The methodology for this review on IVUS and OCT guidance in coronary disease for patients with CKD and diabetes is based on the guidelines for evidence selection from the Journal of Clinical Medicine (JCM). The review aims to provide an in-depth evaluation of the safety and efficacy of IVUS and OCT in guiding coronary interventions in this specific patient population.
A comprehensive literature search was conducted through electronic databases, including PubMed, Embase, and the Cochrane Library. The search was performed up to July 2023 to ensure the most recent and relevant studies were included. The following keywords and medical subject headings (MeSH) terms were used in combination: “Intravenous Ultrasound,” “IVUS,” “Optical Coherence Tomography,” “OCT,” “coronary artery disease,” “CAD,” “diabetes mellitus,” “diabetes,” “coronary intervention,” “percutaneous coronary intervention,” “PCI,” “intravascular imaging,” “CKD,” and “diabetic patients.” The search was limited to studies published in English.
Studies were selected based on their relevance to the topic and adherence to the guidelines provided by Journal of Clinical Medicine. The inclusion criteria encompassed original research articles, randomized controlled trials, observational studies, systematic reviews, meta-analyses, and retrospective analyses. To ensure the focus on CKD patients with CAD and diabetic patients with CAD, studies that did not specifically address this patient population were excluded.
Data from selected studies were extracted and organized into a standardized format (Table 1), including study characteristics (e.g., authors, publication year), patient demographics, sample size, intervention details (IVUS or OCT), and clinical outcomes. The extracted data were then synthesized and analyzed to provide a comprehensive overview of the safety and efficacy of IVUS and OCT guidance in coronary interventions for patients with diabetes or CKD.
The objective of the quality assessment was to guarantee the reliability and validity of the evidence presented in this review. Every effort was made to include all relevant studies. As with any review, potential bias can exist in the selection and interpretation of studies, and the findings should be interpreted considering these limitations.
Safety with IVUS and OCT
Intravascular images are obtained in both techniques after engaging the coronary ostium with the guiding catheter and insertion of a guidewire, which is then followed by the insertion of IVUS or OCT catheter over the wire. There are a few complications associated with using both IVUS and OCT, with higher rates of complications with ACS compared to non ACS patients with stable angina pectoris and in asymptomatic patients (2.1% in ACS compared to 0.8% and 0.4% in stable angina and asymptomatic patients).32 Like any other intravascular procedure, these catheters require use of anti-coagulation with heparin. Nitroglycerine is routinely administered considering 3% reported incidence of coronary spasm associated with these imaging techniques.32,33 Complications other than the spasms include embolism, dissection, acute vessel occlusion, thrombus formation and usually present as acute myocardial infarction or requiring emergency coronary artery bypass surgery. In the IUVS PROSPECT trial which included 697 ACS patients receiving three-vessel coronary imaging, complication rate was 1.6% including 10 dissections and 1 perforation.33,34 In the more recent Thoraxcenter study from Rotterdam, NL, in which 1000 OCTs and 2500 IVUS were performed, the complication rates were much lower with no difference between the two imaging modalities and with no major adverse cardiac events.35 As with any procedure, the complications are lowest in centers using this on a regular basis than those doing fewer studies.
IVUS enables precise measurements of the vessel size and plaque burden, as it can penetrate to the adventitia, including the external elastic membrane. This facilitates mid-wall or true vessel stent sizing, optimizing stent dimensions, and identifying areas with the smallest plaque burden to minimize geographical miss. Proper stent positioning and expansion are crucial factors in reducing the incidence of restenosis and stent thrombosis, both of which can have significant long-term implications for patients.36 IVUS has established predictors of stent failure, such as stent underexpansion, major edge dissections, and geographical miss.
Several meta-analyses have confirmed the benefits of IVUS guidance. One meta-analysis of randomized trials comparing IVUS-guided bare metal stent implantation with angiography-guided procedures revealed a reduction in restenosis and repeat revascularization, without impacting death or myocardial infarction.37 Two recent meta-analyses of studies comparing IVUS-guided drug-eluting stent procedures with angiography-guided interventions showed a decreased incidence of death, major adverse cardiac events, and stent thrombosis.38, 39 These findings are supported by additional clinical studies, including the RESET trial from South Korea and the ADAPT-DES observational study involving over 8,500 patients.40, 41 Collectively, these advantages demonstrate the significant role of IVUS in improving outcomes and safety in coronary interventions.
Some Clinical Uses of intravascular imaging
Stenosis severity: Left main coronary artery lesions
Assessment of the LMCA with angiography can be challenging. IVUS of LMCA has been shown to correlate more with FFR measurement of the LMCA.42 It is important to remember the difference in LMCA sizes between the various ethnic groups. In general, Asian population have a smaller vessel diameter, and so MLA when compared to the western population. In Koreans, an IVUS LMCA MLA of 4.5-5.8 mm2 results in negative FFR (FFR≥0.8) while in the western population, LMCA MLA of less than 6 mm2 has been shown to be associated with an FFR of <0.75.42 In a Spanish registry,43 patients with an MLA>6 mm2 (179/186), who did not get revascularization, had similar cardiac death free survival (p=0.5) when compared to patients who had MLA < 6 mm2 (152/168) and who had revascularization. Also, even free survival in both the groups were similar (P=0.3). The study also showed that people who had MLA between 5 to 6 mm2 did worse when treated only with medical therapy without revascularization. In a study of 122 patients with LMCA lesion not treated at the time of IVUS assessment, the annual event rate was about 14% and minimal luminal diameter on IVUS was the most important predictor of cardiovascular events.44 Ideally, IVUS should be done from both the left anterior descending and left circumflex artery to evaluate LMCA dimensions. OCT has got a few limitations including the requirement of contrast and inability to measure ostial lesions. But OCT is ideal to measure distal left main lesions which is prone to form complex plaques extending left anterior descending and left circumflex arteries.45
Stenosis severity: Non-Left main coronary artery lesions
In non-LMCA lesions, MLA of 4 mm2 has been shown as the cut off to differentiate between vessels with and without ischemia. In a study by Abizaid et al, MLA>4 mm2 was found to be associated with a coronary reserve of ≥2.46 When revascularization was deferred based on MLA > 4 mm2, IVUS MLA and area stenosis (AS) were the only independent predictors of MACE at follow up.47 FFR is known to be the gold standard for evaluation of ischemia in three randomized controlled trials (RCTs) and FFR based revascularization for patients with a value of <0.8 has been shown to improve patient outcomes and prognosis.4,48-51 Comparison between FFR and IVUS in patients with intermediate coronary lesions was performed in a recent study.52 FFR of <0.8 and MLA on IVUS <4 mm2 were used as criteria for revascularization. 94 lesions were treated with IVUS whereas 83 were treated with FFR. A significant number of people in the IVUS arm underwent revascularization therapy when compared to FFR guided therapy (92% and 34% respectively, P<0.001) but there was no significant difference in MACE at 1 year follow up (3.6% in FFR guided PCI versus 3.2% in IVUS guided PCI). In a few published studies, the range of IVUS measurements guiding ischemia ranged from 2.1 mm2 to 4.4 mm2 suggesting inconsistency. One needs to be aware of the difference in vessel dimensions between the western population (higher MLA) and the Asian population (typically lower MLA) while interpreting IVUS MLA. The sensitivity of IVUS MLA (<4 mm2) compared to FFR was only 92% with a 56% specificity, while a longer lesion length of >10 mm had a sensitivity of only 41% with higher specificity of 80%.53 Based on the various studies, it can be concluded that an IVUS MLA of >4 mm2 could be treated conservatively (higher negative predictive value) but treating all lesions <4 mm2 MLA on IVUS leads to treating almost 50% of lesions without ischemia (lower positive predictive value).
There is a good correlation between IVUS and OCT measured MLA with nearly similar sensitivity and specificity.54 OCT guided MLAs are typically smaller in the range of 1.6 mm2 to 2.4 mm2. In an OCT based study treating 62 intermediate lesions in 59 patients, an OCT derived MLA of <1.91 mm2 and percentage lumen AS of > 70% were shown to correlate well with an FFR of <0.75. OCT suffers similar limitations like IVUS with a higher negative predictive value but a lower positive predictive value. There are no RCTs comparing IVUS to OCT similar to FFR and iFR studies. It is important to remember that both IVUS and OCT, do not take into account, the subtended viable myocardial mass, or information on antegrade or retrograde flow through collaterals.
Monitoring Plaque Morphology and Changes with Therapy:
A number of studies were done to evaluate the effect of medical therapy on plaque volumes and IVUS has been the preferred mode of imaging in most of these studies. This has helped us understand plaque biology and effect of treatments including statins and more recently, the PCSK-9 inhibitors (Puri JAMA Cardiology 2018). For example, Von Birglelen et al followed mild LMCA atherosclerosis over a period of 18±9 months and showed that LDL levels correlated with plaque progression whereas HDL levels had an inverse correlation.55 The REVERSAL (Reversal of atherosclerosis with aggressive lipid lowering) is a double blinded RCT that demonstrated IVUS derived atheroma volume showed a significantly lower progression of atherosclerotic plaque in patients treated with atorvastatin (P=0.02).56 Progression of plaque did not occur in the atorvastatin group whereas the pravastatin group had plaque progression. The ESTABLISH trial also showed regression of plaque volume in the atorvastatin group.57 In ASTEROID, the mean percentage atheroma volume (PAV), the most reliable IVUS measure of disease progression and regression, showed significant regression in patients treated with high dose rosuvastatin.58 However, it is essential to standardize the methods for plaque assessment, and this in fact comes with significant challenges.
Some would argue that it is important to identify vulnerable plaques, but this view is controversial.59 The most common finding of the so-called vulnerable plaque is the TCFA, a precursor for thrombotic plaque rupture. Greyscale IVUS has suggested four different morphologies consistent with a TCFA including large plaque burden, shallow echolucent zones, spotty calcifications and attenuated plaque (shadowing without calcification) though only the former three (except attenuated plaque) have been shown to be associated with adverse outcomes including myocardial infarction, hospital admission and need for PCI.34, 60, 61 The largest data comes from the virtual histology IVUS that has shown to predict future adverse events in non-culprit lesions. Both grey scale IVUS and radiofrequency (RF) IVUS (integrated backscatter IVUS and virtual history IVUS) have shown to predict cardiac events. The difference between OCT and radiofrequency IVUS is that RF IVUS can only suggest the presence of TCFA by identifying the necrotic core along the lumen whereas OCT is able to define the thickness of a thin fibrous cap less than 65 µm, macrophages in the fibrous cap and also presence of underlying lipid core. Studies have shown that the presence of a higher plaque burden of >70% can be used to predict a TCFA, able to differentiate between ruptured and non-ruptured atheroma and to identify the culprit versus non-culprit plaque ruptures. Another OCT based study showed that the rapid angiographic lumen loss of >0.4 mm in 7 months was associated with increased frequency of intimal laceration, micro-vessels, TCFA, macrophages, lipid accumulation and intraluminal thrombi.62 There are a few other studies evaluating using the NIRS technique to identify vulnerable plaques, including the LRP (NCT02033694), PREDICT (NCT02792075), and PROSPECT-2 (NCT02171065) trials.
Serial intravascular imaging has shown that plaque morphology could rapidly change over a period of few months without actual rupture, especially in patients treated with high dose statins. As intravascular imaging is invasive, it is important to evaluate the appropriateness of imaging to identify vulnerable plaques, which again depends on the prevalence of TCFAs, their frequency, stability, pharmacotherapy needed during the procedure and complications associated with intravascular imaging. It is essential to understand that there are a lot of grey areas in this space – we don’t have a consistent technique or definition that best predicts outcomes in vulnerable plaques - studies have shown wide disagreement between the different imaging modalities, including grey scale IVUS, RF IVUS, angioscopy, OCT and NIRS, often in the range of 25-30%. These techniques suffer from biased populations and high sensitivity at the expense of low specificity.34
Patients with Chronic Kidney Disease (CKD)
Conventional PCIs often lead to severe complications in patients with CKD. However, both low-to-zero contrast IVUS and low molecular weight dextran (LMWD) OCT-guided PCIs offer a promising alternative for CKD patients. Minimal contrast and contrast-free IVUS-guided procedures demonstrate safety in both cardiac and renal outcomes, comparable to conventional PCIs, even for complex atherosclerotic lesions. The OCT intravascular imaging modality offers a higher axial resolution than IVUS, but its increased use of contrast volume is linked to contrast-induced nephropathy (CIN) development. Zero and LMWD contrast OCT-guided PCI produces safe, effective outcomes comparable to both traditional intervention and IVUS-guided PCI.
Burlacu, et al performed a systematic review to include studies evaluating the efficacy and safety of PCI using IVUS and minimal or zero-contrast in chronic kidney disease patients.63 Of the 238 patients, none of the patients in the studies experienced renal function deterioration or required renal replacement therapy following the zero-contrast IVUS-guided procedures. Moreover, from a cardiovascular standpoint, this technique has proven to be safe with favorable cardiovascular outcomes.63, 64, 65, 66, 67, 68, 69
The CONSaVE-AKI study was a prospective, randomized study that assessed short-term outcomes and safety of ULC-PCI compared to conventional PCI in patients with ACS who were at high risk for contrast induced acute kidney injury (CI-AKI). Patients who had an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m² with a moderate to very high Maioli score for pre-procedural risk of developing CI-AKI were included in the study. All patients (n=82) were randomized and equally divided into two equal groups: ULC-PCI and conventional PCI. IVUS was used in 17% of patients within the UCL-PCI group. The development of CI-AKI, occurred significantly more in patients who underwent conventional PCI (17.1%) than in the ULC-PCI group (0%), (p = 0.012). Contrast volume was also significantly lower in the ULC-PCI group (41.02 ±9.8 ml vs 112.54 ±25.18 ml; P < 0.0001). The use of IVUS guided imaging helped to reduce the contrast utilization drastically and to effectively reduce the incidence of CI-AKI. Intervention by ULC-PCI with IVUS guidance is feasible and can be safely used in patients with renal dysfunction to reduce the incidence of CI-AKI.70
Sakai, et al examined the use of IVUS-guided minimum-contrast (MINICON) PCI (n=98) compared to standard angiography-guided PCI (n=86) in patients with advanced CKD (n total= 184). The IVUS-guided MINICON PCI group showed significantly reduced contrast volume and a lower incidence of CI-AKI compared to the angiography-guided standard PCI group (CI-AKI; 2% vs. 15%; P = 0.001). The success rate of the PCI procedure was similarly high in both groups (100% vs. 99%; P = 0.35). At the one-year follow-up, the IVUS-guided MINICON PCI group had a lower rate of renal replacement therapy (RRT) induction (RRT; 2.7% vs. 13.6%; P = 0.01), but there were no significant differences in all-cause mortality or myocardial infarction between the groups.64 These findings suggest that IVUS-guided MINICON PCI produce high success rates and effectively reduce CI-AKI and RRT induction in patients with advanced CKD.
Sacha, et al performed a retrospective analysis on the safety and efficacy of zero-contrast IVUS PCI in patients with severe renal impairment and hemodialysis subjects. Zero-contrast IVUS PCI was performed within 29 coronary arteries in 20 patients with advanced CKD. This group included four patients who were treated with hemodialysis but presented preserved residual renal function. The estimated median probability of AKI in non-dialysis patients undergoing standard PCI using 100-200 ml of contrast medium was 57%. This median risk estimation reduced to 26% when using the assumption that contrast dye was not used. With the zero-contrast IVUS approach, the factual risk of AKI was reduced to 10% and no patient required renal replacement therapy. The technique also yielded good clinical outcomes in mid-term observations. During the median follow-up of 3.2 (1.2–5.3) months no patient experienced an acute coronary event or required revascularization. IVUS identified the lesion length, determined balloon and stent diameters, and landing zones for stent implantation, as well as verified and documented the final PCI effect. Since the procedure was based on IVUS imaging, it allowed optimization of stent implantation with good procedural results, and consequently no stent thrombosis occurred during the follow-up.65 The study’s results indicate if the patient is at a high risk of AKI, zero-contrast-IVUS PCI should be considered as a preventative solution, even for dialysis patients with residual renal function.
Kumar, et al sought to assess the safety and short-term outcomes of 'absolute' zero-contrast PCI under IVUS guidance in CKD patients. There were 42 CKD patients who underwent absolute zero-contrast PCI under IVUS guidance. A total of 66 coronary vessels underwent intervention, including 14 (21.2%) LMCA PCI (seven of which were LMCA bifurcation PCI) and three chronic total occlusion (CTO) PCI procedures. Even with the inclusion of these complex PCIs, technical success was 92.4% without any major complications. Two patients died of non-cardiac causes on follow up (3–12 months), and all the remaining were symptom free.67 IVUS-guided 'absolute' zero-contrast PCI is feasible and safe for CKD patients, allowing successful completion of the procedure without any contrast or complications, even in complex lesion morphologies.
Ultra-low contrast PCI guided by zero-contrast OCT can be safely performed without major adverse events in non-STEMI patients with high-risk CKD who require revascularization. Liu, et al evaluated the safety and efficacy of zero contrast OCT-guided PCI in CKD patients with NSTEMI. The study involved 29 NSTEMI patients with high-risk CKD (median Cr = 2.1) undergoing revascularization. There were no significant changes in creatinine level or eGFR in the short- or long-term. OCT's high-resolution imaging capabilities enabled precise assessment of coronary lesions and better guided interventional procedures with greater accuracy. During the PCI procedure, OCT revealed 15 (52%) cases of abnormalities post-dilation. The main approach, zero-contrast OCT, resulted in safe and successful PCI without AKI, CIN, and the need for renal replace therapy. Furthermore, no patients experienced post-interventional complications and no MACEs were observed.71
Azzalini, et al also reported that it is feasible to use dextran as a substitute for contrast in OCT guidance. The study evaluated the feasibility of an ultra-low contrast volume percutaneous coronary intervention (ULC-PCI) protocol in patients with severe CKD. Extensive intravascular dextran-based OCT guidance was used to compare the outcomes of the ULC-PCI protocol vs conventional angiography-based PCI in patients with eGFR <30 mL/min/1.73 m². Technical success was achieved in all ULC-PCI procedures, and the incidence of CI-AKI was 0% vs 15.5% in the ULC-PCI and conventional groups, respectively (P = 0.28).72 The implementation of an ULC-PCI protocol with OCT guidance in patients with advanced CKD is both achievable and safe. Furthermore, this approach shows promise in reducing the occurrence of CI-AKI when compared to the conventional angiographic guidance used alone.
Though OCT's 10-fold higher axial resolution than IVUS allows precise plaque and lumen characterization, its contrast flushing requirement increases total volume used, risking contrast-induced nephropathy. Kurogi et. al evaluated OCT-guided PCI using LMWD in patients with CKD. This single-center retrospective study found that OCT-guided PCI using LMWD as a flushing medium did not negatively affect renal function compared to IVUS-guided PCI using contrast media alone. There were no significant differences between 133 matched pairs of OCT and IVUS patients in changes in serum creatinine or eGFR after the procedure. The incidence of contrast-induced nephropathy was also similar between groups (1.5% OCT vs 2.3% IVUS). When stratified by CKD stage, there were again no differences between OCT with LMWD and IVUS with contrast in renal function changes or contrast volumes used. The study suggests OCT imaging with LMWD is a feasible approach that does not impair renal function relative to IVUS imaging with contrast alone, supporting its use as an alternative flushing medium in patients with CKD undergoing PCI.73
Recently, saline has been explored as a replacement for contrast to primarily avoid nephrotoxicity risks and expand FD-OCT to more patients safely. Several studies have aimed to evaluate if saline could provide adequate image quality in coronary FD-OCT.74,75 The SOCT-PCI study demonstrated the feasibility of using heparinized saline as a flushing medium for FD-OCT image acquisition during PCI optimization. In 27 patients undergoing FD-OCT-guided PCI, heparinized saline was used for blood clearance during 118 OCT runs. Overall, 61% of runs were good quality, 27% were clinically usable, and 88% were clinically effective for PCI optimization. There were no significant hemodynamic or arrhythmic changes. Saline FD-OCT enabled visualization of coronary lesions and post-PCI optimization comparably to contrast FD-OCT in one case.74 This suggests saline could replace contrast as the flushing medium for FD-OCT during PCI in patients at risk of contrast-induced nephropathy.
Gupta et. al explored saline as an alternative to radio-contrast for OCT-guided PCI. This prospective study analyzed 13 pairs of OCT runs using both contrast and heparinized saline in the same coronary arteries during PCI. The primary endpoints were quantitative measurements of minimal lumen area, reference diameters, and area stenosis. There were no significant differences in these primary endpoints between saline and contrast OCT. Bland-Altman analysis demonstrated good agreement without proportional bias between the two-flushing media for vessel measurements. All plaque morphologies and post-PCI optimization parameters were clearly visualized in the saline runs similar to contrast. The results indicate heparinized saline can yield comparable dimensional measurements and adequate image quality versus contrast for coronary OCT during PCI optimization. Using saline could not only eliminate the risk of contrast-induced nephropathy, but also produce high quality images in high risk patients.75 While both of these studies show promising results for the use of saline in OCT, further large scale randomized studies directly comparing saline and contrast OCT are still needed to validate these findings.
Patients with Diabetes Mellitus
CAD remains a significant health concern, particularly in patients with diabetes mellitus, who often present with more complex and diffuse lesions. It has been previously demonstrated that coronary remodeling enables patients to develop large atherosclerotic plaques without a reduction in lumen size, leaving diabetic patients at high risk for developing myocardial infarction.2 IVUS guidance during PCI has emerged as a valuable tool in optimizing outcomes for these high-risk patients. IVUS revealed that the prevalence of asymptomatic CAD in T2D patients is high, suggesting a need for a broader residual CV risk management using alternative approaches.76
Numerous studies have reported the benefits of IVUS guidance in diabetic patients undergoing coronary interventions. The ABCD trial is the first trial to date to perform invasive IVUS imaging, a gold-standard technique for evaluation of CAD, in asymptomatic patients with T2DM and revealed a CAD prevalence of 84%, indicating a significantly higher burden of disease than previously assumed.76, 77 IVUS provides accurate measurements of coronary vessels, enabling precise stent sizing and better stent deployment. Specific coronary lesions associated with diabetes are mainly confined to coronary small-vessels. IVUS allows physicians to analyze and diagnose small-vessel lesions to improve the therapeutic effect of available interventional approaches more accurately. Arora, et. al demonstrated that the addition of IVUS guidance was associated with larger post-PCI minimum lumen diameter and more post-dilatation, which translated into clinically and statistically significant lower rates of target lesion revascularization or in-stent restenosis after drug eluting stent (DES) implantation.76 By characterizing plaque morphology, IVUS helps identify vulnerable lesions, leading to a more tailored and effective treatment approach.
Regarding safety, the reviewed studies generally reported no significant increase in adverse events associated with IVUS-guided PCI in diabetic patients. Rahman, et. al’s retrospective observational study demonstrated a significant reduction in MACE in diabetic patients (n = 73/134, 54.5%) who underwent IVUS-guided PCI. MACEs occurred in 9.7% of patients, where 3% of patients experienced heart failure. Furthermore, iatrogenic coronary dissection was zero.78 The use of IVUS resulted in a significant decrease in MACE. IVUS appeared to contribute to a reduction in procedural complications, such as stent thrombosis and restenosis.
The precise stent placement achieved with IVUS may contribute to improved long-term patency and decreased incidence of adverse events. These findings underscore the potential long-term benefits and procedural safety of IVUS guidance in this high-risk population.