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

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

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

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

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

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

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

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.

SUPPLEMENTARY DATA

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

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

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

INTRODUCTION

Fractional flow reserve (FFR) measurement is an invasive procedure performed during coronary angiography to determine the functional significance of coronary stenoses.

In recent years, the instantaneous wave-free ratio (iFR) resting index has been developed to assess the functional significance of coronary stenoses without the need for adenosine administration. The optimal iFR cutoff value—equivalent to 0.80 in FFR—was initially established at 0.89.1 In 2017, 2 clinical studies comparing FFR with iFR found no significant differences in clinical outcomes at follow-up.2-3 After the publication of these 2 studies, the European Society of Cardiology guidelines on myocardial revascularization4 assigned resting indices the same grade of recommendation as FFR for the functional assessment of coronary lesions.

Despite the validation of these 2 techniques in clinical trials and their inclusion in clinical practice guidelines, up to 20% discordance has been reported between iFR+/FFR− or iFR−/FFR+5 Several clinical factors, such as diabetes,6 and anatomical factors, such as lesion location in the left main or proximal left anterior descending coronary arteries, have been identified in association with this discordance.7

Previous studies comparing FFR with iFR using a piezoelectric pressure sensor wire (PPSW) calculated the mean distal-to-aortic pressure ratio beginning 25% into diastole and ending 5 ms before end diastole.1

Recently, a new resting index—the diastolic pressure ratio (dPR)—has been developed to calculate the mean distal-to-aortic pressure ratio over the entire diastolic phase (from the lowest point of the dicrotic notch up to 50 ms before the onset of the upstroke of the next beat)8 using a fiber-optic sensor wire (FOSW).

A study that compared the values of different resting indices (iFR, dPR, dPR25-75, dPRmid, iFRmatlab, iFR50ms, and iFR100ms) revealed that all were numerically identical,8 meaning that the results obtained with the iFR can be extrapolated to other resting indices.

To date, no study has compared the agreement between dPR and FFR measured using a FOSW. One advantage of the FOSW over the PPSW is the lower loss of mean pressure matching in the wire compared with the measurement obtained in the guide catheter (drift).9 Although various iFR studies state that drifts < ± 0.02 are considered acceptable, the drifts reported with the FOSW were even lower at < ± 0.01.10

The diagnostic reproducibility of PPSW decreases significantly when close to the threshold value of 0.80 and is approximately 80% when measurements are < 0.77 or > 0.83, and around 90% with values < 0.76 or > 0.84.11 Since the FOSW is less sensitive to changes in humidity and temperature, greater reproducibility of results can be expected when the measurement is repeated.

Considering that most discordant measurements have been associated with cutoff values, the better reproducibility of measurements and practically nonexistent drift of the FOSW can more accurately determine FFR and dPR measurements and reduce discrepancies.

METHODS

Study design

In this prospective, observational, and multicenter registry of consecutive coronary stenoses, we conducted a study with FOSW based on our routine clinical practice.

We included consecutive patients with clinical signs and coronary angiography findings suggesting the need for a functional study with a pressure wire. We excluded patients with cardiogenic shock, heart failure, severe anemia (hemoglobin < 10 mg/dL), heart rate < 50 or > 100 bpm, baseline systolic blood pressure < 90 mmHg or > 160 mmHg, severe coronary artery lesions in distal segments, and contraindications for the administration of adenosine.

Objective

The aim of this study was to evaluate the incidence and factors related to diagnostic discrepancies between these indices using the FOSW. Secondary aims consisted of assessing the diagnostic reproducibility of FOSW in 2 consecutive measurements of FFR and dPR and evaluating the drift rate.

Procedure

The study was approved by the Drugs Research Ethics Committee of the Basque Country (internal code PS 2019039). All patients received information on the study and were asked to sign a written informed consent form prior to their participation in the study.

We performed coronary angiography using standard methods, with visual estimation of severity after intracoronary nitroglycerin administration. We included lesions with up to 50% to 75% percent diameter stenosis and collected data on the reference luminal diameter, minimum luminal diameter, lesion length, calcification, and vessel tortuosity for each studied lesion.

We performed 2 consecutive measurements of dPR (threshold, 0.89) and FFR (threshold, 0.80) for each studied lesion and analyzed the clinical and angiographic factors to determine their correlation with discordance (FFR−/dPR+ and FFR+/dPR−). We took dPR1 and FFR1 as reference values for discrepancy analysis.

We conducted the FOSW functional study with 5-, 6-, or 7-Fr guide catheters without side holes, using an OptoWire (Opsens Medical, Canada). After advancing the wire toward the tip of the guide catheter, we removed the introducer sheath and flushed the system with saline solution to prevent damping of the pressure wire resulting in equal pressure of the wire and the guide catheter at the tip of the catheter. After advancing the pressure wire distally, we administered 200 μg of intracoronary nitroglycerin before taking any measurements. We took the 2 dPR measurements after waiting the necessary time to obtain confirmation of a stable baseline distal-to-aortic coronary pressure ratio (Pd/Pa).

Subsequently, we took 2 different FFR measurements. Hyperemia was induced according to standard practice in each center (through intracoronary or IV adenosine infusion). If intracoronary adenosine was infused, for the second measurement, we waited until the baseline heart rate, blood pressure, and Pd/Pa were regained and then infused the same dose of adenosine. If IV adenosine was infused, the infusion was stopped until baseline heart rate, blood pressure, and Pd/Pa were regained, and then we infused adenosine at the same rate.

We evaluated the presence of drift upon removal of the pressure wire from the guide catheter. Drift was defined as a difference in Pd/Pa of at least ± 0.02 upon removal of the pressure wire from the guide catheter. In the presence of significant drift, measurements were repeated.

Cutoff values

The cutoff value was ≤ 0.80 for FFR and ≤ 0.89 for dPR.10 We categorized all studied vessels based on dPR and FFR values into 4 groups: concordant positive group (FFR ≤ 0.80 and dPR ≤ 0.89), concordant negative group (FFR > 0.80 and dPR > 0.89), discordant FFR+/dPR− group (FFR ≤ 0.80 and dPR > 0.89), and discordant FFR−/dPR+ group (FFR > 0.80 and dPR ≤ 0.89).

Statistical analysis

Continuous variables are expressed as mean and standard deviation, while categorical variables are expressed as percentages. We measured the association between continuous variables using Pearson’s correlation coefficient. To determine differences in variables in the FFR/dPR concordance groups we used ANOVA (for continuous variables) and the chi-square test (for categorical variables). We used the chi-square test to assess how each variable impacted FFR−/dPR+ and FFR+/dPR− discrepancies, and a multiple logistic regression model with backward elimination to determine the factors impacting FFR−/dPR+ and FFR+/dPR− discrepancies. On univariate analysis, we included variables with P < .1 in the logistic regression analysis and excluded those with a total n < 10. The analysis was conducted using SPSS software (version 20.1) and R (version 4.0.4).

RESULTS

We included a total of 428 stenoses in 361 patients. Table 1 and table 2 show the patients’ baseline characteristics, clinical presentation, and procedural characteristics.

Table 1. Patients’ baseline characteristics

Table 2. Clinical presentation and procedural characteristics

Sixty-seven percent of the patients received intracoronary adenosine; the mean doses of intracoronary adenosine administered were 324 μg (standard deviation [SD] ± 152) via the right coronary artery and 442 μg (SD ± 234) via the left coronary artery.

The medians of dPR measurements were 0.90 and 0.90 (SD ± 0.08) for the first and second measurements, with positivity rates of 27.4% and 27.9%, respectively. For FFR, the medians were 0.83 and 0.83 (SD ± 0.08) for the first and second measurements, with positivity rates of 28.1% and 30%, respectively.

The most widely studied vessel was the left anterior descending coronary artery (63%), followed by the left circumflex (20%) and right coronary arteries (16%).

The left anterior descending coronary artery showed a higher positivity rate (dPR+, 35.3%; FFR, 34%) than the left circumflex (dPR, 11.9%; FFR, 20.5%) and right coronary arteries (dPR, 15.9%; FFR, 17.4%).

Diagnostic reproducibility was 95.8% for dPR, with a correlation coefficient between the 2 measurements (dPR1 and dPR2) of 0.974 (P < .0001) and a mean difference of 0.019 (max, 0.12; min, −0.17). For dPR values < 0.86 or > 0.92, diagnostic reproducibility was 99.6%, decreasing to 90.7% when values were ≥ 0.86 or ≤ 0.92. For FFR, diagnostic reproducibility was 94.9%, with a correlation coefficient (FFR1 and FFR2) of 0.942 (P < .0001) and a mean difference of 0.029 (max, 0.14; min, −0.18) (figure 1). Values < 0.77 or > 0.83 showed a diagnostic reproducibility of 98.6%, decreasing to 86.4% when these values were ≥ 0.77 or ≤ 0.83.

Figure 1. Correlation coefficient and histogram of the differences between the 2 dPR and FFR measurements. dPR, diastolic pressure ratio; FFR, fractional flow reserve; SD, standard deviation.

The diagnostic concordance (figure 2) between FFR and dPR was 82%, with a correlation coefficient of 0.721 (P < .0001), while diagnostic discordance was 18.2% (FFR+/dPR–, 8.2% and FFR–/dPR+, 10.0%). In the FFR+/dPR– discordant group, FFR was 0.76 ± 0.04 and dPR, 0.93 ± 0.03. In the FFR–/dPR+ discordant group, FFR was 0.84 ± 0.03 and dPR, 0.86 ± 0.03.

Figure 2. Distribution of lesions according to FFR and dPR, with the rate of concordant and discordant measurements. dPR, diastolic pressure ratio; FFR, fractional flow reserve.

Out of the 75 discordant results reported, the measurements at the cutoff value (7 stenoses with FFR 0.80 and 18 stenoses with dPR 0.89) showed a discordance rate of 72%, which decreased as it moved away from the cutoff value (figure 3).

Figure 3. Probability of diagnostic discordance between FFR and dPR. The probability of discordance is close to 50% around the FFR cutoff point of 0.80 and decreases as it moves away from this point. Empirical model (bar chart) and model proposed by Petraco et al.11 (in grey). dPR, diastolic pressure ratio; FFR, fractional flow reserve.

Table 1 of the supplementary data illustrates the association between clinical and anatomical characteristics and the extent of agreement between FFR and dPR.

Out of all the variables analyzed in the multivariate analysis, hypertension (odds ratio [OR], 3.48, 95% confidence interval [95%CI], 1.01-11.98; P = .043) and intracoronary adenosine (OR, 7.04; 95%CI, 1.63-30.3; P = .001) were significantly associated with FFR–/dPR+ discordance. Age younger than 75 years (OR, 4.52; 95%CI, 1.03-20; P = .016) and percent diameter stenosis > 60% (OR, 6.69; 95%CI, 2.79-16; P < .001) were significantly associated with FFR+/dPR– discordance (table 3).

Table 3. Univariate analysis and multivariate logistic regression of variables associated with discordance

The drift rate was 5.7%.

DISCUSSION

We present the results of the first study conducted with a FOSW capable of measuring the diagnostic variability of 2 consecutive determinations of nonhyperemic and hyperemic indices, as well as the diagnostic discordance between the 2 techniques.

Previous discordance studies between the 2 indices with PPSW revealed discordance rates ranging from 12% to 22%,12,13 largely depending on the proximity of the values to the cutoff point. In a study by Lee et al.,12 the mean iFR and FFR values were 0.95 ± 0.10 and 0.87 ± 0.11, respectively, with a discordance rate of 12%, while in a study by Warisawa et al.,13 the mean iFR and FFR values were 0.89 ± 0.05 and 0.80 ± 0.03, respectively, with a discordance rate of 22%. In our study, the discordance rate was 18.2%, with a mean dPR of 0.90 (SD ± 0.08) and a mean FFR of 0.83 (SD ± 0.08), which is a slightly lower discordance rate than that reported by previous studies on PPSW and mean iFR and FFR values close to the cutoff point, which may be indicative of the accuracy of measurements obtained with FOSW.

The main findings of this study were the excellent diagnostic reproducibility of the FOSW, the clinical and anatomical variables related to FFR/dPR discordance, and the low drift rate reported in the measurements.

Diagnostic reproducibility with the fiber-optic sensor wire

Diagnostic reproducibility with the FOSW was excellent, with a variation between 2 consecutive measurements < 0.02 for dPR and < 0.03 for FFR. This accuracy in measurement confers excellent diagnostic reproducibility. These data are better than those previously reported with PPSW.11

Clinical and anatomical variables associated with FFR/dPR discordance

For FFR+/dPR− discordance, in the multivariate analysis, only age younger than 75 years and percent diameter stenosis > 60% were significantly associated with FFR+/dPR− discordance. This discordance in participants younger than 75 years could be explained by a slower baseline flow and a greater coronary flow reserve in younger patients with preserved microvascular function.14,15 Although discordance due to a higher percent diameter stenosis has already been described in previous studies,15,16 such discordance requires a preserved coronary flow reserve.6 When arterial flow velocity significantly increases during hyperemia, the pressure gradient does so too, decreasing distal coronary pressure during hyperemia substantially compared with baseline values, resulting in a low FFR value.

For FFR−/dPR+ discordance, in the multivariate analysis, the associated variables were hypertension and the administration of intracoronary adenosine. Although hypertension has not been associated with FFR−/dPR+ discordance in previous studies, it is known that patients with hypertension and left ventricular hypertrophy have a reduced coronary flow reserve17 and a possible lack of vasodilatory response to adenosine due to an increased left ventricular end-diastolic pressure. These 2 factors could play a key role in the association between hypertension and FFR−/dPR+ discordance.

Although IV adenosine is the most widely studied route of administration to achieve maximum hyperemia, intracoronary adenosine at doses > 300 μg may be equally or more effective in achieving maximum hyperemia18 and with fewer adverse events.19 In our study, the FFR−/dPR+ discordance reported when intracoronary adenosine was used could be a result of a failure to achieve adequate hyperemia.

These variables related to discordance demonstrate that dPR and FFR measure different aspects of coronary circulation, which may be affected differently in distinct patients or myocardial territories, leading to discordant FFR values and nonhyperemic indices.20

Drift in the fiber-optic pressure wire

The incidence of drift in clinical studies of pressure wires is not well known, and the drift considered acceptable has varied over the years. Previously, FFR measurement was repeated when drift was > 5 mmHg,21 while in more recent studies, drift > 3 mmHg has been considered significant. When FFR is between 0.77 and 0.82, drift ≤ 3 mmHg can reclassify 18.7% of stenoses,22 and this reclassification may be higher when a nonhyperemic diastolic or whole-cycle index is used.23 In the CONTRAST trial analysis of the PPSW, the drift rate (Pd/Pa ± 0.03) was 17.5%,24 while a more recent study comparing drift between FOSW and PPSW revealed a significantly lower rate with the FOSW (4.8% vs 26.7%; P = .02).9 In our study, the drift rate was 5.7%, which is consistent with other studies on FOSW, and much lower than that reported with PPSW, facilitating the use of pressure wire in routine clinical practice.

Limitations

Our study has several limitations. Both the severity and length of coronary lesions were quantified by the operator’s visual estimation at the time of the procedure, and since this was a study without a core laboratory, we cannot rule out the possibility that some of the discrepancies found were due to technical problems in determining the indices. Since the study was based on our routine clinical practice, most patients received intracoronary adenosine, and the protocol did not specify the intracoronary infusion comprehensively, which may have resulted in the lower hyperemia reported in some patients.

Target lesion revascularization was based on dPR or FFR values according to the operators’ decision. Patient selection for pressure guidance evaluation was also left to the treating physician’s discretion, which may have resulted in biases. However, our intention was to study dPR and FFR indices under real-world conditions.

CONCLUSIONS

Although FFR and dPR measurements with FOSW have excellent reproducibility and a low incidence of drift, the discordance rate remains similar to that reported by previous studies with PPSW, and largely depends on the proximity of values to the cutoff point. Intracoronary adenosine and hypertension, which imply a lack of hyperemia or increased microvascular resistance, are associated with FFR−/dPR+ discordance. Age younger than 75 years and the severity of stenosis, which may be associated with a preserved coronary flow reserve, are related to FFR+/dPR− discordance.

FUNDING

This study received no funding.

ETHICAL CONSIDERATIONS

This study was approved by the Drugs Research Ethics Committee of the Basque Country (internal code PS 2019039) for its implementation. All patients received a patient information sheet about the study and signed an informed consent form before enrollment. The study took into consideration sex and gender variables before drafting this article.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

No artificial intelligence has been used.

AUTHORS’ CONTRIBUTIONS

M. Sádaba Sagredo drafted the protocol, included patients as the lead investigator of his center, and drafted the manuscript. A. Subinas Elorriaga and A. Quirós contributed to the statistical analysis and drafting of the manuscript. The remaining authors are lead investigators of the READI EPIC-14 trial in their respective centers and contributed to patient inclusion and article review.

CONFLICTS OF INTEREST

None declared.

SUPPLEMENTARY DATA

Supplementary data associated with this article can be found in the online version available at https://doi.org/10.24875/ RECIC.M24000448.

ACKNOWLEDGEMENTS

We wish to thank M.ª Ángeles Carmona for her support in data collection and patient inclusion.

REFERENCES