Access to side branches with a sharply angulated origin: usefulness of a specific wire for chronic occlusions

INTRODUCTION

The optimal strategy and timing of complete revascularization in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel coronary artery disease remains unclear, and current recommendations are controversial.1 According to 2023 European Society of Cardiology (ESC) guidelines, complete revascularization, based solely on angiographic severity, is recommended in “stable” STEMI patients.2 Conversely, the 2023 Asia-Pacific Expert Consensus Document suggested a treatment strategy of non-culprit lesions (NCL) based on angiographic severity and invasive physiological assessment with fractional flow reserve (FFR) or non-hyperemic pressure ratios for patients with STEMI.3

FFR and non-hyperemic pressure ratios may be inaccurate in acute coronary syndrome (ACS), as hyperemic flow may be reduced due to microcirculatory dysfunction, while the resting flow may be higher due to neurohumoral compensatory mechanisms.4

Angiography-derived indices are additional physiological tools. They need ≥ 1 angiographic projections plus frame count analysis and/or aortic pressure that may also be different in the acute setting.

Furthermore, drugs such as hypolipidemic agents may promote plaque regression, potentially impacting the results of physiological assessment after a few months into therapy.5

Our main objective was to evaluate the changes in invasive physiological measurements of NCL between the acute and staged phases of ACS.

Secondly, we aimed to evaluate the effects of different therapies on physiological measurements.

METHODS

Eligibility criteria

We included studies that evaluated the physiology of NCL during acute and staged interventions for ACS. Studies conducted on assessments following percutaneous coronary interventions of non-culprit vessels, or with patients with chronic coronary syndrome were excluded.

Case reports, conference abstracts, commentaries, editorials, and reviews were excluded as well. An initial protocol was registered in PROSPERO with registration No. CRD42024574683.

Search strategy, and study selection

We conducted the search across ClinicalTrials.gov, Embase (via Ovid), Google Scholar, PubMed, and Web of Science from inception through 26 April 2024 (initial search). We used the “Review articles” filter in Google Scholar and the “Topic” field in Web of Science. No language restrictions were applied.

Duplicates were removed using Deduplicator (SR-Accelerator) software. Title/abstract and full text screening was conducted independently by 2 authors using Rayyan software.

Back in July, 2 authors conducted a backward and forward citation analysis of the included articles using Citationchaser software.

The search strings were repeated in 6 December 2024 (in Embase, sources with invalid date limits were excluded). Simultaneously, we looked into any online conference news on imaging modalities and physiological measurements.6 Additionally, we looked into the “Slide Library” section using the “2024” filter on another web page.7

Finally, we manually reviewed the references of the articles included after the initial search.

All discrepancies were resolved by consensus.

Selection process was recorded in sufficient detail to complete a Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) flow diagram.8

Data extraction

The following data were extracted from each article: a) study characteristics; b) population characteristics; c) type of physiological index(es); d) follow-up duration; e) primary endpoint.

The primary endpoint was the variation between acute and staged indices regarding statistical significance, mean difference (MD), and disagreement on revascularization decision.

One author extracted the data, and another one checked it independently. We contacted the authors of eligible studies when clarifications were needed.

Risk of bias assessment

Risk of bias was assessed using the Joanna Briggs Institute (JBI) critical appraisal tools,9-11 as appropriate.

Two authors independently assessed the risk of bias for each study. We used red for high, yellow for moderate, and green for low risk of bias based on positive answers being ≤ 49%, 50%-69%, or ≥ 70%.

Data synthesis

We conducted a descriptive synthesis of the evidence. Results from data extraction were shown in separate tables based on risk of bias, or bubble charts. Some data were rounded to the nearest integer (age, diameter of stenosis of NCL, and follow-up) or 2 decimal places (MD).

Unless otherwise specified, P values < .05 were considered statistically significant. When MDs were unreported, they were estimated by calculating the difference between staged and acute mean values. When required, a formula for estimating the means was applied.12

In bubble charts, the size of the bubbles represents the number of patients or lesions if the former was not reported. Acute−/staged+ disagreement indicates an acute value above the threshold, with the staged value below the revascularization cut-off. Acute+/staged− disagreement represents the opposite.

RESULTS

Characteristics of the articles, participants, and indices

Results of the search and selection processes are shown in figure 1. Extracted data are shown in table 1 and table 2.

Figure 1. PRISMA flow diagram. PRISMA, preferred reporting items for systematic reviews and meta-analyses.

Table 1. Extracted data of studies with low risk of bias

A total of 20 articles were included13-32 (1 article in the form of a conference presentation).19 Publication years went from 2010 through 2024. The total number of reported patients was 4379.

In every publication, the patients are predominantly men and non-diabetic. The main clinical presentation was STEMI, except for 3 studies.19,29,31

The following methods were assessed: a) angiography-derived: Murray law-based quantitative flow ratio (muQFR), quantitative flow ratio (QFR), vessel FFR (vFFR); b) hyperemic (FFR); and c) non-hyperemic indices: instantaneous wave-free ratio (iFR), resting distal-to-aortic coronary pressure ratio (P_d/P_a). When reported, the FFR was obtained using adenosine.

Reported patients for each index are as follows: 2340 (muQFR), 1187 (QFR), 710 (FFR), 243 (iFR), 92 (vFFR), and 73 (resting P_d/P_a).

Risk of bias

The studies mainly used an observational (cohort) design. Cohort studies on angiography-derived methods were retrospective, except for 1 article on QFR.28 Those on FFR and non-hyperemic indices were prospective, except for 2 substudies.22,26

QFR was also evaluated by 1 quasi-experimental study27 and 1 randomized controlled trial.13

Finally, the FFR was assessed by 2 randomized controlled trials, in samples with predominance of non-ST-segment elevation myocardial infarction (NSTEMI).19,31,33

Results are shown in table 1 of the supplementary data, table 2 of the supplementary data, and table 3 of the supplementary data. There were no studies with high risk of bias.

Table 2. Data drawn from studies with moderate risk of bias

Primary endpoint

Statistical significance

There were no articles on relevant changes in muQFR,16,30 resting P_d/P_a,25 and vFFR17 at the follow-up.

A significant difference in FFR, iFR, and QFR was found in 3, 2, and 1 article(s),14,22-26 respectively. In 1 study, the difference in QFR was non-significant, with a significance threshold of .001.28

These variations were seen in cohorts of STEMI patients.14,22-26 Studies including non-ST-segment elevation acute coronary syndrome (NSTEACS) did not show any relevant differences regarding the QFR15 or the FFR.19,21,29,31

A total of 4 articles20,22,25,26 evaluated > 1 method. The iFR and FFR were both stable in the study by Musto et al.,20 while the iFR was more stable than the FFR in a different article.25 The QFR was compared to both the FFR26 and the iFR.22 Unlike these indices, the QFR did not show any significant changes in staged phases.22,26

Mean differences

The most valued indices showed varying results. muQFR had MD values close to 0 in both studies.16,30

QFR variations were observed at both lower22,26,28 and higher values.14,15,18 Conversely, the FFR and the iFR varied towards smaller and greater values, respectively.22-26,29,31 Their MDs ranged from − 0.02 to + 0.06 (QFR), − 0.03 to 0.00 (FFR), and 0.00 to + 0.03 (iFR).14,19-21,24,25,28 MD values of 0.01 were observed more often.

In STEMI patients, the MDs of the FFR, the iFR, and the QFR were close to 0 only in studies with mean follow-ups of < 1 week.20,32 In studies including NSTEACS, the FFR MDs were close to 0 after longer mean follow-ups (> 1 month).19,21 Furthermore, Ntalianis et al. showed a greater stability of FFR in patients with NSTEMI (MD, 0.00) vs those with STEMI (MD, − 0.02).21

Disagreement

Disagreement in the indication for revascularization is shown in figure 2. MDs of 0.01 resulted in variable disagreements: 5%-18%.15,18,23,25

Figure 2. Disagreement between acute and staged values in the indication for PCI. B, Barauskas; C, Cortés; E, Erbay; FFR, fractional flow reserve; H, Huang; iFR, instantaneous wave-free ratio; K, Kirigaya; L, Li; muQFR, Murray law-based QFR; N, Ntalianis; PCI, percutaneous coronary intervention; QFR, quantitative flow ratio; SE, Sejr-Hansen; SH, Shukla; SP, Spitaleri; T, Thim; V, van der Hoeven; vFFR, vessel fractional flow reserve.

Unlike the QFR, the FFR and the iFR consistently showed a higher frequency of one type of disagreement: acute−/staged+ for FFR,21,23,25 and acute+/staged− for iFR.24,25

Secondary endpoint

A total of 4 studies compared the effects of different drugs on the physiological parameters.13,19,27,31

Ticagrelor (which can increase the levels of adenosine) was compared to clopidogrel and no significant differences were found in the FFR of non-culprit vessels after 6 months of treatment.31

Another 3 studies compared a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor (eg, alirocumab or evolocumab) plus high-intensity statin (HIST) (eg, rosuvastatin 20 mg/day) vs statin-only therapy.13,19,27

In a nonrandomized study, the QFR values were significantly higher in the evolucumab group at 12 months.27 However, in 2 randomized studies, no significant differences were observed across the 2 treatment groups in the QFR at 12 months or in the FFR at 3 months, respectively.13,19

DISCUSSION

The main findings of this systematic review are these: firstly, in STEMI patients, the muQFR, resting P_d/P_a, and vFFR indices remained relatively stable in retrospective and/or small studies. The FFR, iFR, and QFR showed variability between acute and staged phases. Secondly, the FFR did not change significantly in prospective cohorts or randomized controlled trials including NSTEACS. Thirdly, the QFR was more stable than both the FFR and the iFR in direct comparisons, although only the FFR and the iFR exhibited consistent directions of change. Fourthly, PCSK9 inhibitors added to HIST did not influence physiological measurements compared with HIST in randomized controlled trials.

The muQFR demonstrated stability in a large sample of patients. This index is based on a single angiographic view, unlike other angiography-based methods that require 2 angiographic projections. This characteristic might reduce observer variability and enhance reliability. Future prospective and comparative studies are needed to confirm the validity of this method.

Although low variations for FFR, iFR, and QFR were observed in cohorts of STEMI patients,20,32 these studies were limited by short-term follow-ups. Thim et al. found a non-significant change in the iFR with 5-day follow-ups, whereas there were significant changes with ≥ 5 day follow-ups.24 Therefore, physiological disarrangements initiated at the acute moment of STEMI might still exist if a staged procedure is conducted close to the index event.24,25

Angiographic, hemodynamic, and microcirculatory variables may alter acute physiologic assessment and account for the higher reliability of the FFR in NSTEACS vs STEMI.

In patients with microvascular dysfunction, epicardial blood flow cannot increase sufficiently during maximal hyperemia, thus causing a reduced pressure gradient across the stenotic lesion,29 and higher FFR values.

In STEMI patients, microcirculatory indices (coronary flow reserve and index of microcirculatory resistance) were significantly worse during the acute phase, along with a higher FFR.25 Conversely, studies including NSTEACS did not show any significant differences in the coronary flow reserve and/or index of microcirculatory resistance at the follow-up.21,29,31

Furthermore, STEMI patients showed greater acute angiographic severity, along with lower QFR or iFR values,14,22 which may be attributed to vasoconstriction typically occurring during the acute phase.

Consequently, the FFR seems more reliable in NSTEACS vs STEMI due to reduced acute microcirculatory impairment and/or vasoconstriction.

Literature trials support the use of the FFR in NCL of NSTEMI during the acute phase (eg, within the index hospitalization).34,35 In contrast, acute FFR-guided complete revascularization did not show any significant benefits in terms of death or myocardial infarction in STEMI patients.36-39

The higher stability of QFR when directly compared to the FFR or the iFR was limited to a small number of patients in post-hoc substudies.22,26 A MD of 0.01 sometimes led to non-trivial disagreement on revascularization decision,25 likely due to baseline values being near the cut-off. Therefore, it is essential to have an index which remains stable or demonstrates consistent changes, such as the FFR and the iFR. Similarly, these indices demonstrated a greater frequency of a specific type of disagreement (methodological variations–wire positioning–may explain the less frequent cases of disagreement).24

Therefore, the FFR and the iFR could be considered in the acute STEMI as an alternative to delayed assessments,25 considering that the FFR tends to decrease and the iFR tends to increase. The FFR could guide the revascularization of positive lesions (FFR ≤ 0.80).25 In patients with a FFR > 0.80, acute iFR assessment can be used to delay the revascularization of negative NCL (iFR > 0.89).24 In the remaining cases (iFR ≤ 0.89), some authors suggested a staged reevaluation.24 At least 5 days after the index procedure should go by. This was the minimum time needed to observe the initial resolution of acute physiological disturbances.24

Finally, when plaques are correctly identified as functionally negative, they may still be vulnerable and associated with adverse events. NCL exhibiting thin-cap fibroatheromas as defined by optical coherence tomography, and having a muQFR ≤ 0.80, showed the highest event rate,40 which suggests that imaging can offer additional prognostic information.

PCSK9 inhibitors have shown minimal impact on coronary physiology, despite greatly reducing low-density lipoprotein-cholesterol (LDL-C) levels. A large treatment effect on HIST only,19 minor flow limitation at baseline, and microvascular compensation may account for this finding.13

However, combining alirocumab with HIST resulted in a greater increase in cap thickness of fibroatheromas vs statin monotherapy as assessed by optical coherence tomography.41 Moreover, lower LDL-C levels after an ACS are associated with the occurrence of fewer cardiovascular events.2 Therefore, PCSK9 inhibitor treatment is recommended in patients who do not reach their LDL-C target despite maximum tolerated statin and ezetimibe therapy.2

Limitations

The wide variety of indices to assess coronary physiology has led to a lack of evidence on some of them; similarly, few studies made direct comparisons among such indices.

Our evaluations are mainly based on observational studies with a very different follow-ups.

Angiography-based methods frequently exhibited bias due to their retrospective analysis. Some patients were excluded because of the poor quality of angiographies or anatomic issues, such as ostial lesion or severe vascular tortuosity. Some angiographies were not obtained optimally according to the specific acquisition guide.

CONCLUSIONS

The assessment of functional indices for NCL during the initial procedure for STEMI is not absolutely reliable. This evidence is due to potential variability of the FFR, the iFR, and the QFR outside the acute phase. Although variation was not significant for muQFR, resting Pd/Pa, and vFFR, retrospective and/or limited data limit the generalizability of these findings.

Both the FFR and the iFR showed consistent directions of change. Therefore, during an acute STEMI, the FFR can guide the revascularization of positive NCL, while the iFR can help defer revascularization of negative NCL. A negative FFR with a positive iFR should be reevaluated.

The FFR shows robust data supporting its use in NLC of NSTEMI during the acute phase, meaning that it is a more reliable index for initial ACS procedures.

DATA AVAILABILITY

Search string for Google Scholar: “acute coronary syndrome”|”myocardial infarction” “fractional flow reserve”|FFR| “hyperemic ind”|”resting ind”|iFR|”instantaneous wave-free ratio”| “angiography-based ind”|”angiography-derived ind”|QFR|”quantitative flow ratio”|OFR staged|repeated|later. The remaining search strings are available upon request.

FUNDING

None declared.

ETHICAL CONSIDERATIONS

Ethical committee and patient’s informed consent: not applicable. We followed the SAGER guidelines with respect to possible sex/gender bias.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

Microsoft Copilot was used to help edit the English version of the text.

AUTHORS’ CONTRIBUTIONS

F. Vergni designed the work. F. Vergni, S. Buscarini, L. Ciurlanti, and F.L. Gurgoglione contributed to data acquisition (screening, and/or extraction). F. Vergni, and L. Ciurlanti conducted the critical appraisal. F. Vergni, and S. Buscarini contributed to data interpretation. F. Vergni, and F.L. Gurgoglione drafted, edited and reviewed the work. F. Vergni, S. Buscarini, L. Ciurlanti, F.L. Gurgoglione, F. Pellone, and M. Luzi approved the final version for publication.

CONFLICTS OF INTEREST

None declared.

SUPPLEMENTARY DATA

REFERENCES

INTRODUCTION

The presence of multivessel disease, defined as angiographic lesions with a percent diameter stenosis (PDS) ≥ 50% by visual estimation in patients with ST-segment elevation myocardial infarction (STEMI), is estimated to be approximately 50%.1 The COMPLETE trial compared angiography-guided preventive revascularization with stent implantation added to optimal medical therapy (OMT) for nonculprit lesions with a PDS ≥ 70% vs OMT alone.2 The trial found that angiography-guided preventive revascularization significantly reduced adverse cardiovascular events at 3 years of follow-up.2 Although the COMPLETE trial required physiological assessment using fractional flow reserve (FFR) for lesions with a PDS between 50% and 69% to guide the decision on revascularization, in practice, it was performed in only a very small percentage of patients.

The FLOWER-MI and FRAME-AMI trials3,4 investigated preventive stenting of FFR-guided nonculprit lesions—obtained through intracoronary pressure wire—compared with angiography-guided complete revascularization (visual estimation). Both trials mainly included intermediate lesions and demonstrated that pressure wire-guided preventive revascularization significantly reduces the need for revascularization, with similar or superior efficacy to angiography-guided complete revascularization.3,4 Despite these findings, clinical practice guidelines based on the COMPLETE trial recommend preventive stenting of nonculprit lesions guided by angiography alone.5,6

It is important to note that FFR is considered the gold standard for detecting myocardial ischemia (FFR ≤ 0.80). However, deferring treatment of nonculprit lesions that do not cause ischemia (FFR > 0.80) through OMT raises concerns in selected cases in which the anatomical features of the lesion suggest signs of vulnerability. In the FLOWER-MI trial, the group of patients randomized to undergo pressure-wire-guided revascularization with an FFR > 0.80 (referred for OMT) had more adverse events than those in the same group with FFR values ≤ 0.80 (referred for percutaneous revascularization).7 Several studies using intravascular imaging modalities have also demonstrated an association between the presence of fibro-lipid plaques with high lipid content and thin fibrous caps—known as vulnerable plaques—and the development of future adverse events due to plaque rupture.8,11

The VULNERABLE trial aims to evaluate the efficacy of a combined strategy using intracoronary physiological techniques and intravascular imaging to guide the treatment of intermediate nonculprit lesions in STEMI patients. The study hypothesis is that preventive stenting—in addition to OMT—in intermediate nonculprit lesions with FFR values > 0.80 and characteristics of vulnerable plaque will be superior to OMT alone. The present article includes the rationale and design of the study.

METHODS

Design

The VULNERABLE trial (NCT05599061) includes 3 groups based on the results obtained during the combined functional and anatomical assessment using pressure wires and optical coherence tomography (OCT). Figure 1 shows the study flowchart, which illustrates the 3 groups: patients with FFR ≤ 0.80 treated with stent (search failures), patients with FFR > 0.80 without vulnerable plaque characteristics (included in the registry group), and patients with FFR > 0.80 and vulnerable plaque characteristics (included in the randomized clinical trial).

This is a multicenter, controlled, prospective, randomized, parallel-group, single-blind study with patients included in the clinical trial group. The study will be conducted in accordance with the recommendations outlined in the Declaration of Helsinki on clinical research and has been approved by the lead ethics committee (Hospital Universitari de Bellvitge) and endorsed by the remaining ethics committees of participating centers. The participating centers and principal investigators are shown in table 1 of the supplementary data.

 

Table 1. Objectives of the VULNERABLE trial

Primary endpoint
Compare the percentage of TVF between the 2 groups of patients assigned to the randomized clinical trial (FFR > 0.80 with characteristics of vulnerable plaque by OCT): preventive revascularization with stent + OMT vs OMT alone
Key secondary endpoints
Compare the percentage of TVF between patients allocated to the registry group (FFR > 0.80 without characteristics of vulnerable plaque by OCT and treated with the OMT) and patients allocated to the randomized OMT group (FFR > 0.80 with characteristics of vulnerable plaque)
Other secondary endpoints
Compare the rate of all-cause mortality reported between the 2 subgroups of randomized patients
Compare the percentage of cardiac deaths reported between the 2 subgroups of randomized patients
Compare the percentage of all myocardial infarctions reported between the 2 subgroups of randomized patients
Compare the percentage of target vessel myocardial infarctions reported between the 2 subgroups of randomized patients
Compare the percentage of target vessel revascularization needs between the 2 subgroups of randomized patients
Evaluate the percentage of restenosis and stent thrombosis in the preventive revascularization group with stent + OMT of the randomized clinical trial
* Although all objectives are marked with a complete 4-year follow-up, an interim study will be conducted at 2 years. ** All objectives will be calculated on an intention-to-treat basis according to the statistical plan. An exploratory per-protocol analysis will also be conducted based on the assessment by the study’s core imaging laboratory.
FFR: fractional flow reserve; OCT: optical coherence tomograph; OMT: optimal medical treatment; TVF: target vessel failure.

 

The study has been entirely designed and initiated by researchers and is sponsored by the Spanish Society of Cardiology Working Group on Intracoronary Diagnostic Techniques, which includes a steering committee, a data and safety monitoring board, and an independent event adjudication committee. The members of these committees are listed in table 2 of the supplementary data. The steering committee and all study investigators are committed to accurate data collection and adherence to the study protocol. The funding entity (Abbott Vascular, United States) plays no role in the study design, data collection, analysis, or the writing of the study results. The study sponsor (Foundation for Education in Interventional Cardiology Procedures [EPIC]), along with the principal investigators, is responsible for data management and confidentiality.

 

Table 2. Inclusion and exclusion criteria of the VULNERABLE trial

Inclusion criteria
Patients older than 18 years
With STEMI (ST-segment elevation > 1 mm in, at least, 2 contiguous leads or true posterior ST-segment elevation with > 2 mm depression in anterior leads or new onset left bundle branch block) treated with successful revascularization of the culprit lesion within 72 hours from symptom onset
Presenting with multivessel disease with, at least, 1 angiographically intermediate lesion (PDS of 40% up to 69% by visual estimation) in a native vessel different from the culprit vessel
Planned FFR-guided percutaneous revascularization with a single 2.0 mm-to- 4.5 mm stent
Between 1 and 60 days after the index procedure (revascularization of the STEMI culprit vessel)
Exclusion criteria
Life expectancy < 4 years
Women of childbearing age who wish to become pregnant
Known intolerance to acetylsalicylic acid, heparin, everolimus, or iodinated contrast
Unresolved mechanical complications or infarct-related cardiogenic shock
Lesions suitable for the study located in the left main coronary artery, vessels with previous revascularization, in coronary bifurcations with > 2.5 mm side branches, severe angulations, or segments with severe calcification
History of severe asthma
Chronic kidney disease with glomerular filtration rate < 45 mL/min
FFR: fractional flow reserve; PDS: percent diameter stenosis; STEMI: ST-segment elevation myocardial infarction.

 

Endpoints

The primary objective of the VULNERABLE study (NCT05599061) is to compare the efficacy of preventive stenting combined with OMT vs OMT alone for intermediate lesions in noninfarct-related arteries with an FFR > 0.80 and vulnerable plaque characteristics as identified by OCT over a 4-year follow-up period. The primary endpoint of the study is the rate of target vessel failure (TVF), which is defined as a composite of cardiac death, target vessel myocardial infarction, or the need for target vessel revascularization.

The study also aims to evaluate several secondary endpoints, which are summarized in table 1. Among these secondary objectives, a key focus is the comparison of the TVF rate (the primary endpoint) between the registry group (patients with FFR > 0.80 without vulnerable plaque characteristics treated with OMT) and the randomized OMT arm of the clinical trial (patients with FFR > 0.80 and vulnerable plaque characteristics). The study endpoints are defined in table 3 of the supplementary data.12,13

Patient inclusion and exclusion criteria

The inclusion and exclusion criteria for the study are detailed in table 2. In brief, all patients with STEMI who have undergone successful revascularization of the culprit lesion and have at least 1 intermediate lesion (visually defined as having a DS of 40%-69%) in a noninfarct-related artery will be eligible for the study if percutaneous revascularization with a single stent guided by FFR is being considered. The study procedure must be conducted between 1 and 60 days after the revascularization of the culprit lesion. Patients must provide informed consent prior to the elective procedure for evaluating the nonculprit lesion.

Study protocol for nonculprit lesions and randomization

Eligible lesions will first be assessed with a pressure wire following the standard procedures in each center. Lesions with an FFR ≤ 0.80 will be considered search failures, and revascularization will be recommended based on clinical indications.5,6

Lesions with an FFR > 0.80 will be further evaluated with OCT according to the standard acquisition methods to detect vulnerable plaques in each center. The decision on whether a lesion meets the criteria for vulnerable plaque will be made by an accredited local investigator during the study procedure.

Patients with at least 1 lesion with an FFR > 0.80 without vulnerable plaque characteristics on OCT will be included in the registry group of the study. The protocol recommends OMT for all lesions with an FFR > 0.80 without vulnerable plaque characteristics. These patients will receive the same clinical follow-up as those in the randomized clinical trial group.

Patients with at least 1 lesion with an FFR > 0.80 that meets the criteria for a vulnerable plaque on OCT will be included in the clinical trial group. These patients will be randomized 1:1 to either preventive stenting combined with OMT or OMT alone (figure 1). Randomization will be conducted without stratification by center or clinical condition, using telematic algorithms. This process will be carried out online via the data collection platform provided by pInvestiga (Pontevedra, Spain).

Figure 1. Study diagram. FFR, fractional flow reserve; OCT, optical coherence tomography; OMT, optimal medical treatment; PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction.

 

The supplementary data provide additional details on the FFR assessment method, including special situations where the lesion under study could not be fully evaluated, instances of unstable nonculprit plaques, complications related to diagnostic techniques, or patients with more than 1 nonculprit lesion.

Study device and implantation procedure

Patients with an FFR > 0.80 and vulnerable plaque characteristics identified by OCT assigned to the percutaneous coronary intervention group will be treated with an everolimus-eluting stent (Xience, Abbott, United States). According to the protocol, stent implantation must be guided by OCT. The criteria for OCT-guided stent implantation are detailed in table 4 of the supplementary data.

Optimal medical therapy

All patients included in both the randomized clinical trial and the registry must receive treatment in accordance with the European Society of Cardiology guidelines for managing acute coronary syndromes.5 The study protocol emphasizes managing modifiable risk factors—such as diet, smoking, obesity, exercise, and psychological status—as well as nonmodifiable risk factors, with set targets for blood pressure (systolic < 130 mmHg and diastolic < 80 mmHg), low-density lipoprotein cholesterol (< 55 mg/dL), and glycated hemoglobin A1c (< 7%). Pharmacological therapy should include beta-blockers and renin-angiotensin system inhibitors. Dual antiplatelet therapy is also recommended, but only during the first year after the index procedure, at the discretion of each center. As per the protocol, patient treatment details will be reported annually, and 2 lipid profile tests will be conducted throughout the study.

Vulnerable plaque criteria on optical coherence tomography and investigator training

Based on histopathological data, a plaque is defined as vulnerable when it is caused by a fibroatheroma with a large necrotic core composed of cellular debris and a high number of inflammatory cells, covered by a thin fibrous cap (≤ 65 µm).14 The criteria for identifying a vulnerable plaque in the study are adapted from the classic histopathological definition but modified for OCT assessment. These criteria are shown in figure 2.

Figure 2. Vulnerable plaque criteria by optical coherence tomography. EEM, external elastic membrane; minimal lumen area.

 

According to the protocol, 3 simultaneous criteria are required to define a vulnerable plaque by OCT:

The presence of a fibro-lipid plaque with a necrotic core covering more than 90º of the perimeter of the vessel over a length of more than 5 mm. A necrotic core is defined as a hypointense image with poorly defined borders that attenuates the OCT light beam, preventing visualization of the artery behind the core.

The presence of a thin fibrous cap, defined as ≤ 80 µm (65 + 15 µm axial resolution) in ≥ 3 consecutive images. The fibrous cap is defined as the tissue separating the necrotic core from the vessel lumen. Investigators will be trained to differentiate other findings that could be mistaken for a thin cap on OCT. Figure 3 shows examples of analogous OCT images that may mimic a thin fibrous cap but do not correspond to vulnerable plaques.

Figure 3. Distinction between vulnerable plaques and other findings by optical coherence tomography (OCT). A: plaque with superficial calcium (hypointense core with well-defined margins that do not attenuate the passage of light; arrow) and a thin fibrous cap. B: calcified nodule (arrow) protruding into the lumen and attenuating the signal, despite being composed of calcium. C: tangential signal loss (arrow) due to insufficient light beams caused by the peripheral, noncentral position of the OCT probe. D: superficial accumulation of macrophages (arrow) with a hyperintense appearance relative to the adjacent intima, with signal attenuation behind. E: presence of blood in the lumen due to inadequate flushing (arrow) during image acquisition, which distorts the arterial wall image, creating the appearance of hypointense regions. F: presence of blood between the probe and the OCT catheter (arrow) due to inadequate flushing, which distorts the arterial wall image and mimics hypointense regions.

Investigators will be required to measure a plaque burden of ≥ 70% in the cross-sectional area corresponding to the minimal luminal area (MLA) within the lesion. To perform this assessment, it is necessary to measure the vessel perimeter by delineating the external elastic membrane (EEM). Due to the difficulty of assessing the vessel perimeter in fibro-lipid plaques, especially at the MLA site, investigators will be trained to choose a section as close as possible to the MLA, where at least 60% of the vessel perimeter can be visualized if it is not possible at the same point. This allows for calculation using the following formula (figure 4):

Figure 4. Plaque burden assessment by optical coherence tomography. A: cross-section of the minimal lumen area. B: cross-section where the external elastic membrane (EEM) was measured. Since the EEM cannot usually be assessed in the cross-section corresponding to the MLA, an approximate estimation is made by measuring the EEM within 10 mm proximal or distal to the MLA (preferably distal) in the absence of side branches. The EEM will be assessed in the first cross-section where 60% of the EEM perimeter can be evaluated.

 

As per protocol, at least 1 local investigator from each participating center must have completed an online training course for the detection and assessment of vulnerable plaques using OCT, following the study criteria. Upon completing this course and passing a specific questionnaire, the investigator will be certified and approved to participate in the study.

Angiographic and optimal coherence tomography quantification analyses

The study includes an independent imaging laboratory for angiographic quantification and OCT analysis (Barcelona Cardiac Imaging Core Laboratory [BARCICORE-Lab]) to monitor adherence to the study criteria for diagnosing vulnerable plaques. A blinded analysis of the study results will be conducted, and patients will be assigned according to the protocol for exploratory analysis. A detailed explanation of the angiographic and OCT analysis conducted by the study laboratory is shown in the supplementary data.

Clinical follow-up and blinding

Patients in both the registry group and the randomized clinical trial group will undergo clinical follow-up for 4 years. Follow-up will include telephone consultations at 1 and 3 years, and in-person visits at 2 and 4 years. Each follow-up will involve an electrocardiogram and blood tests with cholesterol determination.

Patients in the randomized clinical trial group will be blinded to their assigned treatment group (single-blind). The details of blinding and monitoring are specified in the supplementary data.

Sample size calculation

The sample size has been calculated for the randomized clinical trial group. The number of patients included in the registry and search failures will depend on the total number needed to achieve the estimated sample size for the randomized trial.

According to previous studies on patients with acute coronary syndrome, theTVF rate for nonculprit lesions meeting vulnerable plaque criteria treated with OMT is estimated to be around 8% to 10% at 4 years. In similar lesions treated with stenting, the rate is approximately 4%.2,7,9 The studies used for the sample size calculation are summarized in table 5 of the supplementary data. Based on the study hypothesis, preventive stenting in nonculprit lesions with an FFR > 0.80 and vulnerable plaque characteristics is expected to reduce the primary endpoint by 60%. The estimated rate of TVF in the OMT group at 4 years is 10%. Assuming an annual loss to follow-up rate of 1.5% (total 6%), randomizing 600 participants 1:1 to preventive stenting plus OMT vs OMT alone will provide 80% power to demonstrate the superiority of preventive stenting with a 2-sided alpha error of .05.

Statistical analysis plan

The primary and secondary endpoints will be analyzed using the intention-to-treat principle at the 4-year follow-up. Comparisons will estimate event proportions between groups using logistic regression and will be reported as odds ratios with 95% confidence intervals. Only 1 event per patient will be counted for the primary endpoint. P values < .05 will be considered statistically significant for the primary endpoint. Kaplan-Meier curves will be used to visualize the time to the first event between groups.

For primary endpoint composites with missing data, a specific monitoring plan will determine if the missing data are random. In cases where data are adjudicated as missing at random, imputation methods will be used. For nonrandom missing data, sensitivity analyses using worst-case and last observation carried forward methods will be conducted.

Subgroup analyses will be performed for the primary and secondary endpoints, which involves comparing TVF rates between registry patients and those randomized to OMT in the clinical trial. Prespecified subgroups include: age > 75 years, sex, diabetes mellitus, left ventricular ejection fraction ≤ 35% at the time of the procedure, lesions in the proximal or mid-left anterior descending artery, and lesions in vessels with a reference diameter ≤ 2.75 mm.

Additionally, a hypothesis-generating parallel analysis will be conducted according to the study protocol. Patients will be included in the analysis only if the imaging laboratory confirms that their assigned treatment group, as determined by the local investigator, is consistent with the presence of vulnerable plaque identified by OCT. Patients will be excluded if there is a discrepancy between the investigator’s assignment and the imaging laboratory’s findings.

Interim analysis

After 2 years of follow-up, an interim analysis of the data is planned to monitor the primary endpoint in the randomized clinical trial group. Clinical follow-up will be extended if the events observed in the OMT arm of the randomized clinical trial are less than 4%.

DISCUSSION

The VULNERABLE trial aims to investigate the combined use of intracoronary physiology and images to guide the treatment of intermediate nonculprit lesions in STEMI patients.

Several lipid-lowering and anti-inflammatory drugs have been shown to reduce thrombotic events in patients with STEMI, likely by stabilizing functionally nonsignificant vulnerable plaques.15,17 In the PACMAN-AMI trial, treatment with alirocumab in addition to statins significantly reduced atheroma, decreased lipid content, and led to thickening of the fibrous cap compared with placebo in coronary regions with angiographically nonobstructive atherosclerosis (DS, 20%-50%).18 However, it is noteworthy that only 31% of patients in that study exhibited all 3 markers of reduced atherosclerosis, and data on more significant plaques (eg, 40%-69% stenosis with vulnerability criteria) were not specified.19

The use of stents in patients with vulnerable plaques is intended to enhance neointimal healing of the struts, which thickens the fibrous cap and stabilizes the plaque. The randomized PREVENT trial assessed the effectiveness of preventive stenting for functionally nonsignificant vulnerable lesions in patients with chronic coronary syndrome compared with OMT. Vulnerable plaques were identified using various intravascular imaging techniques, with most being guided solely by intravascular ultrasound. The study found that preventive stenting resulted in a statistically significant reduction in the rate of TVF at 2 years of follow-up (0.4% vs 3.4%; P = .0003).11

Finally, several observational trials have demonstrated that OCT is an effective method for detecting vulnerable plaques and monitoring the response to intensive treatments aimed at stabilizing these plaques through fibrous cap thickening.18,20 The PECTUS-obs trial included 438 acute coronary syndrome patients with nonculprit lesions with FFR > 0.80 treated with the OMT alone.10 All lesions were examined using OCT, with criteria similar to those used in the VULNERABLE trial to define vulnerable plaques. In that study, 34% of patients had at least 1 vulnerable lesion, which was associated with a higher risk of adverse events (15.4% vs 8.2% for the composite endpoint of death, myocardial infarction, or revascularization in the groups with and without vulnerable plaques, respectively). The VULNERABLE trial is the first to use OCT to guide the treatment of vulnerable plaques in functionally nonsignificant lesions.

CONCLUSIONS

The VULNERABLE trial aims to evaluate the effectiveness of preventive stenting plus OMT vs OMT alone for vulnerable plaques, as defined by OCT, in functionally nonsignificant intermediate lesions in nonculprit vessels of patients with STEMI. In addition, the study will provide information on the clinical relevance of the presence of vulnerable plaques in nonculprit lesions.

FUNDING

This study has been funded by Abbott Vascular.

ETHICAL CONSIDERATIONS

The study is being conducted following the recommendations outlined in the Declaration of Helsinki on clinical research, has been approved by Hospital Universitari de Bellvitge research ethics committee, and endorsed by the remaining ethics committees of participating centers. Informed consent acceptance and signature are required prior to performing any elective procedures to study the nonculprit lesion. Potential sex and gender biases are considered.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

No artificial intelligence was used in the drafting of this manuscript.

AUTHORS’ CONTRIBUTIONS

J. Gómez-Lara and E. Gutiérrez-Ibañes drafted this document. The remaining signatories reviewed the document, made changes at their discretion, and approved the final text.

CONFLICTS OF INTEREST

J. Gómez-Lara and E. Gutiérrez-Ibañes received a grant from Abbott Vascular for this study. A. Jurado-Román has received fees from Abbott, Boston, and Shockwave. E. Fernández received fees from Abbott and Hexacath. C. Cortés received a Río Hortega Contract from Instituto de Salud Carlos III. S. Brugaletta received fees from Abbott, Microport, and General Electric. T. García-Camarero received fees from Medtronic and Boston. J.A. Linares Vicente received fees from Abbott Vascular, Braun, AstraZeneca, Bayer, and IZASA. O. Rodríguez-Leor received fees from Shockwave, WorlsMedica, and Medtronic. S. Ojeda received fees from Abbott, Boston, WorldMedica, and Biosensors. A. Pérez de Prado received grants and fees from Abbot, Boston, iVascular, and Terumo. H.M. García-García received fees from ACIST, Boston Scientific, Medis, Biotronik, InfraRedx/Nipro, Chiesi, and Cordis. S. Ojeda and A. Pérez de Prado are associate editors of REC: Interventional Cardiology; the journal’s editorial procedure to ensure impartial processing of the manuscript has been followed. The remaining authors declared no conflicts of interest whatsoever.

REFERENCES

INTRODUCTION

Currently, distal radial access (DRA) in the anatomical snuffbox for both noncoronary and coronary procedures is gaining popularity. Since its introduction by Babunashvili et al.,1 in 2011, several observational studies have validated the feasibility and safety of DRA,2-4 comparing it with conventional transradial access (TRA). DRA has shown advantages such as a lower incidence of radial artery occlusion (RAO) and shorter hemostasis time, with minimal access-related complications.5,6 The usefulness of ultrasound to guide DRA and evaluate access-related complications has also been described.7,8 Recent randomized trials comparing DRA with TRA have reported conflicting results regarding RAO incidence, crossover rates, and access times.9-11 Nevertheless, meta-analyses consistently support the benefits of DRA, albeit with a higher crossover rate.12-13 One of the limitations of most studies on DRA is the restricted inclusion of patients in emergent situations or complex percutaneous coronary interventions (PCI), such as ST-segment elevation myocardial infarction (STEMI); therefore, the feasibility of the approach in this context is somewhat scarce.2,9-11,14 Despite current evidence, the use of DRA as the default access for coronary procedures is still not widely implemented in most centers. Hence, this prospective single-center cohort aimed to present the experience of our first 1000 DRA in patients undergoing coronary procedures in any clinical settings.

METHODS

Population and study design

The Distal Radial Access for Diagnostic and Interventional Coronary Procedures in an all-comer population (DISTAL) registry is a prospective observational investigation aiming to assess the performance of DRA and compare clinical and procedural characteristics in a diverse population undergoing coronary procedures. This interim analysis presents our initial experience with DRA conducted at a single center. All DRA procedures performed by 4 experienced operators, previously proficient in TRA, were included in the study from August 2020 to November 2023.

This study was approved by the Ethics Committee of our institution (CEIC-2804) and was conducted following the principles of the Declaration of Helsinki. All patients gave their informed written consent before the procedure.

Inclusion and exclusion criteria

The study included patients aged 18 years and older undergoing diagnostic or therapeutic coronary procedures using DRA in any clinical setting. Patients with an unsuitable distal radial artery (DRart) assessed by ultrasound (non-permeable or diameter <1 .8 mm) were excluded, as were patients with no palpable pulse of DRart with such unsuitability characteristics. Additional exclusion criteria encompassed participation in other clinical trials, known allergy to iodinated contrast, inability to provide informed consent, and women of childbearing age without a negative pregnancy test. While the Barbeau test was recommended, it was not mandatory for inclusion.15

Endpoints

The primary endpoint was the success of DRA and the main secondary endpoint was the success of the coronary procedure. Other secondary endpoints included DRA procedure time, total procedure duration, the incidence of radial artery spasm, exposure to ionizing radiation, patient comfort levels, hemostasis time, access-related complications, and the impact of ultrasound guidance on DRA performance. Detailed definitions of these endpoints are provided in the supplementary data.

Distal radial access technique

The DRA technique has been previously described,2,4,16-18 and is explained in detail in the supplementary data. Key aspects of interest included patient selection, the decision to use ultrasound-guided puncture19 (figure 1) vs blind with palpation puncture at the discretion of the operator, patient positioning for right (r) or left (l) DRA, the puncture technique itself, and the hemostasis procedure (figure 2).

Figure 1. A: markers for ultrasound positioning in the anatomical snuffbox. B: patency of the distal radial artery (DRart) confirmed by color Doppler ultrasound. C-D: course of DRart between the metacarpal bones. E-F: recommended puncture sites of the DRart on a surface bone. IM, index metacarpal; SB, scaphoid bone; TB, trapezium bone; TM, thumb metacarpal.

Figure 2. Distal radial access (DRA) technique. Position of the hand for A) right DRA and B) left DRA. C: ultrasound-guided DRA technique. D: blind with palpation DRA puncture. E: final position of the introducer sheaths on the right and left DRA. F: hemostasis devices in DRA.

Statistical analysis

Sample size and statistical power calculations were performed using the GRANMO calculator.20 A sample size of 1000 procedures was determined to provide a statistical power greater than 99% to detect a difference of 3% or more in the proportion of DRA success (primary endpoint) at our center, assuming an alpha risk of 1%. This calculation was based on a reference proportion from previous medical literature estimated around 95%.11,18,21

Categorical variables are presented as counts (percentages), while continuous variables were assessed for normal distribution using the Kolmogorov-Smirnov test. Normally distributed variables are expressed as mean (standard deviation), and nonnormally distributed variables as median [interquartile range].

To evaluate the impact of the learning curve, comparisons were made among quartiles of the study period for variables including access failure, DRA time, total procedure time, and access-related complications. Analysis of variance or the Kruskal-Wallis test was used depending on the normality of the variable. Logistic regression analysis (logit command) was used with the first quartile as the reference to compare percentages among quartiles.

Statistical analyses were conducted using SPSS Statistics 20.0 software (IBM, United States) and STATA 12 (StataCorp, College Station, United States). A p-value < 0.05 was considered statistically significant for all tests.

RESULTS

From August 2020 to November 2023, a total of 1000 DRA procedures (943 patients) were performed. Table 1 shows the patients’ baseline clinical characteristics. The mean age was 68 years, and 29% of the patients were women. A total of 47% of the procedures were performed on an outpatient basis. In 35% of cases, the indication was acute coronary syndrome (13% STEMI).

Table 1. Baseline clinical characteristics

Clinical characteristics	n = 1000
Age, (years), mean (SD)	68.1 (11.7)
Female, n (%)	289 (28.9)
Weight, (kg), mean (SD)	78.0 (14.8)
Height, (cm), mean (SD)	167.9 (8.1)
Body mass index, (kg/m2), mean (SD)	28.0 (4.5)
Hypertension, n (%)	735 (73.5)
Dyslipidemia, n (%)	578 (57.8)
Diabetes mellitus, n (%)	353 (35.3)
Current smoker, n (%)	246 (24.6)
Family history of premature coronary heart disease, n (%)	54 (5.4)
Previous peripheral artery disease, n (%)	50 (0.5)
Previous stroke, n (%)	41 (4.1)
Previous heart failure, n (%)	252 (25.2)
GFR (mL/minute/1.73m2), mean (SD)	72.4 (20.0)
Dialysis, n (%)	27 (2.7)
Left ventricular ejection fraction, mean (SD)	52.6 (16.2)
Atrial fibrillation, n (%)	170 (17.0)
OAC
Acenocoumarin, n (%)	170 (17.0)
Direct OAC, n (%)	81 (8.1)
Previous CAG, n (%)	251 (25.1)
Previous CABG, n (%)	43 (4.3)
Previous PCI, n (%)	218 (21.8)
Previous ischemic heart disease
Previous STEMI, n (%)	133 (13.3)
Previous NSTEMI, n (%)	69 (6.9)
Previous CCS, n (%)	53 (5.3)
CAG indication
Chronic coronary syndrome, n (%)	207 (20.7)
STEMI, n (%)	128 (12.8)
NSTEMI, n (%)	224 (22.4)
Staged PCI, n (%)	60 (6.0)
Diagnostic, n (%)	381 (38.1)
Preoperative CAG in patients with VHD, n (%)	183 (18.3)
Dilated cardiomyopathy, n (%)	158 (15.8)
Ventricular tachycardia, n (%)	24 (2.4)
Others, n (%)	16 (1.6)
Outpatient coronary arteriography, n (%)	470 (47)
CABG, coronary artery bypass grafting; CAG, coronary angiography; CCS, chronic coronary syndrome; GFR, glomerular filtration rate; NSTEMI, non−ST-segment elevation myocardial infarction; OAC, oral anticoagulation; PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction; VHD, valvular heart disease. Data are expressed as No. (%) or mean ± standard deviation.

Table 2 presents the characteristics of the radial artery and the DRA procedure. High rates of preprocedure ultrasound evaluation and ultrasound-guided technique for DRA were noted (83% and 85%, respectively). Notably, the percentage of coronary procedures showing insufficient catheter length due to DRA was low (3.7%).

Table 2. Characteristics of the DRA procedure

Procedure characteristics	n = 1000
Preprocedure characteristics
Arterial pulse strength scale
Absent, n (%)	12 (1.2)
Weak, n (%)	167 (16.7)
Normal, n (%)	652 (65.2)
Strong, n (%)	169 (16.9)
Radial artery preprocedure ultrasound evaluation, n (%)	830 (83.0)
Arterial tortuosity
Radial, n (%)	23 (2.3)
Subclavian, n (%)	62 (6.2)
Calcified radial artery, n (%)	26 (2.6)
Distal radial artery size, mm (SD)	2.3 (0.3)
Proximal radial artery size, mm (SD)	2.5 (0.4)
Depth of the distal radial artery, mm (SD)	3.8 (1.0)
DRA technique
CAG by the same DRA, n (%)	57 (5.7)
Ultrasound-guided access, n (%)	848 (84.8)
DRA side
Right DRA, n (%)	627 (62.7)
Left DRA, n (%)	373 (37.3)
Introducer size
5 French, n (%)	256 (25.6)
6 French, n (%)	744 (74.4)
Introducer sheath type
Prelude Ideal (Merit Medical) Introducer Kit, n (%)	950 (95.0)
Radifocus Introducer II Kit A (Terumo Corporation), n (%)	50 (5.0)
Short length of the radial catheter	37 (3.7)
Postprocedure arterial patency evaluation, n (%)	907 (90.7)
Postprocedure puncture site bleeding, n (%)	55 (5.5)
CAG, coronary angiography; DRA, distal radial access. Data are expressed as No. (%) or mean ± standard deviation.

Table 3 summarizes the characteristics of coronary procedures, including the extent of coronary artery disease, types of procedures, and features of patients who underwent PCI. In general, 64% of the procedures were only diagnostic, while 36% included PCI.

Table 3. Characteristics of the coronary procedure

Procedure characteristics	n = 1000
Coronary disease extent
One vessel, n (%)	285 (28.5)
Two vessels, n (%)	174 (17.4)
Three vessels, n (%)	176 (17.6)
LMCAD, n (%)	55 (5.5)
Coronary bypass graft, n (%)	27 (2.7)
Characteristics of the coronary procedure
Type of coronary procedures
Diagnostic, n (%)	644 (64.4)
PCI, n (%)	356 (35.6)
Ambulatory PCI, n (%)	90 (9.0)
PCI culprit lesion
LMCAD, n (%)	9 (0.9)
Left anterior descending artery, n (%)	164 (16.4)
Circumflex coronary artery, n (%)	95 (9.5)
Right coronary artery, n (%)	100 (10.0)
Coronary bypass graft	2 (0.2)
Specific techniques
Wire-based intracoronary physiological assessment, n (%)	57 (5.7)
Optical coherence tomography, n (%)	21 (2.1)
Intravascular ultrasound, n (%)	30 (3.0)
Guide catheter extension system, n (%)	15 (1.5)
Rotational atherectomy, n (%)	16 (1.6)
Cutting balloon, n (%)	34 (3.4)
Intracoronary lithotripsy, n (%)	8 (8.0)
Thrombus aspiration, n (%)	81 (8.1)
Intracoronary perfusion catheter, n (%)	7 (0.7)
Special PCI procedures
Complex bifurcation, n (%)	60 (6.0)
Chronic total occlusion, n (%)	16 (1.6)
Volume of contrast, (mL), mean (SD)	85.0 (53.1)
Heparin dose, (IU), median [IQR]	5000 (3000-8500)
LMCAD, left main coronary artery disease; PCI, percutaneous coronary intervention.

Table 4 depicts the clinical endpoints. The DRA success rate was 97.4% and the coronary procedure success rate was 96.9%. The median access time was 40 (interquartile range [IQR], 30-60) seconds, and 4% of patients experienced radial artery spasm. The overall rate of access-related complications was low (2.9%).

Table 4. Clinical endpoints

Clinical endpoints	n = 1000
Primary endpoint
DRA success, n (%)	974 (97.4)
Coronary procedure success by DRA, n (%)	969 (96.9)
Secondary endpoints
Access time, (sec), median [IQR]	40 (30-60)
Procedure time, (min), median [IQR]	29.0 [17.3-45.0]
Radial artery spasm, n (%)	44 (4.4)
DAP, (Gy.m2), median [IQR]	32.7 [19.2-63.0]
Fluoroscopy time (min), median [IQR]	4.6 [2.5-10.0]
VAS patient comfort for access, mean (SD)	2.2 (0.6)
VAS patient comfort for hemostasis, mean (SD)	2.1 (0.4)
Hemostasis time, (hour), mean, (SD)	2.9 (1.1)
Access-related complications (all), n (%)	29 (2.9)
Radial artery occlusion, n (%)	10 (1.0)
Hematoma, n (%)
Type I-a, n (%)	11 (1.1)
Type I-b, n (%)	1 (0.1)
Type II, n (%)	1 (0.1)
Type III, n (%)	1 (0.1)
Type IV, n (%)	0 (0)
Radial pseudoaneurysm, n (%)	0 (0)
Radial dissection, n (%)	5 (0.5)
Arteriovenous fistula, n (%)	0 (0)
DAP, dose-area product; DRA, distal radial access; VAS, visual analog scale. Data are expressed as No. (%), mean ± standard deviation, or median [interquartile range].

Combined preprocedure ultrasound evaluation and ultrasound-guided puncture were performed in 82.8% of cases, with successful DRA achieved in 97.7% compared with 95.9% in those who did not undergo ultrasound guidance (P = .183). Based on the strength of the arterial pulse—absent, weak, normal, and strong—ultrasound-guided puncture was performed in 100%, 91%, 89.7%, and 45.5% of cases, respectively. Access time was longer with ultrasound-guided puncture than with nonultrasound-guided puncture (40 s [30-70] vs 35 s [30-45]; P < .001). The success of DRA in relation to the use of ultrasound-guided technique among all strengths of arterial pulse is detailed in table 1 of the supplementary data.

Arterial patency after removal of the hemostatic device was assessed in 907 patients (90.7%), revealing RAO in only 1% (n = 10).

In the quartile analysis, a shift in the selection of DRA side was observed, with lDRA initially more commonly used, shifting to rDRA as the preferred access in later quartiles (figure 3A). DRA failure rates were low in all quartiles but decreased significantly from the third quartile onwards (figure 3B). Access time decreased significantly from the second quartile onwards and remained stable thereafter (figure 3C). However, no significant differences were found in total procedure duration between quartiles (figure 3D).

Figure 3. Stratified analysis by quartiles of patients over the study period. A: use of left vs right distal radial access (DRA). B: DRA access failure rate by quartile. C: DRA access time in seconds. D: total procedural time in minutes.

DISCUSSION

Using data from a large prospective registry of patients who underwent DRA for coronary procedures, with high use of ultrasound-guided techniques, our study showed that DRA achieves high rates of access and procedural success, coupled with a low incidence of access-related complications in an all-comer population.

The usefulness of ultrasound in the distal radial access technique

Understanding the anatomy of the anatomical snuffbox is crucial for successful DRA, and ultrasound serves as a valuable tool in achieving this, offering demonstrated advantages.5,16,17,22 In our study, preprocedure ultrasound evaluation and ultrasound-guided DRA techniques were used in most patients. In addition to assessing arterial diameters and evaluating calcification and tortuosity, ultrasound enabled us to exclude patients with unsuitable distal radial arteries. Overall, we found no significant differences between ultrasound-guided and nonultrasound-guided DRA, although the former was associated with longer access times. However, the role of ultrasound is particularly noteworthy in cases of weak or absent arterial pulses, which are often underrepresented in prior studies. The presence of a suboptimal arterial pulse can stem from various factors, including small DRart, hypotension, collateral blood supply, or depth of DRart.11 In our study, most patients with weak pulses underwent ultrasound-guided puncture, with a favorable trend toward successful access in those who did. However, in patients with normal to strong pulses, no differences in DRA success were found, and even prolongation of access time was observed with its use. Therefore, in this type of pulse, an ultrasound-guided puncture is probably not necessary.

Feasibility, safety, and technical issues in distal radial access

This study corroborates the previously reported advantages of DRA,3,9,10,12,13,18 such as a low rate of RAO, acceptable access time, short hemostasis time, and adequate patient comfort.

Furthermore, the absence of an increased risk of hand dysfunction after DRA has been demonstrated,23 even compared with TRA at 12 months of follow-up, documented by Al-Azizi et al.24 Here, we focus on controversial issues that may have hampered wider adoption of this technique, and our results may provide additional support for DRA.

High success rates of DRA in coronary procedures have been reported in numerous studies.2-4,17,18,25 In addition, recent clinical trials and meta-analyzes describe a higher crossover rate compared with TRA.9-13

In contrast to our results, trials comparing DRA with TRA have reported lower access success and longer puncture times.9-11 Conversely, our study demonstrates remarkably high success rates for DRA and coronary procedures, as well as shorter access time, consistent with registries in which DRA is the default approach among experienced operators, as shown by the largest registries published to date, the DISTRACTION and KODRA studies.2-4,18,21

The KODRA trial included 4977 DRA procedures from a Korean registry.21 The authors reported a DRA success rate of 94.4%, with a crossover rate of 6.7%. In contrast to our work, the use of ultrasound-guided puncture in KODRA was low (6.4%). Additionally, the authors found predictors of DRA failure, such as the presence of a weak pulse and limited operator experience (less than 100 cases).

The equivalence of rDRA and lDRA has previously been demonstrated, and contemporary studies use mainly rDRA.9-11,17 As in the first registries, which suggested a potential advantage of lDRA, we started our experience with lDRA but, based on operator comfort and preference, the use of the rDRA increased over time.

Although the feasibility and benefits of DRA over TRA in STEMI have been observed, the literature on the topic remains scarce.2,9-11 In our registry, all attempted DRA procedures in patients with STEMI were successful. However, the first DRA in STEMI was performed after the operators had surpassed the learning curve for the technique (up to case 320). Similarly, the use of DRA for complex PCI has been previously described.22,26,27 In our cohort, all complex PCI procedures were performed without crossover.

The puncture site in DRA, situated 5 cm distal to TRA, may lead to an inadequate catheter length in specific contexts (such as tall patients, dilated aorta, subclavian artery tortuosity, and the need for retrograde access to PCI for chronic total occlusions).28 We found a low incidence of short catheter length during DRA procedures, with only 1 crossover due to severe tortuosity of the subclavian artery.

DRA-related complications have been consistently reported to be low.2,9-11,18 Similarly, we found a very low rate of complications, the most common being type I-a hematoma. In our study, the incidence of in-hospital RAO was 1%.

The number of DRA procedures to overcome the learning curve and maintain a success rate above 94% is around 150 to 200.2,8 However, in our early experience, we achieved this percentage after the first 20 cases per operator.17 In this study, operators navigated the learning curve in the first quartile; however, success significantly improved to more than 99% in the last 2 quartiles, probably because DRA became the default access for coronary procedures among operators.

Limitations

First, this study was an interim analysis of the leading participating site and coordinator of the DISTAL registry (NTC06165406), conducted because substantial enrollment from other sites was lacking. Although the data cannot be fully extrapolated to other centers, recalculation of the sample size was considered sufficient to evaluate the results.

Second, patient enrollment was not consecutive because the decision to use DRA was at the operators’ discretion. Only one-third of coronary procedures during the study period used this approach. However, we included all patients in whom operators intended to use DRA in any clinical setting were included, with only 21 patients excluded due to DRart ≤1.8mm. Third, this was a descriptive cohort of DRA, without a comparison control group. Fourth, the scale used to assess the arterial pulse is subjective. However, this scale is widely used in routine clinical practice and has been used in multiple DRA studies. Finally, radial artery patency was not evaluated in 9.7% of the patients before discharge, and no evaluation was conducted at 1 month; therefore, the in-hospital rate of radial artery occlusion may be underestimated and no mid-term data are available on the patency of the DRart.

CONCLUSIONS

This study shows the safety and feasibility of DRA primarily guided by ultrasound for coronary procedures in an all-comer population, with high rates of both access and procedural success, in addition to a very low rate of access-related complications.

FUNDING

None declared.

ETHICAL CONSIDERATIONS

This study was approved by the Ethics Committee of our institution (CEIC-2804) and was conducted following the principles of the Declaration of Helsinki. All patients gave their informed written consent before the procedure.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

Not used.

AUTHORS’ CONTRIBUTIONS

K. Rivera and D. Fernández-Rodríguez conceived and designed the study. K. Rivera, D. Fernández-Rodríguez, M. García-Guimarães, J. Casanova-Sandoval, and J. L. Ferreiro analyzed data, and drafted the manuscript. All authors contributed to the treatment of patients, data acquisition and mining, and review and approval of the final version of the manuscript.

CONFLICTS OF INTEREST

J. L. Ferreiro reports a) honoraria for lectures from Eli Lilly Co, Daiichi Sankyio, Inc, AstraZeneca, Pfizer, Abbott, Boehringer Ingelheim, Bistol-Myers Squibb, Rovi, Terumo and Ferrer; b) consulting fees from AstraZeneca, Eli Lilly Co, Ferrer, Boston Scientific, Pfizer, Boehringer Ingelheim, Daiichi Sankyo, Inc, Bristol-Myers Squibb and Biotronik; c) research grants from AstraZeneca. The remaining authors have no conflicts of interest to declare.

REFERENCES

INTRODUCTION

Patients with coronary in-stent restenosis (ISR) represent a clinical challenge.1 Evidence indicates that these patients are at increased risk of recurrent symptoms, myocardial infarction, and repeated coronary revascularizations.2 The use of drug-eluting balloons (DEB) is a novel alternative therapeutic strategy in patients with ISR.1,3,4 The effect of DEBs in coronary angioplasty is based on the rapid and uniform transfer of antiproliferative drugs into the vessel wall using a single balloon through a lipophilic matrix without the need for permanent implants.5

Over time, new DEB technologies are developed and launched onto the market. The Essential Pro (iVascular, Spain) is a paclitaxel-eluting balloon catheter with advancements to enhance catheter pushability and drug delivery. We believe it is essential to report outcomes from real-world settings. In this study, we report our findings on the safety and efficacy of this new DEB in patients with ISR.

METHODS

Design and population

This prospective, single-center study included a cohort of consecutive patients undergoing DEB angioplasty with the Essential Pro. The center treating these patients performs more than 1500 percutaneous coronary interventions per year. The 2 inclusion criteria for this analysis were: a) use of an Essential Pro DEB and b) its application for ISR treatment. ISR was defined as stenosis more than 50% within the stented segment, and treatment was indicated according to the treating physician’s judgment.6 The use of the Essential Pro DEB was prioritized during the study period to treat all eligible patients for DEB angioplasty, while other DEB devices were rarely used due to inventory constraints. There were no exclusion criteria. Patients may have undergone stent coronary angioplasty of other lesions in the same or a different setting.

Drug-eluting balloon characteristics

The Essential Pro is a paclitaxel-eluting balloon with a uniform 3 μg/mm2 eluting formulation, consisting of paclitaxel (80%) and a biocompatible amphiphilic excipient (20%).7 The balloon incorporates the proprietary TransferTech technology (iVascular, Spain), which is based on the ultrasonic deposition of nanodrops, followed by a dry-off process, resulting in a homogeneous microcrystalline drug coating. This allows more uniform and complete treatment of the vessel with the antiproliferative drug. The microcrystalline structure, coupled with the lipophilic nature of both paclitaxel and the excipient, facilitates drug transfer within 45 to 60 seconds. The Essential Pro balloon has been designed with a smooth transition and a very low tip profile of 0.016 inches, enhancing flexibility, trackability, and device crossability. The balloon is compatible with 5-Fr sheaths in all available diameters.

Procedures

All procedures and decisions in this study reflect real-world clinical practice. Therefore, clinical indications, the use and selection of DEBs, procedural steps, and medical treatments were decided by treating physicians without following any specific guidelines. All coronary angiograms performed during follow-up were part of routine clinical practice and were assessed by our research team when available. Baseline and follow-up data were collected in a single anonymized dedicated database. Procedural aspects, as well as both baseline and follow-up angiograms, were independently evaluated by 3 different interventional cardiologists. Physicians were trained to consult senior staff if they had doubts when assessing angiograms or clinical records. Follow-up was conducted using clinical records, and patients with no on-site clinical visits during follow-up were contacted by telephone following standard clinical practice in our institution. This study was approved by our local institutional review board and patients provided consent for the use of their anonymized information for research purposes before inclusion. This was an investigator-initiated study with no sponsoring or funding.

Outcome definitions

Device delivery was defined as successful DEB insufflation in the affected coronary segment. Procedural, angiographic, and other standard outcomes were defined according to the Second Academic Research Consortium criteria.8 Cardiovascular mortality was defined as any death without a clear noncardiovascular cause. Acute myocardial infarction was defined as any myocardial infarction meeting the fourth version of the Universal Myocardial Infarction Criteria.9 Target lesion revascularization (TLR) was defined as any revascularization within or 5 mm beyond the treated segment.8 Target vessel revascularization (TVR) was defined as revascularization of the index treated vessel.8 Coronary-related hospitalization was defined as a new hospitalization in which a coronary origin was suspected as the main reason for admission. The 3 main efficacy outcomes were myocardial infarction, TLR, and TVR.

Statistical analysis

Categorical variables are presented as percentages, and continuous variables as mean standard deviation (SD) when appropriate. Since the same patient may receive more than 1 DEB (for the same or different territory), the denominator for balloon-specific variables was based on the total DEBs used (such as treated vessel, vessel diameter, DEB diameter, and length), while the denominator of patient-level variables (such as age, sex, or clinical outcomes) was each single individual. Clinical outcomes during follow-up are presented at 30 days, 1 year, and total follow-up. The Kaplan-Meier method was used for estimating both the total follow-up risk and generating survival curves. Data were analyzed using IBM SPSS Statistics 25.

RESULTS

From December 2020 to June 2023, 290 patients with 352 coronary lesions were treated with DEB. Among them, 160 patients (206 lesions) underwent DEB angioplasty due to ISR. Out of the 160 patients receiving DEB for ISR, 46 patients (29%) received more than 1 DEB angioplasty for ISR, either during the same procedure or staged to a different lesion.

The patients’ baseline characteristics are summarized in table 1. The mean age was 71.4 ± 14.9 years, 15.5% were women, and 35.5% had diabetes. Clinical presentation was stable angina in 29.7%, unstable angina in 30.5%, non–ST-segment elevation myocardial infarction in 9.9%, ST-segment elevation myocardial infarction in 12.9%, and 16.7% were asymptomatic.

 

Table 1. Baseline characteristics

Patient characteristics
Age, y	71.4 (14.9)
Sex women	20 (15.5)
BMI, kg/m2	29.2 (10.5)
Hypertension	115 (87.7)
Active smoking	8 (6.1)
Diabetes mellitus	46 (35.3)
Previous MI	67 (51.5)
Previous CABG	26 (20)
Reduced LVEF (< 30%)	10 (7.6)
Laboratory parameters
Hemoglobin, g/dL	13.9 (1.5)
GFR, mL/min/1.73 m2	82.9 (25.4)
Active medication
Aspirin	110 (84.6)
Clopidogrel	75 (57.6)
Ticagrelor	3 (2.3)
Prasugrel	2 (1.5)
Anticoagulation	20 (15.2)
Clinical presentation
Silent ischemia	22 (16.7)
Stable angina	39 (29.7)
Unstable angina	40 (30.5)
NSTEMI	13 (9.9)
STEMI	17 (12.9)
BMI, body mass index; CABG, coronary artery bypass grafting; GFR, glomerular filtration rate; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NSTEMI, non–ST-segment elevation myocardial infarction; STEMI, ST-segment elevation myocardial infarction. Data are expressed as No. (%).

 

Procedural characteristics are detailed in table 2. The most commonly treated vessel was the left anterior descending artery (48.7%), followed by the left circumflex (30.7%), and the right coronary artery (17%). Bifurcation was present in 10.7%. Lesion preparation was performed in 98.2% of cases (80% with a noncompliant balloon). Intracoronary imaging was used in 24% of patients. None of the patients underwent rotational atherectomy, and 2.4% underwent balloon lithotripsy before DEB delivery. The mean vessel diameter was 3.1 ± 0.65 mm. The mean DEB diameter was 3.1 ± 0.6 mm, and the mean length was 23.1 ± 6.8 mm. Device delivery was successful in 100% of cases (figure 1). The final angiographic assessment revealed a final dissection in 1.4%, Thrombolysis in Myocardial Infarction flow less than 3 in 1.5%, and residual stenosis more than 30% in 3.4%. Bail-out stenting was needed in 4.8%.

 

Table 2. Characteristics of the treated lesion

Treated vessel
LAD	100 (48.7)
LCx	63 (30.7)
Right coronary artery	35 (17)
Left main coronary artery	5 (2.4)
Graft	2 (0.9)
Anatomical characteristics
Bifurcation lesion	22 (10.7)
Vessel diameter, mm	3.1 (0.65)
Procedural characteristics
IVUS-guided PCI	51 (24)
Lesion predilatation	202 (98)
Predilatation with NC balloon	165 (80)
Intravascular lithotripsy	5 (2.4)
DEB diameter, mm	3.1 (0.6)
DEB length, mm	23.1 (6.8)
Result after DEB PCI
Vessel dissection	3 (1.4)
TIMI flow 3	203 (98.5)
Residual stenosis > 30%	194 (3.4)
Bail-out stenting	10 (4.8)
DEB, drug-eluting balloon; IVUS, intravascular ultrasound; LAD, left anterior descending artery; LCx, left circumflex artery; NC, noncompliant; PCI, percutaneous coronary intervention; RCA, right coronary artery; TIMI, Thrombolysis in Myocardial Infarction. Data are expressed as No. (%).

Figure 1. Central illustration. Main findings on the safety and efficacy of the Essential Pro drug-eluting balloon in patients with in-stent restenosis. Kaplan-Meier shows freedom from TLR. MI, myocardial infarction; TLR, target lesion revascularization; TVR, target vessel revascularization.

 

After discharge, 93.3% of the patients were successfully contacted. The median follow-up was 361 days, including censored patients, with a maximum of 768 days. At 30 days of follow-up, there were no deaths or TLR, there was 1 myocardial infarction (0.6%), TVR occurred in 0.6%, and 6 patients were readmitted to hospital due to a coronary syndrome (4.1%). At the 1-year follow-up, mortality was 0%, myocardial infarction occurred in 3.4%, TLR in 2.5%, TVR in 6.3%, and coronary-related rehospitalizations in 11.8%. At 18 months, the TLR rate was 4.3%. When all available follow-up was included (figure 2), mortality was 0%, myocardial infarction occurred in 5.4% (95% confidence interval [95%CI], 0.69-10.1), TLR in 8.4% (95%CI, 0-17.8), and TVR in 14.2% (95%CI, 3.61-24.78). During follow-up, none of the patients underwent surgical revascularization.

Figure 2. Survival curves of key clinical outcomes. Kaplan-Meier estimates for survival free from myocardial infarction (A), target lesion revascularization (B), and target vessel revascularization (C) in days. 95%CI, 95% confidence interval; TLR, target lesion revascularization; TVR, target vessel revascularization.

 

DISCUSSION

This is the first study to describe a real-world experience with the Essential Pro DEB for the treatment of ISR. In this cohort, all attempts at DEB delivery were successful, and less than 1 in 20 patients required bail-out stenting. The use of this new-generation DEB catheter was associated with high efficacy and a low incidence of adverse clinical outcomes during follow-up.

Patients with ISR are at higher risk of recurrent events than those undergoing non-ISR angioplasty.10 The annual rate of ISR requiring TLR is around 2%,3 representing up to 11% of all percutaneous coronary interventions performed in the United States.11,12 Notably, 52% of patients presenting with symptomatic ISR have unstable angina, and up to 27% have an acute myocardial infarction.12 Therefore, ISR poses a significant clinical challenge due to both its frequency and severity. The use of DEB in the ISR scenario avoids the addition of extra stent layers, which may have detrimental effects in the long term.

The use of DEB in ISR poses certain challenges. DEB platforms commonly have lower lesion crossability than regular coronary balloon catheters. DEBs also have larger profiles than conventional balloons making it difficult to cross the lesion and requiring aggressive maneuvers that could lead to a loss of coating drug during delivery.13 However, in our study, all attempted DEB deployments were successful. This high success rate may be due to improvements in second-generation DEBs, as well as better lesion evaluation and lesion preparation.

In the present study, TLR occurred in 2.5% of the patients and TVR in 6.3% at 1 year, while TLR occurred in 4.3% at 18 months. This event rate may seem low when compared with a prior systematic review of randomized and observational studies, which reported a TVR rate after DEB treatment of 11.3% with a calculated weighted mean follow-up of 18 months.14 In a recent investigational device exemption randomized trial for a paclitaxel-coated balloon in ISR, the rate of TLR at 1 year was 13%.15 However, prior evidence stems from diverse settings, designs, and populations, making it difficult to draw strong conclusions.

The rate of TLR with the previous generation of the Essential Pro DEB in a smaller cohort (n = 31) was 10% at 6 months.16 While this rate may seem higher than that reported in our study, the small number of events (n = 3) makes comparisons challenging.

Limitations

This study has some limitations. First, it was based on a real-world cohort involving different operators from the same center, which does not follow specific protocols. Only a quarter of the patients underwent angioplasty assessment guided by intracoronary imaging. The lack of sponsorship to cover intracoronary imaging costs and its limited use reflects the usual clinical practice of this center. During the performance of this study, few patients with ISR were treated with other DEB catheters due to the lack of specific DEB sizes in stock. Since this situation was rare and was unrelated to clinical or medical coverage characteristics, it is unlikely to introduce significant bias. Since this was a substudy of a larger DEB cohort, some variables specific to ISR, such as the time from prior stent implantation or the type of stent used, were not available.

Second, there were no dedicated follow-up visits for this study. Although most of these patients were followed up by local cardiologists who maintained regular medical records, some required telephone contact for follow-up. Third, angiographic assessment was not duplicated, and no core lab was available. Finally, the number of events was low despite consecutive enrollment from late 2020, impacting the precision of Kaplan-Meier estimates for key clinical outcomes. Some limitations are related to real-world practice settings, which, on the other hand, enhance external validity with less selection bias compared with other more controlled designs.

CONCLUSIONS

Among patients with ISR, the Essential Pro DEB catheter had a high delivery rate and a low incidence of adverse clinical outcomes during follow-up. These results further underscore the safety and efficacy of this new-generation DEB for patients with ISR.

FUNDING

This work received no industry sponsoring or funding.

ETHICAL CONSIDERATIONS

This study was approved by our local institutional review board at the Instituto Cardiovascular de Buenos Aires, and patients provided written informed consent to use their anonymized information for research purposes before their inclusion. Possible sex/gender biases have been considered in the preparation of this paper.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

No artificial intelligence tool was used in the preparation of this study.

AUTHORS’ CONTRIBUTIONS

L. Padilla conceived and oversaw all the process. F. Liberman, J. Tello, P. Rosas, P. Spaletra, G. Pedernera, P. Mascolo, S. Ordoñez, P. Santilli, and A. Candiello collected data and analyzed coronary angiograms. F. Cura and J. Belardi provided senior advice. P. Lamelas performed the statistical analysis and generated the first draft of the manuscript.

CONFLICTS OF INTEREST

L. Padilla has received proctoring and consulting honoraria from Terumo and Boston Scientific. P. Spaletra has received honoraria from Boston Scientific. F. Cura has received honoraria from Medtronic, Boston Scientific, Terumo, and Meril. P. Lamelas has received proctoring and consulting honoraria from Medtronic, Boston Scientific, Meril, Microport. The remaining authors have no conflicts of interest to declare.

 

REFERENCES