All-comEr Registry of OCT (AERO) to Investigate the MLD-MAX Algorithm for OCT-guided-precision-PCI in Daily Routine: Rationale and Study Design of ILUMIEN-V-AERO

Optical coherence tomography (OCT) is an intracoronary imaging (ICI) modality that facilitates quantitative and qualitative assessment of the coronary arteries. OCT uses a rotating fibre-optic system through which it emits near-infrared light that is then directed and reflected within the tissue, generating high-resolution tomographic images (10–20 µm).¹ In the setting of percutaneous coronary intervention (PCI), it permits pre-procedural planning by helping determine plaque morphology, vessel size and identification of landing zones based on disease burden.¹ Additionally, OCT facilitates post-PCI assessment of dissection, malapposition and stent expansion, all of which cannot be accurately assessed on invasive coronary angiography. OCT has evolved significantly since its inception over two decades ago and there is now growing evidence supporting its use in clinical practice.^2–6

The All-comEr Registry of OCT (AERO) to Investigate the MLD-MAX Algorithm for OCT-guided-precision-PCI in Daily Routine (ILUMIEN-V-AERO) registry was designed to prospectively assess the real-world use of OCT in clinical practice. Notably, our study design and inception preceded the results of the ILUMIEN-IV, OCTOBER and OCCUPI randomised controlled trials (RCTs), which compared the outcomes of OCT-guided versus angiography-only guided PCI.^2,3,7 Additionally, a recent network meta-analysis demonstrated that ICI-guided stent implantation reduced the risk of death, MI, repeat revascularisation and stent thrombosis compared with angiography alone.⁵ In light of these findings, the European Society of Cardiology upgraded its recommendation for ICI-guided PCI to class 1, level of evidence a, in chronic coronary syndrome patients with complex lesions (including left main, true bifurcations and long lesions).⁶ Furthermore, recent American guidelines have upgraded the recommendation for ICI-guided PCI in acute coronary syndromes to class 1, level of evidence a, again focusing upon complex lesion subsets including left main stem.⁸

While the clinical benefits of OCT have been demonstrated in RCTs with strict protocols, its real-world use remains unclear. The achievement of optimisation criteria as defined by the OCCUPI study and MLD-MAX criteria has been shown to correlate with improved clinical and imaging-based outcomes.^3,9 When optimal imaging criteria are not achieved, outcomes do not differ significantly from those obtained with angiography guidance alone.³ ILUMIEN-V-AERO aims to examine whether the outcomes observed in the real world align with those achieved in the ILUMIEN-IV study. Additionally, the study evaluates how frequently optimisation criteria are met and how the perspectives of operators and centres – as well as the role of core laboratory feedback – impact this achievement.

Methods

Study Design and Objective

ILUMIEN-V-AERO (NCT05324683) is an investigator-initiated, prospective, multicentre, observational registry involving sites in Germany, the UK and Saudi Arabia. It plans to include 2,000 patients with evidence of myocardial ischaemia (e.g. stable angina, silent ischaemia, unstable angina or acute MI) undergoing OCT-guided lesion evaluation. As of February 2025, 1,073 patients have been recruited. Recruitment (~100 patients/month) will continue until July 2025, with new sites opening in the UK and Saudi Arabia. Results are expected in 2026. An overview of the study design is illustrated in Figure 1. The study protocol has been approved by the local ethics committees of participating nations and the study will be conducted in accordance with the principles of the Declaration of Helsinki.

The primary goal of the ILUMIEN-V-AERO registry is to evaluate the real-world use of an algorithmic approach to OCT-guided PCI (MLD-MAX), with a direct comparison to the results from the ILUMIEN-IV RCT. By including all patients undergoing OCT for diagnostic and PCI-guidance purposes, the registry enables various secondary analyses. In addition to the inclusion criteria of the ILUMIEN-IV trial, this study will allow for an exploration of the role of OCT in diagnosing patients with acute coronary syndrome, the frequency and impact of achieving stent optimisation criteria in real-world practice, evaluation of its use in guiding drug-coated balloon PCI and assessing how core laboratory support and critical evaluation influence operator performance throughout the study. Additionally, access to individual UK recruiting site British Cardiovascular Intervention Society (BCIS) audit submissions will facilitate an analysis of institutional interventional practice, capturing proportions of angio-, physiology-, intravascular ultrasound- and OCT-guided treatment (including those recruited to the ILUMIEN-V-AERO registry).

Study Population

This is an all-comer registry and all patients over the age of 18 are eligible if undergoing OCT-guided evaluation for PCI or diagnostic purposes only (Supplementary Material 1 and 1A). Patients who meet the inclusion criteria will be compared with those in the ILUMIEN-IV angiography and OCT arms using propensity score matching. The matching process will include demographics (age, sex), cardiovascular risk factors (e.g. diabetes, hypertension, hyperlipidaemia, smoking status), clinical presentation (stable angina, acute coronary syndrome [ACS]) and angiographic characteristics (lesion location, complexity as defined by ILUMIEN-IV).⁷

Follow-up

Follow-up will be performed at 1 month and 6 months by the study sites via telephone. Due to the observational registry design of the study, regular monitoring visits are not planned. However, sites will be trained on study-specific details at remote site initiation visits. Close-out of sites at the end of the study will also be performed remotely.

Optical Coherence Tomography Image Acquisition and Analysis

OCT images will be acquired using commercially available ILUMIEN and OPTIS (Abbott Vascular) imaging systems that incorporate a rapid exchange catheter with an integrated pullback system (18–36 mm/s). During image acquisition, blood displacement will be achieved through manual or automated injection of contrast medium or saline, decided at the discretion of the operator. OCT assessment for the purpose of diagnosis only or to guide PCI will be performed according to institutional clinical practice.

OCT analysis will be performed using the AptiVue^TM (Abbott Vascular, Santa Clara, CA) offline workstation at an independent and recently established core laboratory (University of Bristol), with a dedicated expert and analyst. The analyst underwent structured training under the supervision of the expert, including joint review of the first 100 cases to ensure consistency and accuracy. Both qualitative and quantitative data were externally validated to confirm reliability. In addition, a standard operating procedure was generated, containing definitions of OCT metrics to maintain repeatability. Core laboratory analysis of primary and secondary endpoints will be conducted using definitions described in the ILUMIEN-IV study (Supplementary Material 2A and B).⁷ Qualitative analysis will be performed in all diagnostic quality frames (0.2 mm frame interval for 75 mm pullback and 0.1 mm frame interval for 54 mm pullback). Quantitative analysis will be performed on the stented segment, along with 5 mm proximal and distal reference segments.

Optical Coherence Tomography Feedback

Operators from the recruiting sites will be allocated a unique investigator identification (ID). Each investigator will receive feedback summarising quality of the OCT pullback(s), assessing achievement of optimisation criteria (composite of minimum stent area [MSA] >4.5 mm², relative expansion >80%, absence of major dissection/malapposition), concordance of measurements with the core laboratory and qualitative commentary on procedural decision-making. Additionally, there will be quarterly investigator meetings involving study updates and discussion of interesting cases that have been recruited to the study.

Endpoints

ILUMIEN-IV Comparison Sample

Primary Endpoint

The primary endpoint for comparison with ILUMIEN-IV is an ICI endpoint of relative stent expansion, in contrast to the original ICI primary endpoint of MSA, as ILUMIEN-V-AERO intends to recruit all-comers without restriction of treated vessel size. The stented segment is divided into two equal parts, unless the stent spans a significant sidebranch, in which case the stent is divided at the carina of the bifurcation. Expansion metrics are classified as below:

• Optimal stent expansion (categorical variable): the MSA of the proximal segment is ≥90% of the proximal reference lumen area and the MSA of the distal segment is ≥90% of the distal reference lumen area.
• Acceptable stent expansion (categorical variable): the MSA of the proximal segment is ≥80% of the proximal reference lumen area and the MSA of the distal segment is ≥80% of the distal reference lumen area.
• Unacceptable stent expansion (categorical variable): the MSA of the proximal segment is <80% of the proximal reference lumen area, and/or the MSA of the distal segment is <80% of the distal reference lumen area.

A detailed description of the primary endpoint is provided in Supplementary Material 2A.

Secondary Endpoints

Secondary endpoints include ICI-derived, procedural and clinical outcome parameters. The ICI metrics include core laboratory assessments of MSA, mean stent expansion, intra-stent plaque protrusion, presence of untreated reference segment disease, major/minor edge dissection and major/minor stent malapposition (Supplementary Material 2B). Procedural outcomes include assessment of procedural time, fluoroscopy time, contrast use, contrast-induced nephropathy and need for renal replacement therapy. Clinical endpoints include target lesion failure (composite of target vessel MI, ischaemia-driven target lesion revascularisation or cardiac death) and unplanned hospitalisation for unstable angina. A detailed description (including definitions of individual components of target lesion failure) and complete list of the secondary endpoints are provided in Supplementary Material 2B.

Total Study Sample (n=2,000)

Real-world Practice

Metrics captured for assessment of real-world practice include the use of contrast versus saline for image acquisition, automated or manual triggering of the OCT pullback, pump injector versus manual contrast injection, use of co-registration, table-side controller use versus console image assessment, the impact of OCT software on ICI interpretation/engagement (AptiVue software versus Ultreon 1.0 software versus Ultreon 2.0 software; (Abbott Vascular) and procedural duration. Furthermore, an analysis of OCT indication will be conducted, with a dedicated analysis of ‘diagnostic’ OCT activity, including its role in MI with unobstructed coronary artery.

Operator Engagement and Learning Curve

For the analysis of operator interaction with OCT, we will capture the following for each case: total number of interpretable OCT runs (including presence of a pre-stent and final OCT run), vessel preparation strategy, use of calcium modification techniques, where severe calcification identified (calcium thickness >0.5 mm, calcium arc >180^o and longitudinal calcium extension >5 mm), device size and length, concordance of operator assessment of stent optimisation with the core laboratory, frequency of untreated focal edge disease, incidence of untreated significant malapposition and edge dissections, radiation exposure, contrast volume and procedural time.¹⁰ An operator-level analysis will enable a temporal assessment of concordance between the physician and core laboratory-defined stent optimisation – a composite of relative expansion >80%, MSA >4.5 mm², absence of major dissection and malapposition (Supplementary Material 2B).

Additionally, our objective is to obtain the BCIS audit data, which offer valuable insights into institutional and operator usage of ICI. This will facilitate an analysis of how operator ICI volumes influence concordance with the core laboratory and the attainment of optimal post-PCI outcomes across UK centres. Furthermore, comparing the patient, lesion and procedural characteristics from the AERO registry with the BCIS database will allow us to evaluate how closely these align with real-world practice.

Landing Zone and Stent Edge Assessment

Reference segments (5 mm upstream and downstream of the stent) will be assessed for plaque morphology (fibrocalcific, fibrolipidic, intimal thickening, normal), arc of external elastic lamina, plaque free arc (<0.5 mm intimal thickness in the absence of disease), calcium and lipidic arc, calcium thickness, fibrous cap thickness, presence of dissection (arc, effective flow area, length, involvement intima/media/adventitia) and lumen area. Additionally, the incidence of focal untreated disease within the reference segment (defined as a focal segment with minimum luminal area <4.5 mm² in the absence of diffuse disease and/or natural vessel taper) will be recorded.

Data Management and Statistical Analysis

All study-specific patient data will be anonymised and documented in the electronic case reporting form (software: EBogen, Institut für Herzinfarktforschung GmbH [IHF]). The study database can only be accessed with an assigned user ID and password. Authorised users have access to the study database at all times. OCT images will be pseudonymised by the recruiting sites and uploaded to a secure online server, which is password-protected and can only be accessed by the sponsor and the core laboratory. A contractual agreement between IHF and the University of Bristol ensures the secure transfer of images from IHF to the core laboratory. Data sharing and confidentiality will be maintained in full compliance with General Data Protection Regulation and local regulations.

Statistical analysis will be performed using SAS (release 9.4 or higher). Because of the observational design of the study, a formal power calculation or statistical hypothesis testing will not be performed. It is expected that 50% of all OCT cases will meet the clinical inclusion criteria of ILUMIEN-IV, which should generate a cohort comparable with the original experimental and control arm of the ILUMIEN-IV study. The primary and secondary endpoint analysis for the ILUMIEN-IV comparison group will be performed after database closure and will only be conducted on patients with a final OCT run. Descriptive statistical methods will be applied to the data and percentages will be presented for optimal stent expansion, acceptable stent expansion and unacceptable stent expansion according to the study protocol. Median and interquartile range will be calculated for stent expansion following PCI.

Discussion

ILUMIEN-V-AERO will be the largest prospective multicentre registry offering insights into the use of OCT in routine clinical practice. The initial intention of AERO was to match a cohort, by clinical indication for OCT-guided PCI, with the control and experimental arms of the ILUMIEN-IV study.⁷ The primary endpoint of relative stent expansion was chosen to accommodate unrestricted vessel size and improve comparability across real-world lesions. Both relative expansion (primary) and MSA (secondary) will be reported, enabling comparison with ILUMIEN-IV while reflecting contemporary concepts of stent optimisation.

However, since the original design of the study, additional studies have been reported and thus further comparison may be made with matched bifurcation cases from the OCTOBER and OCCUPI studies.^2,3

It is important to acknowledge that ILUMIEN-IV failed to meet its primary clinical endpoint of target vessel failure – defined as cardiac death, target vessel MI, or ischaemia-driven revascularisation – at 2 years, despite achieving the OCT endpoint of MSA.⁷ In contrast with the findings of ILUMIEN-IV, the OCTOBER and OCCUPI studies demonstrated that OCT guidance was superior to angiography in patients with bifurcation and complex lesions, respectively. ^2,3,7 The authors of ILUMIEN-IV suggested that the impact of OCT-guidance might have been diminished by factors such as physician and patient behaviours during the COVID-19 pandemic and the inclusion of diabetes and ACS as a criterion, which could have facilitated the recruitment of patients with simpler lesions.⁷ Consequently, the observed event rates in both the control and experimental arms of ILUMIEN-IV were lower than those seen in other RCTs. This then raises questions about whether the study was appropriately powered, given the lower-than-expected event rates. A sub-analysis of the ILUMIEN-IV study evaluating predictors of stent failure found that the presence of any proximal edge dissection (whether major or minor) and a smaller stent area significantly increased the risk of future adverse events.¹¹ Presently, there remains a need to further explore the metrics of optimisation, with the aspiration for ILUMIEN-V-AERO to provide additional data that will help develop clearer stent optimisation metrics for real-world applications.

Notably, the OCCUPI definition of complex lesions was more representative of the real-world setting compared with ILUMIEN-IV, as it included left main disease, ST-elevation MI presentation, bypass graft lesions, thrombus presence and small reference vessels (<2.5 mm).^3,7 Therefore, it is hoped that AERO will extend its comparison to the OCCUPI study, as a larger proportion of our cohort will match the OCCUPI inclusion criteria.

The LightLab initiative has demonstrated that the use of a standardised OCT-workflow using the MLD-MAX algorithm improves operator decision-making during PCI without any significant increase in contrast use or radiation exposure.⁹ We aim to expand this analysis to further examine how imaging is applied in real-world settings, using the MLD-MAX algorithm. Additionally, we will evaluate the impact of factors such as feedback, education and the volume of OCT-guided procedures performed. Our goal is to determine whether meeting MLD-MAX criteria correlates with improved outcomes in real-world scenarios and whether this achievement varies across centres or countries.

Limitations

There are several limitations in this prospective observational registry. Given that this is not a randomised study, we cannot truly adjust for unknown confounders when comparing real-world OCT use with ILUMIEN-IV, despite matching for lesion characteristics and planned use of methodologies to eliminate bias. A key limitation is that clinical follow-up is restricted to 6 months, which significantly limits the assessment of the long-term impact of OCT guidance on clinical outcomes. Extended follow-up will be considered in patients recruited in the UK (approximately 1,000 patients) through the Office for National Statistics and Hospital Episode Statistics.

Despite this, recent RCT data from OCCUPI highlighted separation of event curves in early follow-up, so it is hoped that meaningful results will be obtained despite the shortened period of follow-up. Core laboratory analyses of the angiographic images associated with diagnosis and PCI are not included in the protocol, limiting our understanding of procedural challenges that may have influenced decision-making, and we are reliant on the information provided to us in the electronic case reporting form for completeness and accuracy. This will be taken into account during OCT analysis and assessment of operator learning curves, as there may be findings on the coronary angiogram that have an impact on decision-making (e.g. Thrombolysis in MI I–II flow, perforation, vessel occlusion, etc). Additionally, if gross anomalies are detected on OCT and not acted upon, the OCT core laboratory will contact the site team providing detailed feedback and offer the opportunity to discuss the case virtually. Furthermore, our study is also limited in that the adverse events and clinical outcomes will not undergo review by independent adjudication entities.

Trial Update

To date, we have opened eight UK sites and nine German sites. Recruitment as of February 2025 is 1,073, with continued recruitment of approximately 100 patients/calendar month. We are due to open more sites in the UK and Saudi Arabia and recruitment continued until July 2025. Results are expected in 2026.

Conclusion

ILUMIEN-V-AERO will capture multinational real-world OCT use and offer insights into the benefits of ICI beyond the strict protocols of RCTs.

Click here to view Supplementary Material.