Intermedias de TROnco) study involving 22 Spanish centers and 354 patients. A total of 152 (90%) of the 186 patients with an IVUS MLA of <6mm2 underwent revascularization, and invasive treatment was deferred in 179 (96%) of 186 patients with an IVUS MLA of ≥6mm2. At 2-year follow-up, the death-free and event-free survivals were 97.7% and 94.5% (P = 0.5) and 87.3% and 80.6% (P = 0.3) in the deferred and revascularized groups, respectively. During the same period, there were eight (4.4%) LMCA revascularizations and no infarction in the deferred group.[37]

Though the MLA cutoff values are different between the studies, only an MLA of 6mm2 has been prospectively evaluated in an adequate sample size of population, and the current guidelines recommend this criteria for guiding revascularization in patients with intermediate ULMCA disease.[38] In a recent meta-analysis of 12 studies (7 FFR and 5 IVUS) involving 908 deferred patients, FFR- and IVUS-based deferrals were associated with similar MACE (5.1% vs. 6.4%), death (2.6% vs. 3.0%), MI (1.5% vs. 0.5%), and revascularization involving LMCA (1.8% vs. 2.2%).[39]

Procedure planning

With the inherent limitations of CAG, an IVI modality is often needed to guide revascularization in ULMCA disease. Though OCT has higher resolution and better plaque characterization capabilities, the need for blood clearance and limited penetration limits its utility in this subset. IVUS remains the modality of choice for guiding PCI in ULMCA. The various roles of IVUS during PCI are: (a) clarifying angiographic ambiguity such as haziness. Angiographic haziness may result from thrombus, CN, or ruptured plaque. IVUS by characterizing them accurately, helps in management decisions. (b) Assessing the need for lesion preparation: Calcification is very common in the LMCA segment and is predicted poorly on angiography. IVUS not only identifies angiographically silent calcification but also quantifies its severity and distribution, which helps in selecting appropriate debulking strategy. In addition, IVUS also helps in confirming the adequacy of lesion preparation. (3) Selecting the stenting strategy: Stenting technique depends on the distribution of plaque in different regions of the LMCA and their extension into the LAD coronary artery and LCX artery. In ostial and shaft regions, IVUS helps in sizing the stent appropriately and also identifies the landing zone with minimum PB.[40] In case of distal LMCA disease, IVUS shows the extension of disease into the SBs. Severity and extent of disease at the ostium of LCX artery determines the stenting strategy. An LCX ostial PB of 56% and area of <3.7mm2 identified postprocedural FFR of <0.80 in a study.[41] These lesions may need upfront two-stent strategy and others may be managed with single-stent crossover technique.

IVUS-guided stent optimization

Post-stenting IVUS helps in identifying and treating various parameters of suboptimal stent deployment: underexpansion, malapposition, geographic miss, major tissue prolapse, significant dissection, and IMH.[40]

As in other epicardial coronaries, stent expansion is a major determinant of outcomes following DES implantation in ULMCA [Figure 4]. Kang et al.[42] examined the predictive value of IVUS MLAs in the distal LM bifurcations treated with DES in a single-center observational study of 403 patients. The distal LM bifurcation was divided into four regions: ostial LAD, ostial LCX, polygon of confluence (POC, confluence zone of LAD, and LCX), and proximal LM above the POC (LM). At 9 months, angiographic restenosis occurred in 4.5% of the ostial/shaft LM lesions, 6.3% of the bifurcation lesions treated with single-stent crossover, and 25.4% of the bifurcations treated with two-stent strategy. The optimal IVUS MLA cutoff values that predicted restenosis were 5.0mm2, 6.3mm2, 7.2mm2, and 8.2mm2 at ostial LCX, ostial LAD, POC, and LM, respectively. On the basis of these criteria, underexpansion in at least one segment was identified in 33.8% of the patients. Restenosis was more common in patients with underexpansion compared with those with well-expanded stents (24.1% vs. 5.4%; P < 0.001), and underexpansion was associated with poor MACE-free survival at 2 years (90±3% vs. 98±1%; P < 0.001). Though this IVUS criterion is widely applied, it is not prospectively validated and needs to be individualized based on the size of the ULMCA and SBs.
Figure 4: IVUS guided distal left main (LM) bifurcation stent optimization. The distal LM disease was extending into both left anterior descending artery (LAD) and left circumflex coronary artery (LCX) on pre procedural IVUS (not shown). Patient was treated with double kiss crush stenting technique. (A) Pre procedural angiogram showing distal LM bifurcation disease. (B) Final angiogram showing optimal angiographic result. (C–F) IVUS images showing optimal stent expansion in all 4 segments of distal LM bifurcation. POC: Polygon of confluence

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Impact of IVUS-guided ULMCA PCI

There have been no prospective randomized trials that compared the strategy of IVUS-guided PCI with angiography alone in the setting of ULMCA PCI. To date, only two major retrospective studies[43],[44] and two meta-analyses[45],[46] are available that report outcomes of ULMCA PCI with IVUS guidance.

In the revascularization for unprotected left main coronary artery stenosis: comparison of percutaneous coronary angioplasty versus surgical revascularization (MAIN COMPARE) registry, 756 patients underwent ULMCA PCI with IVUS guidance and 219 patients underwent PCI with angiography alone. Park et al.[43] analyzed 3-year outcomes of 201 propensity-matched pairs of patients from this registry. Overall, there was a trend toward better outcomes with IVUS-guided PCI (6.0% vs. 13.6%; P = 0.061). On subgroup analysis, in the 145-matched pairs receiving DES, IVUS guidance was associated with significantly lower mortality (4.7% vs. 16.0%; P = 0.055); however, no such improvement was observed in the 47 pairs receiving bare metal stent (BMS, 8.6% vs. 10.8%; P = 0.38). In addition, no difference was observed in the incidence of MI or target vessel revascularization (TVR).

de la Torre Hernandez et al.[44] performed a pooled level analysis of 1670 patients, from four Spanish registries, who underwent ULMCA stenting with DES. Of which 505 patients underwent IVUS during PCI (IVUS group) and were matched to 505 patients who underwent PCI with angiographic guidance alone (angiographic group). The diameter of the stent implanted both in the main branch (MB) and SB was bigger in the IVUS group than that in the angiographic group. Additional balloon dilatations and a new stent implantation were performed in 40% and 7.9% of the cases in the IVUS-guided group. Overall, MACE (cardiac death, MI, and TLR) free survival at 3 years was 88.7% in the IVUS group and 83.6% in the angiographic group (P = 0.04), and in the distal LM subset, it was 90% and 80.7%, respectively (P = 0.03). Further, there was a significant reduction in the incidence of definite and probable ST in the IVUS group (0.6% vs. 2.2%; P = 0.04). On multivariate analysis, IVUS guidance was an independent predictor of MACE both overall (hazard ratio [HR]: 0.70, 95% CI: 0.52–0.99; P = 0.04) and particularly in the distal LM subgroup (HR: 0.54, 95% CI: 0.34–0.90; P = 0.02).

Two meta-analyses comparing IVUS guidance versus angiography guidance for LMCA revascularization have been published recently.[44],[45] The first meta-analysis included 10 studies (one randomized and nine nonrandomized) with a total of 6480 patients. IVUS guidance was associated with significantly lower incidence of all mortality (risk ratio [RR]: 0.60, 95% CI: 0.47–0.75; P < 0.001), cardiac mortality (RR: 0.47, 95% CI: 0.33–0.66; P < 0.001), TLR (RR: 0.43, 95% CI: 0.25–0.73; P = 0.002), and ST (RR: 0.28, 95% CI: 0.12–0.67; P = 0.004) compared with angiography guidance.[45] The second meta-analysis included seven studies (one randomized and six nonrandomized) with a total of 4592 patients. Compared to angiography-guided PCI, IVUS-guided PCI was associated with significantly lower incidence of MACE (RR: 0.61, 95% CI: 0.53–0.70; P < 0.001), all mortality (RR: 0.55, 95% CI: 0.42–0.71; P < 0.001), cardiac mortality (RR: 0.45, 95% CI: 0.32–0.62; P < 0.001), MI (RR: 0.66, 95% CI: 0.55–0.80; P < 0.001), and ST (RR: 0.48, 95% CI: 0.27–0.84; P = 0.01). In contrast to the first meta-analysis, no difference was observed in the TLR and TVR between the groups.[46]


  Bifurcation Lesions Top


Coronary bifurcation lesions represent 15%–20% of all PCIs in daily practice and are associated with a lower procedure success rate and a higher incidence of stent failure compared to non-bifurcation PCIs.[47],[48] The anatomical and procedural complexity makes angiographic information alone insufficient for procedure guidance. IVI provides valuable additional details in every stage of the procedure to facilitate stenting strategy, device selection, and stent optimization. For accurate assessment of bifurcation disease, it is important to image both the main vessel and SB separately, as SB dimensions are overestimated by the assessment from main vessel imaging alone.[49],[50]

The various roles of IVI during bifurcation PCI are guidance in the selection of stenting strategy, predicting the chance of SB compromise, assessment of the jailed SB ostium, confirmation of optimal SB wire recrossing, stent size selection, and finally stent optimization. Although both IVUS and OCT may assist in the above functions, the higher resolution of OCT and its ability to provide real-time three-dimensional (3D) rendering of bifurcation (3D bifurcation mode in the current OCT system; ILUMIEN OPTIS FD-OCT System, Abbott [Abbott/St. Jude Medical, Minneapolis, MN, United States]) makes it more suited for this purpose.

Selecting stenting strategy

Preprocedure imaging identifies plaque distribution in various segments of the bifurcation and helps in decision-making between a single- versus double-stent strategy based on the PB and lumen area of the SB.[49] It helps in identifying the exact cause of angiographic SB ostial narrowing before stenting. The most common mechanisms are (1) true atherosclerotic ostial disease, (2) atherosclerotic plaque in the main vessel without real involvement of the SB ostium, or (3) negative remodeling without much atherosclerotic PB. The latter two situations are associated with lower incidence of SB compromise following single-stent crossover technique.[51] Kang et al.[52] evaluated 90 bifurcation lesions with <75% angiographic DS treated with single-stent crossover technique by pre- and postprocedure IVUS. A preprocedure MLA cutoff value of 2.4mm2 (sensitivity, 94%, specificity, 68%, PPV, 40%, and NPV, 98%) and a PB of 51% (sensitivity, 75%, specificity, 71%, PPV, 36%, and NPV, 93%) predicted postprocedure FFR of <0.80. Thus, preprocedure imaging may help in avoiding unnecessary stenting of the SB when a two-stent strategy was planned based on the angiographic findings.

Predicting SB compromise during provisional stenting

SB compromise is an important limitation of the provisional PCI strategy in bifurcation lesions even in the absence of significant PB at the ostium of the SB. The various IVI parameters associated with SB compromise following main vessel stenting are the presence of a carina with a spiky morphology (“eyebrow” sign), absence of plaque at the carina, eccentric plaque accumulation opposite to the carina, carina tip angle of <50°, and bifurcation point to carina tip distance of <1.7mm.[53],[54] Carina shift constitutes the main mechanism of SB compromise in these patients, and stent overexpansion in the distal main vessel is noted to be the most important cause of carina shift. This phenomena may be avoided by sizing the stent to the distal main vessel and optimizing the proximal main vessel segment of the stent with proximal optimization technique. IVI helps in accurately sizing the stent to the distal main vessel and avoiding this complication.[53],[54]

Assessment of jailed SB ostium and SB recrossing

In patients undergoing provisional stenting, the SB ostium is jailed with MB stent struts. The malapposed struts across the SB ostium may act as a nidus for thrombus formation, or neointimal coverage of the struts may result in SB compromise. In addition, it may result in difficult SB access during future interventions. SB dilatation followed by kissing balloon inflation (KBI) is used to “unjail” the SB ostium. However, routine final KBI during provisional stenting has been shown to either not improve outcomes or even increase MB restenosis and repeat revascularization rates. 3D OCT imaging of the bifurcation (cutaway view and fly-through functions) has revolutionized our understanding of the jailed SB morphology, wire recrossing patterns, and possible causes of poor outcomes following KBI, following provisional stenting.[55],[56],[57],[58]

As with angiography-based classification (narrow angle and wire angle bifurcations), the bifurcation is classified into two types with 3D OCT imaging depending on the visibility of the SB ostium and proximal course of the vessel when viewed at right angle to the vessel wall: (1) perpendicular type: when the bifurcation opening is fully visible and not obscured by the carina and (2) parallel type: when the SB runs parallel to the main vessel and its proximal course is obscured by the carina. The jailed SB ostial strut morphology is divided into two types depending on the relationship of the connector to the carina: (1) free carina type: when no link is attached to the carina and (2) connecting to the carina type: when a link is committed to the carina. In addition, the SB cell morphology is classified into three types depending on the proximity to the carina: distal (closer to carina) and proximal (away from carina). Further, the distal cell is named as far distal when no distal top of the hoops of the strut is visualized in front of the SB ostium. Thus, the wire recrossing may result in following combinations: (1) distal cell/free carina type, (2) distal cell/connecting carina type, (3) proximal cell type, and lastly, (4) far distal type [Figure 5]. The bifurcation type in each of the aforementioned positions may be parallel or perpendicular. In the studies published thus far, the distal/free carina type was the most suitable one for KBI and associated with largest SB opening and lowest incidence of malapposed struts. In contrast, the far distal type was associated with extensive deformation of the stent struts of the distal main vessel. The distal cell/connecting carina type and proximal types were associated with significantly more malapposed struts in front of the SB ostium when compared to the distal cell/free carina type. However, in the presence of the distal cell/connecting carina type, the proximal crossing was associated with lower incidence of malapposed stent struts across the ostium when compared to distal cell crossing. In parallel bifurcations, the proximal crossing was associated with a higher incidence of malapposed struts, and in the distal cell/free carina type, the perpendicular bifurcation morphology was associated with higher incidence of malapposed struts. The 3D OCT guidance significantly improved the distal cell crossing (83%) overall, and in patients with distal cell/free carina type, it went up to 100% when compared to two-dimensional OCT guidance.[58] Thus, 3D OCT guidance may help in wire recrossing through the appropriate cell location, which in turn may improve the outcomes of the KBI [Figure 6].
Figure 5: Jailed side branch ostial morphology and different positions of wire crossing. Side branch-1 has a connecting to the carina/far distal cell morphology. Far distal wire crossing may result in severe distortion of the distal main branch part of the stent. Distal cell crossing may result in malapposition and deformation of the struts across the side branch ostium. Proximal cell crossing may be appropriate in this situation to avoid major malapposition and strut deformation. Side branch-2 has a free carina morphology and here a distal cell crossing is associated with optimal side branch scaffolding and a very low incidence of malapposed struts following kissing balloon dilatation

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,
Figure 6: OCT guided provisional stenting to distal RCA bifurcation. (A) Angiography showing distal RCA bifurcation post provisional stenting into posterolateral branch (yellow circle). (B) 3D bifurcation, (C–F) cross-sectional, and (G) longitudinal OCT views showing link-free carina with distal cell crossing (yellow arrows). (H) 3D bifurcation, (I–L) cross-sectional, and (M) longitudinal OCT views showing optimal side branch opening with no malapposed struts (red arrows). (Figure courtesy of Dr. Rony Mathew)

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In patients undergoing two-stent bifurcation strategy, 3D OCT also helps in confirming the wire recrossing through an appropriate location. This is important as inadvertent abluminal recrossing is not uncommon with distal cell crossing following SB stent implantation.[57]

Post-stent assessment

As in any other lesion subset, IVI following stent implantation helps in identifying and correcting the abnormalities not visible on angiography. Suboptimal stent deployment is very common with bifurcation stenting. In a systematic IVUS study of two-stent bifurcation treatment with T-stenting technique, the MLA occurred most commonly at the SB ostium and was closely correlated with the follow-up MLA. In addition, the percentage neointimal hyperplasia was significantly higher at the SB ostium. The postprocedure MLA at the SB ostium that predicted follow-up lumen area of ≥4mm2 was 4.83mm2.[59] Similarly, Costa et al.[60] also observed MLA at the SB ostium following crush-stent technique. Further, incomplete crushing (lack of apposition of the SB or MB struts in the proximal main vessel) was noted in >60% of the lesions.[60] In an OCT study, malapposition was observed more frequently with two-stent technique compared to that with single-stent crossover, and OCT guidance was associated with lower incidence of malapposition.[61]

Clinical evidence for IVI-guided bifurcation stenting

No prospective studies that evaluated IVI-guided stenting in bifurcation lesions are available. Five retrospective/prospective registries have been published till date, and a large, randomized study is enrolling patients.[62],[63],[64],[65],[66],[67]

Kim et al.[62] analyzed the long-term outcomes (4 years) of 758 patients (IVUS guidance in 473) who underwent stent implantation for non-LM bifurcation lesions in the Asan Medical Center, Korea. IVUS guidance was associated with a lower incidence of all-cause mortality (HR: 0.31, 95% CI: 0.13–0.74; P = 0.008) overall and in the DES group (HR: 0.24, 95% CI: 0.06–0.86; P = 0.03). This difference was not observed in the BMS group. No difference was observed in the rates of overall ST and TLR. However, in the DES group, IVUS guidance was associated with lower incidence of very late ST (0.4% vs. 2.8%; P = 0.03).

Kim et al.[63] compared 487 patients with IVUS-guided bifurcation stent implantation with 487 propensity-matched patients with angiography-guided bifurcation stent implantation in the Korean multicenter bifurcation registry. Patients in the IVUS-guided group more often underwent two-stent technique and final KBI and had lower incidence of periprocedural creatinine kinase myocardial band elevation. The primary end point of death or MI was significantly lower in the IVUS-guided arm (3.8% vs. 7.8%; P = 0.04).

Patel et al.[64] evaluated the outcomes of 449 patients who underwent bifurcation stent implantation (247 in the IVUS group and 202 in the angiography group). True bifurcation lesion (Medina 1, 1, 1) was present in 89% of the lesions. IVUS guidance was associated with lower rates of death or MI (odds ratio [OR]: 0.38, 95% CI: 0.20–0.74; P = 0.005), death (OR: 0.40, 95% CI: 0.18–0.88; P = 0.02), MI (OR: 0.37, 95% CI: 0.14–0.98; P = 0.04), TVR (OR: 0.28, 95% CI: 0.14–0.53; P < 0.0001), and TLR (OR: 0.27, 95% CI: 0.14–0.53; P = 0.0003).

Chen et al.,[65] in a retrospective analysis, compared 324 patients with IVUS-guided bifurcation stent implantation with 304 patients with angiography-guided stent implantation. At 1-year follow-up, the IVUS-guided group was associated with significantly lower incidence of cardiac death (0.9% vs. 3.3%; P = 0.049), MI (4.6% vs. 8.9%; P = 0.038), and ST (1.2% vs. 6.9%; P < 0.001). When 123 paired patients were propensity matched, IVUS guidance was still associated with lower incidence of ST (0% vs. 4.9%; P = 0.029) and STEMI (2.4% vs. 9.8%; P = 0.030).

In a prospective study, Chen et al.[66] evaluated the utility of IVUS-guided stent implantation in patients with true bifurcation lesions (Medina 1, 1, 1 or 0, 1, 1) presenting with UA. They compared 310 patients with IVUS-guided stent implantation with 620 propensity-matched patients with angiography-guided stent implantation. The primary end points of MACE (composite of cardiac death, MI, or clinically driven TVR) at 1-year (10.0% vs. 15.0%; P = 0.036) and at 7-year follow-up (15.2% vs. 22.4%; P = 0.01) were significantly better with IVUS guidance. In addition, IVUS guidance was associated with lower incidence of cardiac death, MI, and any revascularization at 7-year follow-up.

The European randomized Optical Coherence Tomography Optimized Bifurcation Event Reduction (OCTOBER) trial is the first randomized study evaluating the systematic usage of OCT guidance during stent implantation in a population of 1200 patients with true bifurcation lesions. This study is expected to ultimately show the real use of OCT guidance in patients undergoing bifurcation stent implantation.[67]


  Calcified Lesions Top


Coronary artery calcification (CAC) is a marker of advanced atherosclerosis, and its extent correlates with disease burden and future adverse events. In patients undergoing PCI, the presence of CAC predicts failure of device delivery and optimal lesion dilatation. It is associated with increased incidence of stent underexpansion, malapposition, and periprocedural MI, and remains an important predictor in both ISR and ST.[68],[69]

Calcified coronary lesions may require aggressive preparation before stenting to achieve optimal stent expansion, which is a strong predictor of good, immediate, and long-term outcomes. The choice of lesion preparation strategy depends on the severity and extent of the lesion calcification. Though angiographically moderate-to-severe calcification predicts the need for some form of debulking, it is very difficult to make the choice of debulking strategy based on angiography alone. This was shown in the randomized trials where angiography-based selections of atherectomy strategies were not associated with improved outcomes compared to that of balloon angioplasty and stenting.[70]

Although technically demanding, in a significant proportion of patients, some form of IVI may be useful to evaluate the morphologic characteristics of calcium, whenever feasible. Both IVUS and OCT identify calcification with a high degree of accuracy. They also clearly delineate the location, circumferential, and longitudinal extent of calcification. In addition, with the ability of light to penetrate calcium, OCT provides information regarding plaque calcium thickness.[71]

Assessment of the need for plaque modification

With the current evidence, the extent of calcification that warrants plaque modification is not very clear. Few recent studies have attempted to answer this question. In a systematic OCT study, Kubo et al.[72] showed that a calcium plate thickness of <505µ predicted calcium fracture after high-pressure balloon angioplasty. In addition, successful calcium fracture was associated with better minimal stent area (MSA, 5.02±1.43mm2 vs. 4.33±1.22mm2; P = 0.47), lower binary restenosis (14% vs. 41%; P = 0.024), and ischemia-driven revascularization (7% vs. 28%; P = 0.046). Maejima et al.[73] evaluated the effects of rotational atherectomy and subsequent balloon angioplasty on calcified lesions using OCT. Similar to the previous study, formation of crack in the calcium was associated with better MSA (7.38±1.92 vs. 7.13±1.68mm2; P = 0.035) and lumen gain (3.89±1.53 vs. 3.40±1.46mm2; P < 0.001). The calcium arc and thickness of 227° and 0.67mm, respectively, predicted cracks following rotational atherectomy and balloon angioplasty. Fujino et al.[74] assessed the thresholds for calcium plate fracture in a population of 261 patients treated with balloon pre-dilatation alone before stenting. They observed calcium fracture only in 10.7% of the lesions. Calcium fracture occurred in patients with smaller thickness and wider arc, and the best cutoff values that predicted calcium fracture were a calcium arc of >225° and a thickness of <0.24mm. The same group of investigators developed an OCT-based scoring system that assigned the maximum calcium arc, maximum calcium thickness, and calcium length, scores of 2 points, 1 point, and 1 point, respectively. In the validation cohort, a score of 0–3 was associated with optimal stent expansion and a score of 4 was correlated with stent underexpansion.[75]

From the above discussion, it is clear that calcium arc is the main determinant of stent expansion. When the calcium is eccentric, balloon dilatation stretches the noncalcified arc of the vessel and causes disruption of the vessel wall at the junction of the calcium with noncalcified vessel wall without calcium modification. This allows adequate stent expansion, but the expansion is asymmetric with a “D”-shaped stent configuration and malapposition at the shoulders. Hence, calcium modification is not necessary in eccentric calcification. In contrast, when the calcium is concentric, at least an area of calcium fracture is essential for the stent to expand optimally [Figure 7]. If the calcium plate has an area of thickness <500µ, calcium fracture may be achieved with balloon dilatation alone. However, when it is thicker (>500µ), an atherectomy strategy is necessary for reducing the thickness below this threshold value for balloon dilatation to be effective in preparing the lesion for optimal stent expansion.[71]
Figure 7: Intra vascular imaging insights into mechanism of rotational atherectomy. (A–D) Eccentric calcification. (A) Angiography showing eccentric calcification on the septal side (yellow arrow). (B) OCT image showing 180o superficial thick calcium plate (>500 µ) (red star). The OCT catheter was not adherent to the calcium plate and hence rotational atherectomy burr did not modify the plaque. (C) Post rotational atherectomy/balloon dilatation image showing dissection at the shoulders of the calcium plate (blue arrows). (D) Stent expanded in a ‘D’ shaped pattern. (E–H) Concentric calcification. (E) Mid right coronary artery calcified stenosis (blue arrow). (F) IVUS images showing concentric calcification and adherent IVUS catheter (favorable wire bias). In contrast to OCT, the depth of the calcium is not visualized. Rotational atherectomy followed by balloon dilatation resulted in calcium break at 5 O’clock position (red arrow). This resulted in well expanded stent (H)

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Assessment of response to plaque modification

OCT with its high resolution and capacity to penetrate calcium, enables monitoring the response to atherectomy. After each ablation, the residual calcium thickness can be accurately accessed and burr may be safely upsized if the threshold value is not achieved. After adequate plaque modification and balloon dilatation, OCT imaging may be used to confirm calcium plate fracture. In case of eccentric calcium, IVI helps in identifying wire relationship to the calcium plate. If the wire bias is favorable (the imaging catheter adherent to the calcified plaque), an atherectomy device may be safely used to modify the lesion. If the imaging catheter is away from the plaque and adherent to the noncalcified part of the vessel wall, the plaque modification may not be effective, and may sometimes result in injury to the noncalcified part of the vessel wall.

Post-stent optimization

Following DES implantation, IVI helps in verifying optimal stent expansion and edge-related problems. It is important to remember that eccentric stent expansion and malapposition of the struts at the shoulders of the calcium are very common in patients with calcification, particularly in eccentric calcification. If the stent is well expanded, no further attempt should be made to correct the eccentricity or malapposition to avoid perforation/rupture of the noncalcified part of the vessel.[71]


  Chronic Total Occlusion Top


IVI plays two important roles during chronic total occlusion (CTO) revascularization: (1) assists wire crossing when angiographic information alone is inadequate and (2) stent optimization as in any other PCI. Though both IVUS and OCT are useful for stent optimization, only IVUS can be used for guiding wire crossing.[76],[77],[78] The solid-state IVUS catheters offer multiple advantages over mechanical catheters for this purpose. The tip to transducer distance is shorter (2.5 vs. 25mm, respectively) and the monorail segment is longer in solid-state catheters compared to the mechanical catheters.

IVUS-guided wire crossing

Antegrade approach

Angiographic imaging remains the cornerstone for wire handling during CTO PCI. However, this information is inadequate when the proximal occlusion site is blunt without a clear entry point or when the wire enters the subintimal space (SIS) and results in collapsing of the distal true lumen.

In the first situation, IVUS can be used to identify the optimal entry point when a suitable SB is available. The IVUS catheter is introduced into the SB and slowly pulled back proximally till the MB intimal plaque is visualized. The optimal site for wire entry is the center of the intimal plaque. Further wire handling may be proceeded with real-time IVUS imaging where wire entry into the plaque is continuously monitored. Alternatively, once the optimal site for wire entry is localized, an angiographic image is performed. The position of the IVUS catheter is marked on the angiogram and targeted for the wire entry. Once the wire enters the proximal cap, IVUS is once again used to confirm the correct position of the wire [Figure 8]A. An 8F or two 6F guide catheters are required for simultaneous insertion of an IVUS catheter and a microcatheter for real-time imaging in the first approach but a 7F guide catheter is adequate for the second approach.[76],[77],[78]
Figure 8: (A) Side branch IVUS guided proximal cap wiring. The IVUS catheter is pulled back from the side branch and centre of main branch intimal plaque is identified for wire-crossing. Post wire crossing IVUS confirms the correct location of the wire. (B) Different IVUS patterns during reverse CART. Patterns 1 & 2 are more favourable. Pattern 3 requires large antegrade balloon dilatation. Pattern 4 needs change in retrograde wire position for successful wire crossing. IP = intimal plaque, MB = main branch, SB = side branch, AW = antegrade wire, RW = retrograde wire, SIS = subintimal space

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During antegrade wire crossing, the wire may inadvertently enter the SIS. Different techniques, such as parallel wire technique, seesaw wire technique, and reentry with dedicated reentry devices or switching to a retrograde approach, have been proposed for further lesion crossing. However, when none of the antegrade crossing strategies are successful and no suitable interventional collaterals are present or retrograde crossing has failed, an IVUS-guided true lumen reentry is recommended as a last resort. IVUS-guided true lumen reentry is technically demanding and associated with low success rate. In this technique, the SIS is enlarged with a small balloon (1.5–2mm) and IVUS catheter is introduced into the SIS over the first wire to obtain information on the position of the guidewire and the plaque morphology. The site of wire deviation from intimal plaque into the SIS is identified. Then, the position of the intimal plaque is co-registered angiographically based on its relation to the SBs (toward or away from the SB on IVUS imaging) or its relation to the first guidewire in the false lumen, then a second guidewire is directed into the intimal plaque. Subsequently, the IVUS catheter and the second wire are advanced sequentially millimeter by millimeter in the SIS till it reaches the distal true lumen.[76],[77],[78],[79]

Retrograde approach

During retrograde CTO PCI, IVUS helps in resolving wire position in two situations. In retrograde wire crossing, when the CTO is at the ostio-proximal RCA, the subintimal crossing of the retrograde wire may result in aortic dissection. Positioning of the bare short tip of IVUS catheter in the aorta close to the ostium helps in resolving the position of the tip of the guidewire and hence subintimal exit of the wire may be avoided. Similarly, in ostial LAD or LCX CTOs, the subintimal wire course with an exit in the LMCA beyond the origin of the other branch may result in its occlusion following stent implantation. Confirming the position of the wire in the true lumen with an IVUS catheter positioned in the second branch prevents this devastating complication.[80]

During retrograde dissection reentry, reverse controlled antegrade and retrograde tracking (CART) is the most common mode of retrograde wire crossing into the proximal true lumen. In this technique, both the antegrade and retrograde wires pass through the true lumen proximal and distal to the CTO segment, respectively, and then enter the vessel architecture in the CTO segment. An appropriately sized balloon inflated over the antegrade wire connects the antegrade and retrograde spaces that allow retrograde wire entry into the antegrade true lumen. The wires may be in the intimal plaque or in the SIS in the CTO segment. This results in four different combinations [Figure 8]B. When both the antegrade and retrograde wires are either in the SIS or in the intimal plaque, the retrograde wire crosses easily into the proximal true lumen after antegrade balloon dilatation. If there is difficulty in retrograde wire crossing after antegrade balloon dilatation, IVUS helps in identifying the exact location of the antegrade and retrograde wires, the morphology of the intervening plaque, and the true vessel size. So that the strategy may be appropriately altered to facilitate wire crossing into the proximal true lumen.

When the antegrade wire is in the intimal plaque and retrograde wire is in the SIS, significant amount of intimal tissue is present between the wires and a larger balloon is required to break the tissue and connect the spaces. When the antegrade wire is in the SIS and the retrograde wire in the true lumen, the wire crossing is extremely difficult, particularly in the presence of intervening calcified intimal tissue. This situation may be resolved by either antegrade dilatation with a larger balloon and puncturing it with a retrograde Conquest Pro guidewire (Asahi Intecc, Japan), proceeding with retrograde wire crossing under the guidance of IVUS catheter positioned in the SIS, pulling back and knuckling of the retrograde wire into the SIS, and finally switching to retrograde balloon dilatation and antegrade wire crossing (conventional CART).[76],[77],[78]

Stent optimization

Once successful wire crossing is achieved, IVI helps in the assessment of plaque morphology, vessel size, lesion length, and extent of vessel wall damage. The vessel beyond the occluded segment is usually underfilled and negatively remodeled. IVI helps differentiating between diseased and negatively remodeled vessels and this avoids unnecessary stenting of the disease-free segments.

Clinical evidence for IVUS-guided CTO PCI

Two prospective, randomized trials compared IVUS versus angiography-guided DES implantation in patients with CTO lesions. In the comparisons of IVUS versus angiography-guided DES implantation for patients with CTO lesions (AIR-CTO) study, 230 patients with CTOs were randomly assigned to an IVUS-guided or angiography-guided DES implantation after successful recanalization. The primary end point of in-stent late lumen loss at 1-year follow-up was significantly lower in the IVUS-guided group (0.28±0.48 vs. 0.46±0.68mm; P = 0.025). This translated into a significantly lower “in-true-lumen” restenosis in the IVUS group (3.9% vs.13.7%; P = 0.021). However, no difference was observed in the clinical adverse events at 2-year follow-up between the groups (IVUS vs. angiography, 21.7% vs. 25.2%; P = 0.641).[81] In the second study (CTO-IVUS), Kim et al.[82] enrolled 402 patients after successful CTO recanalization into IVUS-guided (n = 201) and angiography-guided (n = 201) groups. At 1-year follow-up, the MACE (the composite of cardiac death, MI, or TVR) was significantly lower in the IVUS-guided group (2.6% vs. 7.1%; P = 0.035). Similarly, cardiac death or MI was also better with IVUS guidance (0% vs. 2%; P = 0.045). However, no difference was observed in the rates of cardiac death (0% vs. 1.0%; P = 0.16) or TVR (2.6% vs. 5.2%; P = 0.16) between IVUS guidance and angiography guidance.


  Saphenous Vein Graft Disease Top


Saphenous vein grafts (SVGs) remain the most commonly used conduits during coronary artery bypass graft surgery. Compared to arterial conduits, they have a very high-attrition rate with 10% graft occlusion at 1 month and 50% at 10 years. Similar to native coronary arteries, SVGs are also prone to develop atherosclerosis. However, the incidence is higher and the progress much faster. This leads to high repeat revascularization rates and resultant high morbidity and mortality.[83] As in native coronary atherosclerosis, IVI may be useful in understanding the pathology of vein graft failure (VGF) and may also guide revascularization.

Vein graft atherosclerosis

In the first year following implantation, the SVGs slowly adapt to the arterial circulation with the development of intimal thickening. Early atherosclerotic changes occur in the form of foam cell accumulations in the intima (intimal xanthoma) at approximately 1 year. Between 2 and 5 years, necrotic core develops in the intima that results in the formation of fibroatheroma. After 5 years, the necrotic core rapidly expands with intraplaque hemorrhage with severe lumen narrowing. The fibroatheromas in SVG have poorly developed fibrous cap and are more prone to rupture. PR with thrombus is commonly observed between 5 and 10 years. The lesions at the anastomotic sites contain predominantly fibrointimal thickening with little atherosclerotic changes.[7],[84]

IVI for assessment of vein graft atherosclerosis

Angiography poorly visualizes graft atherosclerosis and the majority of the graft occlusions occur in angiographically normal-appearing grafts. Adlam et al.[85] evaluated angiographically normal-appearing vein grafts in asymptomatic patients more than 3 years following surgery with both IVUS (n = 21) and OCT (n = 16) imaging. All the grafts showed intimal thickening with no stenotic disease. However, OCT showed features of TCFA (6/16) and luminal adherent thrombus (4/16) all of which were not apparent on IVUS. Davlouros et al.[86] assessed 28 SVGs in patients presenting with ACS. Most of the culprit lesions were angiographically complex with ulceration and thrombus. OCT visualized lipid-rich plaque in all the patients and calcium in 32.1%. Thrombus was observed more often with OCT compared to that with angiography (46.5% vs. 21.4%; P = 0.016) and the prevalence increased progressively toward STEMI. PR was noted in 60.7% and followed a similar trend as thrombus. TCFA was seen in all patients with STEMI (100%) compared to 53% and 20% in those with UA and NSTEMI, respectively (P = 0.03). Furthermore, they observed some of the features specific to vein grafts. In patients with PR, OCT showed large cavities, which are infrequent in native atherosclerotic PR. In addition, there were areas of signal-free zones along the circumference of the vessel wall with loosely adherent layer of signal-rich tissue (friable tissue) consistent with degeneration on angiography [Figure 9].
Figure 9: OCT images of vein graft. (A) Minimal intimal thickening, (B) Prominent intimal thickening, (C) Lipid rich plaque (yellow arc), (D) Solar eclipse (circumferential thin cap-fibro atheroma or macrophage infiltration), (E) Plaque rupture (yellow arrow), F-white thrombus (blue star), (G) Red thrombus (yellow star), (H) Friable tissue (signal free-zone in the vessel wall with superficial signal rich tissue, blue arrows)

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OCT for PCI guidance

PCI is patients with SVG disease is associated with very high incidence of distal embolization and resultant no-reflow and periprocedural MI. Hence, embolic protection devices are routinely recommended for PCI in vein grafts. In addition, the long-term outcomes following PCI are poor, resulting either from high incidence of restenosis or from progression of disease in other parts of the graft. This led to the practice of native vessel revascularization in patients with VGF.

Understanding the mechanism of vein graft failure: VGFs that occur within 1 year of implantation are mostly nonatherosclerotic and may not warrant additional evaluation with OCT. They may be treated with PCI without embolic protection device under angiographic guidance alone. Similarly, when the vein grafts are angiographically degenerated, PCI is associated with poor acute and long-term outcomes. OCT again does not provide any additional information, and it is worthwhile attempting native vessel revascularization if technically feasible. However, when patients present with a focal stenosis in a graft that is more than 1 year old, OCT evaluation may provide additional prognostic information. PR is the most common underlying mechanism in these patients and the extent of disease (TCFA or occult degeneration) in the angiographically normal-appearing parts of the graft determines the need for protection device and long-term prognosis. Patients with focal disease on OCT may be treated with direct stenting without embolic protection and may be associated with good long-term graft survival. If OCT imaging shows extensive disease, they may need embolic protection device and may be associated with poor long-term prognosis. This mandates aggressive secondary prevention treatment or consideration of native vessel revascularization. Stent sizing: SVGs are inherently large vessels, which make angiographic stent sizing inaccurate. Accurate stent sizing is important in vein grafts as too small a stent may result in large malapposition and early failure. In contrast, larger stents may increase the risk of distal embolization/no-reflow or cause edge dissections. Stent sizing is more difficult when the lesion is at the distal anastomotic site with the distal landing zone in the native vessel. In this situation, OCT provides accurate vessel size on either side of the lesion, and hence, a stent sized to the native reference site and with adequate expansion capacity to match the vein graft proximally may be selected. In addition, OCT also helps in selecting appropriately sized balloons for stent optimization. Selection of landing zones and complete lesion coverage: As discussed earlier, vein graft atherosclerosis is more extensive than that visualized on angiography. OCT delineates the longitudinal extent of disease and identifies disease-free landing zones and thus an appropriate length of stent is selected to cover the entire extent of disease.


  Stent Failure Top


Stent failure refers to failure of the scaffolding function of the stent. It results either from narrowing of the lumen with tissue growth (ISR) or occlusion with thrombus (ST). On the basis of the timeline of occurrence, ISR is divided into two types: early ISR (≤1 year) and late ISR (>1 year) and ST into four types: acute (<24h), subacute (1–30 days), late (30 days–1 year), and very late (>1 year). Both the pathologies occur from two basic elements: (1) abnormalities of the neointimal healing and (2) mechanical complications of the stent. The contribution of each varies with the duration of the implant.[87] IVI, particularly OCT, characterizes these abnormalities in vivo and enables pathology-targeted treatment of stent failure. The first part of this discussion deals with IVI evaluation of these two basic elements and the second part with application of IVI-derived information for the treatment of stent failure.

Neointimal healing following DES implantation

After coronary stent implantation, the vessel wall responds to injury with a healing process similar to wound healing. The healing process involves aggregation of fibrin and platelets around stent struts and transmigration of inflammatory cells into them (inflammatory phase), followed by smooth muscle proliferation and extracellular matrix synthesis (granulation phase). Later, smooth muscle cells redifferentiate to contractile phenotype and rearrange along the lumen (remodeling phase). This results in the formation of a compact neointima that is rich in smooth muscle cells with little matrix. Endothelialization of this neointimal surface completes the process of healing. Although this process is smooth and complete in a months’ time in BMS, presence of antiproliferative drugs in DES either delays this process or results in the formation of unhealthy neointima that predisposes them to stent failure.[88]

Stent strut coverage following DES implantation

Stent strut coverage is an important predictor of ST following DES implantation. OCT with its high resolution better suits for evaluation of strut coverage. Stent strut coverage is classified into four types on OCT imaging: (1) covered-embedded: struts that are covered by tissue and not disturbing the lumen contour; (2) covered-protruding: struts that are covered but extending into the lumen disturbing the lumen contour; (3) uncovered-apposed: struts that are not covered but in contact with the vessel wall; and (4) uncovered-malapposed: struts that are neither covered nor in contact with the vessel wall [Figure 10].[88] First-generation DESs were associated with a high prevalence of uncovered stent struts at 3-month follow-up and a persistent low level of uncovered stent struts at long-term follow-up. Compared to first-generation DESs, second-generation DESs with biocompatible polymers were associated with a low prevalence of uncovered stent struts both at short- and long-term follow-up. Similarly, biodegradable polymer DESs fared better than first-generation DESs.[89] However, no difference was observed in the strut coverage between second-generation DES and biodegradable polymer DES. In addition, OCT-guided stent optimization was associated with better strut coverage compared to angiography-guided stent optimization.[88]
Figure 10: : Types of stent strut coverage after drug eluting stent implantation. (A) covered-embedded. (B) covered-protruding. (C) uncovered-apposed. (D) uncovered-malapposed

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OCT patterns of neointima

OCT imaging recognizes three types of neointimal growth in patients implanted with DES: homogenous, layered, and heterogeneous [Figure 11]. The homogenous pattern is characterized by high backscattering and low attenuating tissue with no focal variation (smooth muscle cells in extracellular matrix, rich in collagen and proteoglycans or organized thrombus). The layered pattern consists of a high backscatter adluminal layer and a low backscattering abluminal layer (healed neointimal rupture or erosion). The heterogeneous pattern is made up of tissue with nonuniform optical properties with areas of high and low backscatter throughout (stent-related hypersensitivity vasculitis).[90]
Figure 11: OCT patterns of neointimal growth. (A) Homogenous pattern. (B) Layered pattern. (C) Heterogeneous pattern

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OCT neointimal patterns and long-term outcomes

Kim et al.[91] selected 336 patients with DES treated lesions and <50% angiographic DS and divided them into three groups based on the aforementioned OCT patterns. At a median follow-up of 31 months, MACE (a composite of cardiac death, nonfatal MI, or TLR) occurred more often in patients with heterogeneous neointima compared to those with homogenous and layered patterns (13.7% vs.2.7% vs. 7.3%; P = 0.001).

ISR neointimal type and response to treatment

Tada et al.[92] assessed the outcomes of three different modes of treatment (plain old balloon angioplasty [POBA], paclitaxel-coated balloon [PCB] dilatation, and DES) for ISR based on the OCT patterns of the neointima in a population of 379 patients. At a mean follow-up of 211 days, POBA group was associated with higher ISR and TLR rates compared to DES and PCB groups and no difference was observed between DES and PCB groups. In lesions with homogeneous and layered patterns, DES was associated with significantly larger lumen gain and PCB with smaller late loss. In contrast, in lesions with heterogeneous pattern, no significant difference was observed in the acute gain and late loss between the three treatments. The POBA group was associated with higher ISR rates in lesions with homogeneous and layered patterns compared to DES and PCB groups and higher TLR rates in lesions with homogeneous pattern. In lesions with heterogeneous pattern, no difference was observed in the ISR and TLR rates between the three treatments. Similar results were observed when lesions are classified into high and low backscatter types. The authors speculated that homogeneous and layered patterns are associated with high proliferative activity and need treatment with antiproliferative treatment. In contrast, heterogeneous pattern is less cellular and as it may result from hypersensitivity reaction to the drug or polymer, treatment with PCB or DES may not be effective.

Neoatherosclerosis

Neoatherosclerosis refers to the development of atherosclerotic changes in the neointimal tissue and is increasingly being recognized as an important cause of very late stent failure with both BMS and DES. Dysfunctional endothelium covering the neointimal tissue promoting transmigration of macrophages and accumulation of lipoproteins has been proposed as the possible cause of neoatherosclerosis. This may result either in progressive increase in the atherosclerotic tissue volume and ISR or PR and ST. It is more common and occurs much earlier with DES compared to that with BMS. The prevalence increases with the duration of the implant with both BMS and DES. No difference is observed in the prevalence between the first- and second-generation DES or between DES with permanent or biodegradable polymers. Though these changes have initially been reported with pathological studies of very late stent failure, with the availability of IVUS tissue characterization algorithms and OCT, it is currently possible to diagnose neoatherosclerosis in vivo. It is characterized by lipid-laden intima, calcification, intimal rupture, and luminal thrombus [Figure 12]A–E.[93] Although it was perceived that stent restenosis is a benign process presenting with chronic stable angina and ST as acute presentation with dramatic outcomes, a significant number of patients with late ISR present with ACS and neoatherosclerosis with rupture serves as the common denominator between the two forms of late stent failure.[94]
Figure 12: OCT images showing underlying pathologies in late and very late stent thrombosis. (A–E) instent neo-atherosclerosis. (A) lipid rich plaque (yellow star) with white thrombus (white arrows), (B) TCFA with rupture (orange arrows) and (C) red thrombus (red star). (D) in stent neo-atherosclerosis with macrophages (red arrow heads) and (E) calcification (green star) with no superimposed thrombus. (F–H) uncovered stent struts resulting from (F) persistent malapposition, (G) late acquired malapposition and (H) apposed persistently uncovered stent struts with white thrombus (white arrows)

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Early versus late ISR

In a study comparing DES with early ISR (≤1 year) and late ISR (>1 year), it was found that early ISR was associated with higher prevalence of heterogeneous pattern (36.8%) and lower prevalence of homogeneous pattern (31.6%) and neoatherosclerosis (15.8%). In 15.8% of the patients, the neointimal thickness was <100µ. In contrast, late ISR was characterized by a higher prevalence of homogeneous patterns (47.5%) and neoatherosclerosis (28.9%), a lower prevalence of heterogeneous pattern (21.9%), and very low prevalence of neointimal thickness <100µ (1.8%).[95] In another study of second-generation DES, early ISR group had higher prevalence of homogeneous neointima, whereas late ISR group had higher prevalence of neoatherosclerosis.[96] Lee et al.[97] evaluated the neointimal patterns between early and late ISR groups and compared their response to treatment with drug-coated balloon (DCB). Early ISR was associated with higher incidence of MACE after DCB treatment compared with late ISR and heterogeneous pattern was associated with higher MACE compared to other patterns. No difference was observed in the outcomes between neoatherosclerosis and non-neoatherosclerosis patterns.

Mechanical complications of the stent

Underexpansion

Gross underexpansion of the stent may result in lumen compromise in the presence of normal neointimal growth. The immediate post-stenting MSA has repeatedly been shown to be an important predictor of ISR both with BMS and DES. With BMSs, a post-stenting MSA of <6.5mm2 identified ISR at follow-up.[98],[99],[100] In addition, the incidence of ISR decreased by 19% for every 1-mm2 increase in the lumen area.[101] This led to the concept of “bigger is better” with BMS implantation. Though DES has suppressed the neointimal hyperplasia significantly, MSA continues to be an important determinant of ISR. The IVUS MSA cutoff, which predicted DES restenosis at 9 months, varied between 5 and 5.7mm2 among different DES.[99],[100],[102],[103] Similarly, in a recent OCT study, the MSA was an important determinant of MACE and the cutoff value was 4.5–5mm2 for DES and 5.7mm2 for BMS.[104],[105] Another OCT study comparing early versus late DES ISR observed a higher incidence of small MSA (<4mm2) in patients presenting with early ISR.[95] Further, underexpansion is commonly observed with longer stents (>28mm).[106] In an IVUS study, stent length >40mm was associated with increased incidence of restenosis.[100]

Malapposition

Although most of the prospective studies did not show any association between malapposition and MACE, it was one of the most common abnormalities observed in patients presenting with entire spectrum of ST.[107],[108],[109],[110],[111],[112] Malapposition that occurs during late stent thrombosis (LST) and very late stent thrombosis (VLST) results from a persistent malapposition that existed at the time of stent implantation or develops later from either thrombus resolution or from vessel wall inflammation and positive remodeling [Figure 12]F and G. Late-acquired malappositions from the later cause take the form of either coronary evaginations (focal outpunching) or gross aneurysms. These malappositions may easily be differentiated from persistent malappositions by identifying the positive vessel remodeling at the site of malapposition.[113] The cause and effect association between late-acquired malappositions and VLST is yet to be demonstrated conclusively. It is postulated that vessel wall inflammation may be the initial event in the pathogenesis of VLST. Malapposition with resultant flow disturbances and poor stent strut coverage may culminate in thrombosis.[114] In a study evaluating patients with VLST with both IVUS and OCT, mean length of the uncovered stent struts on OCT and remodeling index by IVUS were predictors of ST.[115]

Other mechanical complications

The other mechanical complications that result in stent failure are stent fracture, longitudinal deformation, stent gap, uneven strut distribution, geographic miss, edge dissection, and tissue or thrombus prolapse.[116]

Early versus late/very late stent thrombosis

A number of IVUS studies have evaluated the underlying abnormalities in patients presenting with both early ST and LST/VLST. In patients with early ST, the various underlying abnormalities were stent underexpansion, stent malapposition, edge dissections, significant inflow and outflow disease, and thrombus and tissue prolapse.[117],[118],[119],[120],[121] The dominant IVUS mechanisms of VLST were malapposition, in-stent neointimal tissue and neointimal rupture, and underexpansion. Malapposition was observed only in DES.[114],[115],[122]

There are six recent registries that have evaluated patients with DES/BMS thrombosis with OCT imaging.[107],[108],[109],[110],[111],[112] Two of them evaluated both early and late events and the remaining four only VLST. In patients with early (acute and subacute) ST, the predominant findings were uncovered stent struts (50% and -), malapposition (11.3% and 48%), severe underexpansion (20.9% and 26%), edge-related disease progression/edge dissection (2.1% and 8%), and no identifiable cause (3.2% and 18%).[107],[108]

The predominant mechanisms of LST were uncovered struts (33.3% and 0%), malapposition (9.5% and 44%), underexpansion (14.3% and 14%), restenosis (19.1% and 14%), ruptured neoatherosclerosis (- and 14%), coronary evagination (- and 14%), edge pathology (9.5% and 0%), and no dominant cause (14.3% and 0%).[107],[108]

In patients with VLST, the principal findings were neoatherosclerosis (27.6%–70%), uncovered stent struts (11%–70.5%), malapposition (14.2%–46%), restenosis (1.7%–11.9%), underexpansion (4.5%–7%), edge pathology (4.5%–9%), extra-stent cavity/evagination (2.2%–10%), neointimal erosion (0%–4.1%), and no dominant cause (0%–11.2%).[107],[108],[109],[110],[111],[112]

OCT to guide treatment of in-stent restenosis

Treatment of ISR is associated with inferior outcomes with high recurrence rates compared to the treatment of native atherosclerotic disease. With the advent of IVI, particularly OCT, it is possible to offer pathology-targeted therapy in patients presenting with ISR. OCT imaging clearly separates the mechanical causes of ISR from neointima-related ISR. In addition, it enables spatial mapping of the ISR and hence treatment is limited to the sites with disease, sparing the areas with a normal healing pattern.

Correction of mechanical abnormalities

In all patients presenting with ISR, stent expansion should be assessed in the first instance. If underexpansion is identified and neointimal thickness is <100µ, it may be treated with expansion of the stent with balloon dilatation alone. If the underlying plaque is highly resistant, treatment with excimer laser may be considered. In patients with underexpansion associated with predominant neointimal hyperplasia, underexpansion needs to be corrected before proceeding with definitive treatment. In those with progression of disease at the stent edges, additional stent implantation is undertaken extending to a disease-free landing zone. In addition, ISR related to other mechanical causes, such as stent fracture, stent gap, and uneven strut distribution, are treated with additional DES implantation.

Treatment of neointimal disease

From the previous discussion, it is clear that neointima in patients with ISR shows different OCT patterns and they respond differently to various treatment options. First, OCT imaging is obtained and the underlying neointimal pattern is delineated. Then, the lesion is treated with appropriately sized high-pressure POBA (heterogeneous pattern) or cutting balloon/scoring balloon dilatation (homogeneous and layered patterns) and rarely rotational atherectomy in lesions with extensive intra-stent calcification (calcified neoatherosclerosis). Care should be taken in patients with neoatherosclerosis and long-segment TCFA as aggressive balloon dilatation may result in no-reflow. After balloon dilatation, the lumen gain is assessed with OCT imaging. If the lumen gain is adequate and the underlying pattern is heterogeneous, this completes the treatment as this pattern responds poorly with DCB and DES. If the lumen gain is adequate and the underlying pattern is homogeneous or layered, it may be treated with DEB. Similarly, patients with neoatherosclerosis may also have favorable response with DCB if post-ballooning lumen gain is adequate. In any of the patterns, if the neointima burden is large and the lumen gain is inadequate, scaffolding the tissue with DES after optimal preparation may improve the lumen gain. It is important to keep in mind that the above algorithm is based on limited data available from the current literature and we need larger patient data sets to derive more insights into the efficacy of different treatment modalities.

In general, DES is avoided in ISR lesions with multiple layers of stents, ISR in small vessels, ISR in stents across SBs, and stents that are not fully expanded with maximum dilatations.

OCT for treatment guidance in ST

ST is a rare but life-threatening complication of PCI associated with high in-hospital mortality and poor long-term outcomes with high recurrence rate. Hence, when a patient presents with ST, the opportunity must be used to thoroughly evaluate the underlying mechanism and every effort should be made to resolve it. IVI should be considered as mandatory in ST.

After IRA flow is established with thrombosuction, OCT imaging may be safely performed. In patients with early ST, the use of OCT imaging is to differentiate mechanical causes of stent failure from antiplatelet resistance. In case of underexpansion and malapposition, the stent is dilated with an appropriately sized balloon guided by OCT imaging. When an edge dissection or severe inflow/outflow disease is identified, additional stent implantation extending to an appropriate landing zone is undertaken. In the absence of mechanical complications, an appropriate adjustment in the antiplatelet therapy is warranted.

In patients with LST/VLST, OCT imaging clearly delineates one of the three common underlying mechanisms: uncovered stent struts, malapposition, and neoatherosclerosis with rupture [Figure 12]A–C and F–H. In cases of more than one underlying mechanism, the dominant mechanism is identified by locating the adherent thrombus. Underexpansion should be identified and treated appropriately. Uncovered stent struts require only thrombosuction and indefinite continuation of DAPT. In case of malapposition, the differentiation has to be made between persistent/thrombus dissolution-related malapposition and hypersensitivity-related malapposition by identifying positive vessel remodeling. IVUS may have a role in visualizing the full extent of positive remodeling where OCT is limited by its penetration. First type necessitates correction with appropriately sized balloon, and hypersensitivity-related malapposition is treated with indefinite DAPT. When neoatherosclerotic rupture is the underlying pathology, it is treated with additional stenting. In all cases, additional causes, such as edge disease, need to be addressed.

OCT insights into the outcome of LST/VLST patients treated with IVI guidance

Although patients with LST/VLST are at risk of recurrent ST, the exact mechanism of recurrence is not known. Ñato et al.[123 evaluated 34 patients with LST/VLST treated with IVI guidance during index procedure by 1-year follow-up OCT imaging. They were divided into two groups: malapposition group (n = 17],[ 50%) and non-malapposition group (neoatherosclerosis [n = 9]],[ underexpansion [n = 3]],[ and unknown mechanisms [n = 5]). Patients with malapposition underwent aggressive correction during index procedure with significant reduction in malapposition volume (6.4–1.3 mm3; P = 0.02). However],[ in 13 (76.5%) patients],[ it was not fully corrected. At 1 year],[ two patients in the malapposition group had silent target vessel occlusion],[ and malapposition was persistent in 9 (60%) patients. In addition],[ the malapposition group also had a higher prevalence of major coronary evaginations and uncovered stent struts. Patients in the non-malapposition group had favorable healing pattern. Neoatherosclerosis was not identified in any of the patients.

Bioresorbable vascular scaffold thrombosis

Bioresorbable vascular scaffold is a novel technology],[ which offers many potential advantages compared to the current generation metallic DES from its complete degradation potential. However],[ the current technology was associated with inferior outcomes compared to the contemporary DES. With the recognition of an increased incidence of late and very late scaffold thrombosis],[ the device was withdrawn from the market. Although the device is not available for clinical use],[ the interventionist will continue to encounter patients presenting with scaffold thrombosis. The mechanisms of scaffold thrombosis are different from that of DES. Scaffold discontinuity is the most common mechanism],[ followed by malapposition],[ neoatherosclerosis],[ and underexpansion/scaffold shrinkage. In case of biodegradable vascular scaffold thrombosis],[ the mechanical disintegration is corrected with an appropriately sized DES. OCT imaging confirms adequate jailing of the scaffold elements],[ preventing them from exposure to the flowing blood and recurrent thrombosis.[124]

IVI, particularly OCT imaging, is the cornerstone in the treatment of patients with stent failure. In line with this, the current guidelines recommend evaluation of stent failure with IVI (Class IIa, level of evidence B).[125]


  Cardiac Allograft Vasculopathy Top


Cardiac allograft vasculopathy (CAV) remains the major cause of late transplant failure. It is noted as early as 1 year after transplantation and the incidence at 10 years is as high as 50%.[126] CAV results primarily from immune-mediated injury to the endothelium of the coronary arteries of the transplanted heart. It usually occurs in the form of diffuse intimal thickening and develops atherosclerotic changes in the later stages. Importantly, CAV remains asymptomatic because of cardiac denervation and manifests with graft failure, arrhythmias, or sudden cardiac death. CAG and noninvasive stress testing are commonly used to monitor transplant patients for CAV. Although they provide valuable prognostic information by predicting obstructive CAD, they are insensitive to detect early CAV as it is diffuse in nature and mostly non-flow limiting.[127]

Introduction of IVUS imaging improved the detection rates of early CAV that was not apparent by conventional angiography. Early CAV appears as diffuse intimal thickening on IVUS imaging. In an IVUS study, an increase in maximal intimal thickness by ≥0.05mm between baseline and 1-year posttransplant imaging predicted subsequent mortality, MACE, and development of CAV on angiography within 5 years.[128] In another study, Okada et al.,[129] using serial 3D volumetric analysis, noted a phenomenon of paradoxical remodeling in transplanted coronary arteries where there was an overall decrease in vessel volume despite the increase in the intimal volume. Development of paradoxical remodeling at 1-year IVUS follow-up predicted mortality or retransplantation. Although IVUS can reliably detect intimal thickening and vessel remodeling, its resolution is inadequate to detect very early neointimal changes.

OCT, with its superior resolution, detects very early neointimal changes of CAV. In addition, its ability to clearly delineate intima from media makes it an ideal imaging tool to monitor progression of CAV. In addition to intimal thickening, OCT detects atherosclerotic changes more often than IVUS. Hou et al.[130] evaluated the three segments of LAD coronary artery (proximal, mid, and distal) in seven long-term transplant survivors with both IVUS and OCT imaging. OCT imaging identified intimal hyperplasia (intimal thickness >100µ) more frequently compared to IVUS (14/21 segments [66.7%] vs. 3/21 segments [14.3%]; P < 0.01). In addition, OCT observed lipid-rich plaques with thin fibrous caps in three patients. In another study, Cassar et al.[131] assessed the LAD in 53 posttransplant patients with OCT imaging in addition to CAG and IVUS imaging. The proximal 30mm of the LAD was divided into three segments of 10mm each and additionally into three groups based on the time since transplantation. They reevaluated areas of IVUS-visualized CAV plaques with OCT imaging. OCT imaging showed progressively increasing prevalence of both atherosclerotic changes (eccentric plaques, calcification, lipid pools, thin-cap fibroatheroma, macrophages, and microchannels) and complicated lesions (intimal laceration, intraluminal thrombus, and PR) with the duration since transplantation. In a recent study by Clemmensen et al,[132] layered fibrous plaque (a layered structure with signal intensity lesser than that of deep intimal tissue) was the most prevalent plaque type and was strongly associated with CAV progression [Figure 13]. Although OCT detects the early abnormalities and atherosclerotic changes better than IVUS, the clinical relevance of these findings needs to be evaluated in future studies.
Figure 13: Transplant vasculopathy. (A) Angiogram showing three focal stenoses in LAD. (B–G) and (H–M) show corresponding OCT and IVUS cross sectional images of mid to ostio-proximal LAD. OCT frames (B), (C), (D) and (F) show layered fibrous plaque (the dark appearance of the plaque results from immature fibrous tissue) and (D), (E) and (G) intimal thickening. Corresponding IVUS images show predominantly fibrous tissue morphology in (H), (I) and (K) and intimal thickening in (J), (L) and (M). Balloon dilatation induced dissection is shown at 3 O’clock position in (F). Longitudinal OCT and IVUS views are shown in (N) and (O) respectively. Red lines on CAG indicate the proximal and distal limits of IVUS and OCT imaging

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  Minimal or Zero-Contrast Angioplasty Top


Contrast-induced nephropathy (CIN) is a rare but potentially serious complication following angiographic procedures and has been associated with poor short- and long-term outcomes. The severity of preexisting renal compromise and the volume of contrast administered during the catheterization procedure are the main determinants of CIN. Although numerous preventive and therapeutic strategies have been tested, none of them except for reduction in the volume of contrast administered have been shown to reduce the incidence of CIN. Hence, a significant proportion of patients of CAD with renal dysfunction are denied diagnostic and therapeutic angiographic procedures. IVI guidance, during invasive procedures, reduces the need for multiple contrast injections that in turn reduce the volume of contrast administered. This led to the development of IVI-guided minimum or zero-contrast PCI [Figure 14].[133],[134]
Figure 14: IVUS guided zero contrast PCI. (1) Diagnostic angiogram in postero-anterior cranial view showing mid LAD lesion (red arrow). (2) Metallic silhouette using three wires in LAD, Diagonal and LCX was created. IVUS run after predilatation showing (A) Proximal reference diameter at ostio-proximal LAD (mean diameter- 2.75 mm), (B) Calcium at 6–7 O’clock position, (C) Critical lesion site, (D) Diagonal wire entering LAD, (E) Distal reference (mean diameter- 2.25 mm). (3) IVUS longitudinal view showing the lesion length-53mm (yellow line). Length from diagonal to distal reference site (double headed red arrow)-24mm and the length from proximal reference to diagonal (double headed white arrow)-29mm. Hence a 2.25 x 28 mm stent for distal half and a 2.75 x 28 mm stent for proximal half with 3 mm overlap proximal to the diagonal was planned and executed. (4) Final IVUS after stent optimization (F) proximal edge of stent—no edge dissection with good expansion (Stent area: 7.57 mm2) and apposition. (G) Good circular expansion at calcium site. (H) Well expanded stent at critical lesion site (MSA: 6.54mm2). (I) Diagonal ostium was not pinched. (J) Well expanded and apposed stent at distal edge (MSA: 4.22 mm2) without edge dissection. (5) IVUS longitudinal view after post dilatation shows well expanded and apposed stent without geographic miss, edge dissection or tissue prolapse. Blue arrow shows well opened LCX

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Mariani et al.[133] randomly allocated 83 patients at high risk for CIN or volume overload to either IVUS-guided PCI or angiography-guided PCI. All the patients at risk for CIN were treated with intravenous hydration for 12h pre- and postprocedure. All general measures were taken to reduce the volume of contrast administered in both the groups: (1) limiting contrast volume to less than two times of contrast volume/creatinine clearance ratio, (2) detailed preplanning of angiographic views and stenting strategies, (3) avoiding baseline angiography in patients with good-quality diagnostic CAG, (4) preference for smaller size guiding catheters without side holes and small volume syringes, (5) use of diluted contrast media, (6) general use of auxiliary monitors for continuous display of reference images of the target vessels, (7) extensive use of the stent and vessel enhancement functions, (8) liberal use of high frame rate acquisitions, and (9) aspiration of residual contrast in the guiding catheter before insertion of devices. In addition, in the IVUS-guided PCI group, automatic/manual IVUS pullback imaging was used instead of angiography to decide on the need for lesion preparation, to identify the stent landing zones, and to estimate stent diameter and length. Postprocedure, IVUS was again used to confirm stent expansion, apposition, and edge-related problems. Final angiography was avoided if the IVUS results were satisfactory. The IVUS-guided PCI group was associated significantly with lower median total contrast volume (20.0 vs. 64.5mL; P < 0.001) and median contrast volume/creatinine clearance ratio (0.4 vs. 1.0; P < 0.001) compared to the angiography-guided PCI group. However, no difference was observed in the in-hospital and 4-month clinical outcomes.

Ali et al.[134] evaluated the safety and feasibility of imaging and physiology-guided zero-contrast PCI in 31 patients with advanced chronic kidney disease. All patients underwent ultralow volume contrast CAG (contrast volume/estimated glomerular filtration rate ratio <1) in predefined views (left anterior oblique/cranial for RCA and anteroposterior/caudal and anteroposterior/cranial for left coronary artery). The lesions that were not properly visualized or were borderline were evaluated by FFR. Patients underwent PCI at least a week after diagnostic angiography. Before the PCI procedure, echocardiography was carried out to rule out preexisting pericardial effusion. The diagnostic angiograms were uploaded to the monitor and used as a guide during procedure. Guide catheter engagement was confirmed by wire entry into the coronary artery. Once the wire crossed the lesion, it was looped to prevent distal perforation. Additional guidewires were inserted into the SBs to create a metallic silhouette of the artery. Then baseline FFR and CFR were measured. Automatic IVUS pullback imaging was carried out to decide on the need for lesion preparation, to identify the stent landing zones, and to estimate the stent size. Stent diameter was based on the smaller of the reference mean external elastic membrane diameters, and landing zones were chosen to have <55% of PB. The IVUS catheter was positioned manually at the landing zones (proximal and distal) and the location of the transducer was recorded. Stent was deployed based on the landing zones identified by IVUS and SB wire references. Postprocedure, IVUS examination was repeated to confirm the stent expansion, apposition, and edge-related problems, and the stent was further optimized if required. The procedure was completed with final FFR (>0.80) and CFR (>2) assessment and an echocardiographic assessment to rule out new pericardial effusion. Angiography was indicated for chest pain, ischemic electrocardiogram changes, suboptimal physiological indices, or new or enlarging pericardial effusion. This approach resulted in successful completion of PCI procedure in all patients with no MACE and deterioration of renal function.

Recently, zero-contrast PCI has also been reported with OCT guidance using low-molecular-weight dextran. The additional advantage with OCT-guided zero-contrast PCI is the feasibility of co-registration of fluoroscopic images with OCT longitudinal and cross-sectional images.[135],[136]


  Discontinuation of Dual Antiplatelet Therapy Top


The current guidelines recommend 12 months of DAPT in patients treated with a DES. However, it is not uncommon for some patients with DES to temporarily discontinue DAPT for various reasons during this time. This may be associated with an increased incidence of ST. Suboptimal stent deployment and uncovered stent struts predispose these patients to ST in the absence of DAPT.[87] OCT clearly delineates various features of suboptimal deployment, such as underexpansion, malapposition, and edge abnormalities, and in addition, its high resolution enables assessment of neointimal coverage. This may provide an opportunity to risk stratify patients who require temporary discontinuation of DAPT.

Iliescu et al.[137] evaluated 40 patients with cancer who required transient discontinuation of DAPT with OCT imaging. Patients were divided into two groups based on the following features: underexpansion, malapposition, uncovered stent struts, ISR, or intraluminal mass. Twenty-seven patients (68%) without these features were considered low risk and allowed to discontinue DAPT. The remaining 13 patients with one or more of these features were considered high risk and underwent further intervention. At 12-month follow-up, no cardiac events were reported in the low-risk group, whereas one MI occurred in the high-risk group. Fourteen patients died of cancer progression during this period. Although this approach is intuitive, it needs to be evaluated in a large population study.


  Conclusion Top


IVUS is a time-tested imaging modality with large volume of clinical evidence. It has been shown to improve outcomes independent of clinical presentation or lesion subset. With its large field of view and depth penetration capabilities, it remains the modality of choice for the assessment of intermediate lesions and treatment guidance in LMCA territory. Similarly, the ability to image through blood makes IVUS imaging the cornerstone in the procedure guidance during CTO interventions. OCT with its unsurpassed resolution has revolutionized our understanding of the coronary atherosclerosis and stent and vessel wall interactions. This has opened new avenues in the treatment of CAD, particularly in the management of patients presenting with ACS, bifurcation disease, and stent failure. The ongoing clinical studies will clarify the clinical relevance of the wealth of information derived from OCT imaging.

Acknowledgement

We would like to thank Ms. Nandhini Livingston, Ms. Deva Preethi, and Mr. Avinash K. for their technical support in art work and manuscript editing.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  In this article
Abstract
Introduction
Acute Coronary S...
Left Main Corona...
Bifurcation Lesions
Calcified Lesions
Chronic Total Oc...
Saphenous Vein G...
Stent Failure
Cardiac Allograf...
Minimal or Zero-...
Discontinuation ...
Conclusion
References
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