Use of physioLogy to evaluaTe procedural Result After percutaneous coronary intervention of Chronic Total Occlusion (ULTRA-CTO): protocol for a prospective, single-arm, multicentre, exploratory study

Abstract

Introduction

Post-percutaneous coronary intervention (PCI) fractional flow reserve (FFR) is associated with future major adverse cardiac events and may reflect residual ischaemia and suboptimal stent result (SSR). Post-PCI FFR should therefore be considered to identify patients at high risk. Whether abnormal post-PCI FFR and non-hyperaemic pressure ratios, including resting full-cycle ratio (RFR), represent SSR after PCI remains to be determined, especially after chronic total occlusion (CTO) PCI. In addition, little is known about the association between post-PCI intracoronary physiology and SSR with residual anginal complaints.

Methods and analysis

The physioLogy to evaluaTe procedural Result After percutaneous coronary intervention of Chronic Total Occlusion study is a prospective, multicentre, exploratory, mechanistic, investigator-initiated, single-arm study with a non-inferiority design. A total of 200 patients, undergoing CTO PCI, with FFR and RFR measured in all patients, will be included at two study sites in the Netherlands. The primary endpoint is the area under the curve (AUC) of post-PCI RFR, in comparison to the AUC of post-PCI FFR, for prediction of optical coherence tomography-detected SSR and its individual components.

Ethics and dissemination

The study is approved by the local ethical review board (‘Medisch Ethische Toetsing Commissie Isala Zwolle’). Written informed consent will be obtained from all patients before enrolment. The outcomes of this study are intended to be disseminated in a peer-reviewed journal.

Study registration

NCT04780971.

Strengths and limitations of this study.

• This is a prospective multicentre study, including patients undergoing chronic total occlusion (CTO) percutaneous coronary intervention (PCI) in high-volume and experienced CTO PCI centres.

• All optical coherence tomography (OCT) images will be assessed by an independent core lab specialised in invasive coronary imaging.

• A potential limitation might be the heterogeneity of included CTO lesions, whether it is the location or the complexity of the lesion.

• As a limitation, OCT images might be performed at different time points, leading to different suboptimal stent results.

Introduction

Post-percutaneous coronary intervention (PCI) intracoronary physiology emerges as a useful tool to assess the angiographic result after PCI. Despite good angiographic results, 50% of all patients have suboptimal fractional flow reserve (FFR) (≤0.89) after PCI.¹ Suboptimal post-PCI FFR has been associated with future adverse cardiac events, with an increasing risk of adverse events as the FFR decreases.2,4 This risk is even higher if suboptimal FFR is accompanied by a trans-stent gradient (TSG) of >0.04.⁵ Physiological assessment should therefore be considered at the end of the procedure to identify patients at high risk of clinical events (Class 2A recommendation).⁶

Suboptimal post-PCI FFR reflects impairment of residual flow during hyperaemia. This could be caused by residual focal or diffuse atherosclerosis or suboptimal stent result (SSR).^{7 8} SSR includes geographical miss, underexpansion, edge dissections, strut malapposition or intra-stent protrusion (figure 1) and can be detected by intracoronary imaging. The FFR-REACT trial concluded that additional intravascular imaging using intravascular ultrasound (IVUS) for stent assessment and optimisation improved post-PCI physiology, although it did not lower target vessel failure (TVF).⁹ This trial was underpowered, though, to formulate robust conclusions, especially for the low numbers of patients with complex coronary lesions. The data suggest, however, that post-PCI FFR was particularly disturbed in patients after complex PCI, such as chronic total occlusion (CTO; n=24, 7.8%). This may be caused by longer stented segments with potentially more SSR and the presence of severe coronary calcification and diffuse disease.

Figure 1. PhysioLogy to evaluaTe procedural Result After percutaneous coronary intervention of Chronic Total Occlusion study design. CTO, chronic total occlusion; FFR, fractional flow reserve; MLA, mean reference lumen area; MSA, minimal stent area; OCT, optical coherence tomography; RFR, resting full-cycle ratio; PCI, percutaneous coronary intervention.

Whether intracoronary physiology using FFR after CTO PCI is an adequate representative for SSR needs to be elucidated. There is an evidence gap, especially for CTO lesions, concerning to what extent post-PCI physiological assessment is a “modifiable” risk factor.⁶ Patients with CTO lesions are a relevant population to investigate, because of a higher incidence of suboptimal post-PCI FFR, SSR and repeat revascularisation.^{10 11}

When performing post-PCI FFR measurement in patients undergoing CTO PCI, the role of the microcirculation needs to be taken into consideration. Several studies have demonstrated that the microcirculation is impaired directly after PCI and will recover over time.^{12 13} Microcirculatory dysfunction influences the flow over the epicardial stenosis, potentially underestimating the pressure gradient. As the microvascular resistance increases, the coronary flow over the stenosis is impeded and the FFR increases.¹⁴ This potential pitfall may open the door for the use of non-hyperaemic pressure ratio (NHPR), like resting full-cycle ratio (RFR). RFR is measured across a coronary lesion under resting conditions,¹⁵ hence omitting the need for a vasodilator. The RFR seems less influenced by microcirculatory dysfunction, assessed with coronary flow reserve (CFR) and index of microcirculatory resistance (IMR).¹⁶ In addition, it is potentially useful in assessing tandem lesions with minimal interaction between individual coronary stenoses, theoretically favouring NHPR over FFR.¹⁷

This study is primarily designed to provide answers on the pathophysiological evidence gap whether intracoronary physiology corresponds to intracoronary imaging after PCI of a CTO lesion. Obtaining high-quality prospective data immediately after CTO PCI, with respect to simultaneous intracoronary physiology and intracoronary imaging, may answer two important questions. First, whether intracoronary physiology using FFR is an adequate representative of optical coherence tomography (OCT)-assessed SSR after CTO PCI. Second, whether post-PCI RFR is non-inferior to post-PCI FFR with respect to SSR assessment in patients undergoing CTO PCI.

Methods and analysis

Study design and organisation

The physioLogy to evaluaTe procedural Result After percutaneous coronary intervention of Chronic Total Occlusion (ULTRA-CTO) is a prospective multicentre exploratory mechanistic investigator-initiated single-arm non-inferiority study enrolling 200 patients with an indication for PCI of a CTO lesion, including the presence of angina or angina-like symptoms with ischaemia and viable tissue within the myocardial target area, performed in two centres in the Netherlands (figure 1). Participating centres are the Isala Heart Centre (Zwolle, the Netherlands) and the Radboud University Medical Centre (Nijmegen, the Netherlands). All centres are high-volume CTO centres and have been selected based on their experience in complex PCI and vast experience with intracoronary imaging and physiology.

The study is approved by the local ethical review board (‘Medisch Ethische Toetsing Commissie Isala Zwolle’). The full study protocol is provided in online supplemental material 1. Written informed consent will be obtained from all patients before enrolment. The study will be conducted in compliance with the protocol, principles of the Declaration of Helsinki, Medical Research Involving Human Subjects Act (WMO), ICH-Good Clinical Practice, as well as local regulations and applicable regulatory requirements.

Radboud Technology Centre (Nijmegen, the Netherlands) is appointed as Clinical Research Organisation (CRO) and will be responsible for the overall study, as well as data management and monitoring of the study. All data will be collected in an electronic data capturing system, CASTOR.

The ULTRA-CTO study has been initially registered in March 2021 at clinicaltrials.gov database, reference number: NCT04780971.

Objectives

The primary objective of this study is to compare the predictive value of post-PCI FFR and subsequently RFR with respect to SSR and its individual components in CTO patients. In addition, this study has four secondary objectives. First, the predictive value of the FFR and RFR gradient across the stented segment with regard to SSR will be assessed. Second, the correlation between positive FFR (≤0.80) and RFR (≤0.89) with regard to SSR following angiographically satisfactory CTO PCI will be evaluated. Third, the correlation between post-PCI physiology (FFR, RFR, IMR, CFR) and SSR with anginal complaints (measured using the Seattle Angina Questionnaire (SAQ),¹⁸ cardiovascular events and other clinical classifications (Canadian Cardiovascular Society (CCS) and New York Heart Association (NYHA)) will be evaluated. Lastly, the impact on physician decision-making based on OCT and physiology findings will be assessed. As exploratory objectives, the change in FFR, RFR and other physiological parameters will be assessed over a time period of 1 month, when a second procedure was indicated in this time period.

Inclusion criteria

Patients are eligible to participate in this study if they meet all of the following criteria: (1) age 18 years and older, (2) angiographically successful PCI of a CTO lesion (i.e. no remaining lesion proximal or in-stent ≥30%, confirmed in two orthogonal projections with an angle of ≥25 degrees apart), which is considered acceptable and final by the operator, (3) possibility to perform physiological measurements and OCT of sufficient quality after PCI and (4) patients willing and capable to provide written informed consent. Patients with a contraindication to adenosine are excluded from participation in this study. Figure 2 depicts the study flow chart.

Figure 2. Study flowchart. CTO, chronic total occlusion; FFR, fractional flow reserve; MACE, major adverse cardiovascular event; NYHA, New York Heart Association; OCT, optical coherence tomography; RFR, resting full-cycle ratio; PCI, percutaneous coronary intervention; SAQ, Seattle Angina Questionnaire.

Endpoints

Primary study endpoint definition

The area under the curve (AUC) of post-PCI FFR with respect to SSR and its individual components and, subsequently, the AUC of post-PCI RFR. The individual components of the combined endpoint of SSR are geographical miss, edge dissection, stent malapposition, intra-stent plaque protrusion/thrombus and stent underexpansion. Individual components are subdivided into major and minor SSR. Definitions are described in table 1.

Table 1. Optical coherence tomography definitions for suboptimal stent result.

Geographical miss	Incomplete lesion coverage or geographical miss is defined as a residual plaque within 5 mm adjacent to proximal and distal stent endings. Major: minimal reference lumen area of <4,5 mm2 in the presence of significant residual plaque adjacent to stent endings, defined as an eccentric or concentric plaque without visibility of the media.29 37 Minor: minimal reference lumen area of <4,5 mm2 with the presence of residual plaque adjacent to stent endings, defined as an eccentric or concentric plaque with visibility of the media.29 37 Any: geographical miss meeting the criteria for major or minor geographical miss.
Edge dissection	The presence of a dissection at the site of the stent edge, defined as the proximal or distal segment within 5 mm from the edges of the stent.29 Dissection can affect the intimal, medial or adventitial layer of the vessel wall. Major: presence of a linear rim adjacent to stent edge with a length in the longitudinal direction of the vessel of ≥3 mm from the stent edge,30 38 dissection extending into the media or adventitia38 or width of ≥200 µm.29 Minor: any edge dissection with a length in the longitudinal direction of the vessel of <3 mm30 and confined to the intima and width of <200 µm. Any: edge dissection meeting the criteria for major or minor edge dissection.
Malapposition	Stent malapposition of modern drug-eluting stents is defined as the lack of full contact between stent struts and the vessel wall following PCI.38 Major: incomplete apposed stent struts separated from the vessel wall without any tissue behind the struts with a distance from the adjacent intima ≥400 µm, not associated with any side branch,39 or a longitudinal length >3 mm.38 Minor: incomplete apposed stent struts separated from the vessel wall without any tissue behind the struts with a distance from the adjacent intima ≥200 µm and <400 µm, not associated with any side branch,29 30 and longitudinal length ≤3 mm. Any: stent malapposition meeting the criteria for major or minor stent malapposition.
Intrastent protrusion	Intraluminal mass attached to the luminal surface of the stent or floating within the lumen of the stent.30 Major: protrusion ≥500 µm within the luminal edge of the stent struts29 or a ratio of protrusion area to the stent area at the site of tissue protrusion ≥10%0.30 Minor: protrusion ≥200 µm and <500 µm within the luminal edge of the stent struts29 30 and a ratio of protrusion area to the stent area at the site of tissue protrusion <10%0.30 Any: intrastent protrusion meeting the criteria for major or minor intrastent protrusion.
Stent underexpansion	Stent expansion is defined by the MSA achieved in the proximal and distal stented segment in relation to the respective reference lumen area, for which the stent is divided into two equal proximal and distal segments.30 The stent is adequately expanded if the stent does not close or is equal to the diameter of the artery. An MSA of ≥90% of the mean reference area on OCT is considered acceptable.30 The mean reference area is defined as the largest proximal reference lumen area plus the largest distal reference lumen area (within 10 mm of the stent edge), divided by two. Major: MSA <80% of the mean reference area,40 MSA of the proximal segment is <80% of the proximal reference lumen area and/or MSA of the distal segment is <80% of the distal reference lumen area. Minor: MSA ≥80% and <90% of the mean reference lumen area40 or MSA of the proximal segment is ≥80% and <90% of the proximal reference lumen area and/or MSA of the distal segment is ≥80% and <90% of the distal reference lumen area.30 Any: stent underexpansion meeting the criteria for major or minor stent underexpansion.

MSA, minimal stent area; OCT, optical coherence tomography; PCI, percutaneous coronary intervention.

Secondary study endpoint definitions

• The predictive value of the FFR and RFR gradient across the stented segment with regard to SSR and its individual components, subdivided with major and minor criteria, in patients with CTO.

• The correlation between positive FFR (≤0.80) and positive RFR (≤0.89) with regard to SSR and its individual components, subdivided with major and minor criteria, following angiographically satisfactory CTO PCI.

• The correlation between post-PCI physiology (RFR, FFR, CFR, IMR) and SSR and its individual components, subdivided with major and minor criteria, with anginal complaints (SAQ score), NYHA and CCS classification and major adverse cardiac event at follow-up.

• The correlation between OCT and physiology findings, including the presence of SSR or impaired FFR/RFR, and physician decision-making (perform or refrain from additional PCI).

Overall treatment

The treatment will be according to international guidelines. PCI, intracoronary physiological assessment and OCT will be performed according to local guidelines and common practice. After angiographically successful PCI of the CTO target vessel, intracoronary physiological assessment will be performed, according to the study protocol (see Physiological assessment section). OCT will also be performed according to the study protocol (see OCT section) and if deferred during index procedure (ie, in case of high contrast use, long procedural duration, major dissection or safety reasons considered by the operator), OCT will be performed during a staged procedure within 4±2 weeks after index PCI. Intracoronary physiological assessment of the CTO vessel will also be repeated during a staged FFR-guided PCI of a non-CTO vessel or major side branch of the CTO, as described in the study protocol (see Staged procedure section).

Physiological assessment

Physiological measurements are performed with the Coroflow system (Coroventis, Uppsala, Sweden) in combination with the PressureWire X (Abbott Vascular Inc, Santa Clara, USA). Measurements are performed in the following order. First, ensure adequate guide catheter position and adequate peripheral proximal venous access, after which intracoronary nitrate (100 or 200 mcg) can be administered. RFR and Pd/Pa are measured 10 mm proximal to the proximal stent edge. In the case of ostial right coronary artery (RCA) or left main stenting, measurements will be performed in the aorta. Second, the pressure wire must be placed 10 mm distal to the distal stent edge. RFR and Pd/Pa are measured again. As the pressure wire remains in place distally, the Coroventis software is switched to CFR/IMR mode. The steps are followed as indicated by the Coroventis software. Saline is injected for CFR and IMR measurements during rest as well as during hyperaemia (achieved by administering intravenous adenosine with a dosage of 140 mcg/kg/min. The software automatically calculates CFR and IMR. Hyperaemia is maintained by continuing infusion of adenosine, in order to acquire FFR. First, FFR needs to be measured 10 mm distal to the distal stent edge, after which FFR can be measured 10 mm proximal to the proximal stent edge. Physiological measurements are finished if no significant drift (≥0.03) is present at the end of the measurements.¹⁹

OCT

OCT is performed with the Dragonfly OpStar Imaging Catheter (Abbott Vascular Inc, Santa Clara, USA). A segment of 75 mm will be standardly scanned in each pullback, after injection of 100% contrast for effective blood clearance. A second pullback will be performed if one pullback does not fully cover the entire stent plus 5 mm proximally and distally from the stent. Images are acquired with the FD-OCT ILUMIEN (Abbott Vascular Inc, Santa Clara, USA) system to visualise the stented segment of the CTO target vessel. The treatment of SSR components (by post-dilatation or additional stent placement) is left to the discretion of the operator. If PCI optimisation is performed, additional FFR and RFR will be repeated behind the stented segment. If deemed necessary by the operator, additional OCT is left to the discretion of the operator.

All OCT images will be assessed by an independent core lab specialised in invasive coronary imaging. The core lab is blinded for patient characteristics and physiological measurements. The assessment will be performed according to a prespecified OCT core lab document (online supplemental Material 2). OCT variables and endpoints are described in the OCT core lab document.

Staged procedure

OCT may be deferred to a staged procedure within 4±2 weeks for clinical reasons, such as high contrast use, long procedural duration, major dissection or safety reasons considered by the operator.

When a FFR-guided PCI of an intermediate stenosis (angiographically 30–90%) is planned for clinical reasons within 4±2 weeks after the index CTO PCI, intracoronary physiological assessment of the CTO vessel will be repeated for exploratory study purposes.

Follow-up

Follow-up will be performed 4±2 weeks after index CTO PCI, either by phone call or outpatient clinic visit. The occurrence of cardiovascular events will be monitored, and the clinical status will be assessed with the CCS and NYHA classification, and SAQ. Adverse events will be monitored and documented until follow-up at 4±2 weeks after index CTO PCI.

Sample size calculation

The sample size calculation was performed to evaluate the primary difference in the AUCs of paired data where each subject with and without SSR is subjected to FFR and RFR measurement after PCI. As a result, we expect that the sample size will also be adequate to evaluate the individual AUC of FFR and RFR in relation to SSR. No specific sample size calculation has been performed to establish the individual AUC of the FFR and RFR. The study is powered for non-inferiority. Based on previous studies, the AUC of FFR in relation to SSR is assumed to be 0.90, and the incidence of SSR is assumed to be 40%.20,22 Assuming an AUC of 0.90 for FFR with a significance level α of 5%, a non-inferiority limit margin of 0.10 and an estimated prevalence of SSR of 40%, a total of 190 patients are needed to obtain a power of 80%. To account for dropouts or non-analysable OCT images (n=10), the sample size will be 200 patients.

Statistical analysis

Categorical variables will be described using frequencies and percentages. Continuous variables will be described using mean (± SD) or medians (IQRs) depending on the distribution of the data.

The primary analysis will be performed after the last subject follow-up. After establishing the AUC of FFR with respect to SSR, non-inferiority of post-PCI RFR to post-PCI FFR with regard to SSR with a pre-specified non-inferiority margin of 0.10 and AUC of 0.90 will be evaluated. Non-inferiority is established if the lower limit of a (1-2α) × 100% CI of the difference between AUC_RFR and AUC_FFR is above −0.10 rather than the usual (1 − α) × 100% CI. A 90% two-sided CI will be constructed, and the lower bound will be used to determine non-inferiority. If the lower boundary of the 90% CI of the difference is above −0.10, then RFR is non-inferior to FFR.

For the secondary outcomes, Pearson r correlation and Spearman correlation coefficient rho (r) will be used to evaluate a degree of relationship between variables, depending on the distribution of the data. For repeated measurements (RFR, FFR and other physiological parameters), we will use the paired t-test for normally distributed variables and the Wilcoxon signed-rank test for skewed continuous data. A p value of <0.05 will be considered to be statistically significant.

Sensitivity analyses will be performed with respect to all measurements performed during staged procedures, under the condition that a sufficient amount of follow-up data is available.

Patient and public involvement

None.

Ethics and dissemination

The study was approved by the local ethical review board (‘Medisch Ethische Toetsing Commissie Isala Zwolle’, reference: NL76172.075.21), after reviewing all relevant documents, including protocol and site-specific informed consent forms. Trained physicians involved in the trial will introduce the trial to eligible patients. Patients receive, after introduction, the patient informed consent file (PIF). After discussing the trial with patients in light of the information provided in the PIF, written informed consent will be obtained from the patients.

All data will be collected in an Electronic Case Report Form (CASTOR EDC). Modifications will only be made if deemed necessary by the sponsor (Isala). Data entered in the eCRF will be taken from source documentation. Electronic patient records will be considered as source documents. If no standard hospital or office document exists, a worksheet will be developed to record the necessary information and used as a source document, which is signed by the person responsible for the registered data at the given site. The investigators will maintain all records pertaining to this study for 15 years following study completion, as otherwise instructed by the CRO or per local requirements, whichever is longer.

All OCT records will be anonymised and sent to the core lab for image assessment. The core lab is blinded to the clinical and physiology data.

Published study data will not be traceable to individual patients. Safety and progress reports will be annually submitted to the ethics committee, including inclusion date of the first subject, number of subjects included, subjects that have completed the study, serious adverse events, other problems and amendments. Amendments will be made if modifications to the protocol are deemed necessary. Amendments will be implemented after approval is granted by the ethics committee. A major amendment has been made in December 2023, because of structural changes (sponsor, CRO and participating centres) and some protocol changes to optimise patient inclusion. The sponsor of the study was changed from Maatschap cardiologie Zwolle to Isala. CRO Diagram BV was replaced by Radboud UMC Technology Centre. Radboud UMC was added as a participating study site. In the initial study protocol, OCT was standardly performed during a staged procedure and patients required an intermediate lesion for which a staged FFR-guided PCI was indicated. In the current protocol, a clinically indicated FFR-guided PCI of an intermediate stenosis during a staged procedure was removed as an inclusion criterion and OCT may also be performed during the index procedure.

This study is intended to be disseminated in a peer-reviewed journal and as an abstract at medical congresses, regardless of the results.

Study status and timeline

The study has started officially in July 2021 with the enrolling of the first study patient in the Isala hospital. Radboudumc included the first patient in June 2024. The study reached 100 inclusions in May 2025. The final study patient inclusion is expected in the first quarter of 2026.

Discussion

Several studies have demonstrated that despite a good angiographic result after PCI, suboptimal FFR (≤0.89) is present in more than half of the patients.^{1 10} Suboptimal FFR is demonstrated to be related to future cardiac events.2,4 Uretsky et al demonstrated that a suboptimal FFR accompanied with a TSG >0.04 increases the risk of adverse events, particularly TVF.⁵ The recently published European Society of Cardiology guideline for chronic coronary syndromes stated therefore that physiological assessment should be considered (Class 2A recommendation) at the end of the procedure to identify patients at high risk of clinical events.⁶

As the pathophysiological substrate of impaired physiological assessment after PCI is open to debate, this question should be further investigated. The FFR-SEARCH trial indicated that suboptimal post-PCI FFR could be caused by SSR.^{1 7} In patients with FFR ≤0.85, stent underexpansion and malapposition were found in 74% and 23%, respectively. The FFR REACT trial was subsequently performed to assess and evaluate whether the use of IVUS in 291 patients with a post-PCI FFR <0.90 could improve the 1 year TVF. Post-PCI FFR increased significantly in the IVUS-guided optimisation arm (0.82 vs 0.85, p<0.001). The 1 year TVF was, however, comparable between both study arms (IVUS: 4.2% vs control: 4.8%, p=0.79). A trend was visible, though, with respect to lower clinically driven target vessel revascularisation (IVUS: 0.7% vs control: 4.2%, p=0.06). The authors suggested as a result that additional use of IVUS in patients with impaired physiological assessment after PCI for stent assessment and optimisation might improve clinical outcome, as a result of improved post-PCI physiology.⁹ Due to power issues, no robust conclusion could be made with respect to clinical outcomes. Intracoronary imaging, either by using IVUS or OCT, has nevertheless a class 1A recommendation when performing anatomically complex PCI and could play a vital role in assessing the stent result.^{6 23 24} In the HAWKEYE study, residual stenosis is present proximal or distal to the stent in 87% of the vessels with residual stenosis. The remaining 13% is located in the stent itself.²⁵ Previous studies have demonstrated the benefit of IVUS to guide PCI, which was mainly driven by reduction of repeat revascularisation for restenosis.^{26 27} OCT is also a proven intracoronary imaging modality to optimise PCI results and might be more effective to assess stent edge dissections and stent malapposition due to its higher resolution.^{20 28} Incomplete lesion coverage, stent underexpansion and intrastent plaque protrusion could be detected as well.^{29 30} The DOCTORS trial demonstrated that OCT-guided optimisation after stent implantation using post-dilatation resulted in higher post-PCI FFR values when compared with angiography-guided optimisation.³¹ It is unclear though to what extent this results in improved clinical outcomes, particularly for patients undergoing PCI CTO. As these patients are scarcely included in previous studies, the question remains for CTO PCI whether SSR is adequately represented by intracoronary physiology, including the distal FFR as well as the trans-stent FFR gradient, after PCI.

In this context, it is relevant to further focus on this particular patient group. Complex lesion characteristics, use of multiple stents and smaller reference vessel diameter were associated with suboptimal FFR, which might explain an even higher rate of suboptimal FFR in patients with CTO lesions in the FFR SEARCH registry.¹ As a result, one can also expect that in these patients not only the FFR, but particularly the TSG, is affected, further increasing the risk of adverse events.

Furthermore, physicians should be cautious to make conclusions on post-PCI FFR measurements in patients with CTO PCI. Although the use of FFR is widely considered as the golden standard for functional significance of identifying (residual) stenosis,^{32 33} overestimation of FFR values can occur if maximal hyperaemia is not achieved. Hyperaemic flow is reduced due to lesion characteristics or certain comorbidities, leading to a disturbed microcirculation. FFR measurements in tandem lesions are underestimated, because the lesions have an impact on each other. This effect is diminished in resting conditions, making NHPR, including instantaneous wave-free ratio (iFR) and RFR, suitable alternatives.^{15 17} Comorbidities, including diabetic microangiopathy, previous myocardial infarction and left ventricular hypertrophy, result in microvascular impairment, leading to reduced maximal hyperaemia.³⁴ If hyperaemic microvascular resistance is high, flow through the stenosis is reduced. As a result, FFR will increase, underestimating the pressure gradient.¹⁴ RFR is, however, not influenced by microvascular function.¹⁶ Microvascular dysfunction, measured with CFR and absolute flow by using continuous thermodilution, is frequently observed in patients with CTO PCI.^{12 13} CFR increases, however, during 5 months of follow-up, because of a decrease in baseline average peak velocity.¹² The investigators interpreted these findings as a result of resolution of microvascular dysfunction caused by the CTO, but this is not confirmed with specific parameters, including index of IMR. In addition, the study by Karamasis et al¹⁰ showed distal vessel enlargement during 4 months of follow-up. They did not remarkably find an association between change in FFR and change in distal lumen diameter,. However, based on these combined findings, it could be questioned whether FFR is the optimal physiological tool for assessing PCI result immediately following CTO PCI.

The alternative for FFR as a physiological tool for assessing PCI might be NHPR, including iFR and RFR. Although iFR has been thoroughly investigated, resulting in a class 1A recommendation in the guideline to guide PCI,⁶ the use of RFR and particularly post-PCI RFR has not been thoroughly investigated yet, let alone the value for detecting SSR.

Although post PCI-FFR is the gold standard, the reliability of FFR for assessing the PCI result of a CTO could be disputed. The ULTRA-CTO study is the first study that will focus on evaluating the value of post-PCI RFR in comparison to post-PCI FFR for assessing SSR. Because an SSR could be the pathophysiological substrate of an impaired physiological assessment, either measured by FFR or RFR, OCT will be used to assess stent result post-PCI. The ULTRA-CTO study will primarily evaluate whether the value of post-PCI FFR and post-PCI RFR is sufficient for detecting SSR and its individual endpoints in the early phase after stenting.

Potential limitations of the ULTRA-CTO study might be the heterogeneity of included CTO lesions, whether it is the location of the lesion (ie, left anterior descending artery (LAD), RCA or left circumflex) or the complexity of the lesion. However, the heterogeneity will probably represent daily practice, supported by the low number of inclusion and exclusion criteria. Selection bias of lesion complexity will be minimised by the fact that the participating sites are high-volume experienced CTO centres with high success rates, which probably leads to inclusion of low and high complex CTO procedures. Optimal cut-off values of post-PCI FFR in LAD lesions seem to be different from those in non-LAD lesions.³⁵ In addition, LAD lesions are associated with high FFR and low RFR values.³⁶ Furthermore, the fact that OCT may be performed at different time points (index procedure or staged procedure) might lead to different SSR rates, especially for components that will change over time such as edge dissections and tissue protrusion.

ULTRA-CTO is the first prospective multicentre non-randomised investigator-initiated non-inferiority study evaluating the association of post-PCI FFR and RFR with SSR in the early phase after stenting of CTO lesions. Outcomes of this study could lead to a better understanding of the functional and anatomical aspects of CTO PCI, particularly with respect to intracoronary physiology and intracoronary imaging.