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

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

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

	N = 361
Age (years)	65.80 ± 10.5
Male sex	76.9
Hypertension	63.3
Diabetes mellitus	31
Hypercholesterolemia	60.4
Active/former smoker	19.7/40.5
Previous acute coronary syndrome	30.5
Atrial fibrillation	14.7
Heart failure/dysfunction	15.4
Peripheral artery disease	10
Valvular heart disease, previous bypass, stroke	< 6
Data are expressed as No. (%) mean ± standard deviation.

 

Table 2. Clinical presentation and procedural characteristics

	N = 361
Clinical presentation	N = 361
Chest pain	45.8
Acute coronary syndrome	23.1
Unstable angina	7.1
Left ventricular dysfunction	9.9
Others	14.2
Procedural characteristics
Baseline systolic blood pressure (mmHg)	132 ± 24
Systolic blood pressure during hyperemia (mmHg)	125 ± 25
Baseline heart rate (bpm)	70 ± 12
Heart rate during hyperemia (bpm)	69 ± 15
Reference luminal diameter (mm)	3.09 ± 0.53
Stenosis (%)	54 ± 8
Lesion length (mm)	17.9 ± 12.2
IV/intracoronary adenosine	33/67
Catheter size (5-Fr/6-Fr)	17.5/81
Drift ≥ ± 0.02	5.7
dPR	0.90 ± 0.08
FFR	0.83 ± 0.08
dPR, diastolic pressure ratio; FFR, fractional flow reserve. Data are expressed as No. (%) mean ± standard deviation.

 

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

Variables	FFR+/dPR−				FFR−/dPR+
	Univariate analysis		Multivariate logistic regression		Univariate analysis		Multivariate logistic regression
	OR (95%CI)	P	OR (95%CI)	P	OR (95%CI)	P	OR (95%CI)	P
Age < 75 years	9.5 vs 3.3	.039	4.52 (1.03-20)	.016	7.1 vs 8.9	.347
Female sex	5.7 vs 8.9	.231			11.4 vs 6.2	.079
Hypertension	7.2 vs 10.4	.178			10 vs 2.2	.002	3.48 (1.01-11.98)	.043
Diabetes mellitus	7.3 vs 8.6	.406			11.7 vs 5.3	.018	2.11 (0.95-4.69)	.064
Dyslipidemia	7.5 vs 9.5	.304			7.1 vs 6.7	.525
HF/LV dysfunction	4.4 vs 9.0	.154			11.8 vs 6.7	.118
Valvular heart disease	7.7 vs 8.3	.635			19.2 vs 6.8	.037
Coronary calcification	6.7 vs 8.6	.387			5.3 vs 8	.302
Moderate/severe tortuosity	7.8 vs 8.3	.516			10.6 vs 5.7	.054
Left main coronary artery	0 vs 7.9	.612			50 vs 6.9	.007
Left anterior descending coronary artery	7.9 vs 7.6	.531			9.4 vs 4.4	.041
Right coronary artery	10.8 vs 7.1	.176			2.4 vs 8.8	.029
Left circumflex artery	4.3 vs 8.5	.179			2.9 vs 8.4	.081
RLD > 3 mm	6.6 vs 13.3	.049			7.5 vs 8	.518
Length > 20 mm	12.5 vs 5.4	.010			7.8 vs 7.3	.492
Stenosis > 60%	16 vs 3	< .001	6.69 (2.79-16)	< .001	5.8 vs 8.3	.227
Heart rate > 80 bpm	8.4 vs 8	.527			10.8 vs 6.8	.155
Intracoronary adenosine	7.4 vs 8.5	.713			13 vs 3.8	.004	7.04 (1.63-30.3)	.001
95%CI, 95% confidence interval; dPR, diastolic pressure ratio; FFR, fractional flow reserve; HF, heart failure; LV, left ventricle; OR, odds ratio; RLD, reference luminal diameter. Data are expresed in %.

 

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

INTRODUCTION

Coronary artery disease is the leading single cause of mortality worldwide, accounting for more than 7 million deaths annually1 and its prevalence has been increasing in the last 20 years.2 Percutaneous coronary intervention (PCI) has been crucial in the treatment of coronary artery disease.3,4 The advent of drug-eluting stents (DES) has substantially reduced restenosis rates through the deposition of antiproliferative drugs in the vessel wall. DES have evolved over the years and have become the gold standard in PCI.5 Drug-coated balloons (DCB) represent an alternative in the setting of PCI. DCB consist of a balloon coated with antiproliferative agents encapsulated in a polymer matrix.6 Upon inflation, the balloon brings the antiproliferative drug into contact with the vessel wall. The main goal of DCB is to eliminate the risk of stent thrombosis and achieve lower restenosis rates by not leaving any type of metal structure in the treated segment.6

The safety and efficacy of DCB have been extensively studied in de novo coronary artery disease.6 In small vessel disease, DCB have demonstrated noninferiority to DES in several randomized clinical trials.7 A recent meta-analysis has shown that the use of DCB, compared with that of DES, is associated with a lower risk of vessel thrombosis and a trend toward a lower risk of acute myocardial infarction.8 In large vessel de novo lesions, current data do not support the widespread use of DCB over DES, although DCB appear to be safe and effective.9,10 Nevertheless, there is a need to elucidate the elution on the vessel wall, healing processes, plaque remodeling, plaque composition and the impact on the coronary microcirculation following PCI with DCB.

The present report describes the design and rationale for a study of plaque modification and impact on the microcirculation after PCI with DCB (the PLAMI study).

METHODS

The study will be an investigator-initiated, single-center, single-arm, open-label, pilot study in patients undergoing PCI with DCB for de novo lesions. The study has been approved by the hospital ethics committee on research involving medical products. The study has been registered in ClinicalTrials.gov (NCT06080919).

Procedure

Eligible patients will be informed about the study and will be required to provide signed informed consent prior to inclusion. Patients will undergo DCB-PCI under intravascular ultrasound (IVUS) guidance. Angiography-derived coronary physiology will be assessed after the procedure using Angio Plus software (Pulse Medical Imaging Technology, China). The angiography images will be used to obtain the angiography-derived index of microcirculatory resistance (IMRangio) values, before and after DCB-PCI. All procedures will be performed according to current European guidelines5: the target lesion will be predilated with semicompliant balloons or noncompliant balloons, with a diameter equal to the reference vessel diameter and with an appropriate length. Multiple predilations will be accepted. The DCB will be the paclitaxel-coated balloon Pantera Lux (BIOTRONIK AG, Switzerland).

The lesion will then be treated with a DCB with a reference vessel diameter/balloon diameter ratio of 1:1. DCB length will be equal to lesion length + 5 mm. DCB inflation time will be set at 45 to 60 seconds to guarantee correct and complete drug elution. The prespecified reasons for DES implantation after DCB-PCI will be residual stenosis > 30%, dissections > type B and TIMI flow < 3.6 Angiographic follow-up with IVUS and IMRangio evaluation will be performed 3 months after the index procedure. The study timeline is summarized in figure 1.

Figure 1. Timeline of the PLAMI study. DCB, drug-coated balloon; IMRangio, angiography-based index of microcirculatory resistance; IVUS, intravascular ultrasound; PCI, percutaneous coronary intervention.

 

IVUS images will be taken before the DCB-PCI, immediately after, and at 3 months of follow-up using the Opticross HD 60 MHz (Boston Scientific Corp, United States) system. All IVUS studies will be performed after intracoronary administration of 200 μg of nitroglycerin. The IVUS images will be acquired at 30 frames per second with an automatic transducer pull back (at 0.5 mm/second) to the proximal reference vessel lesion. As there will be no stents to take as a reference, the proximal and distal side branches adjacent to the treated lesion will serve as references, matching the coronary angiographic images (figure 2). All IVUS images will be analyzed by an independent core lab.

Figure 2. Schematic representation of IVUS acquisition. The IVUS images will be acquired before (A) and after (C) DCB-PCI (B) at 30 frames per second with an automatic transducer pull back (at 0.5 mm/second) to the proximal reference vessel lesion. The same anatomic slice will be analyzed before, after, and at 3 months of follow-up after the PCI by using reproducible landmarks (side branches). The first frame analyzed will be the distal point of the treated vessel before the exit of the DB (represented by the rightmost dotted line), and the last frame analyzed will be the proximal point of the vessel before the split of the proximal branch. DB, distal branch; DCB-PCI, drug-coated balloon percutaneous coronary intervention; IVUS, intravascular ultrasound; PB, proximal branch.

 

Angiography-derived assessment of coronary physiology will be performed with Angio Plus software (Pulse Medical Imaging Technology, China). For the evaluation of each lesion, at least 2 projections with a difference of > 25° will be selected. The operator will manually mark the points proximal and distal to the lesion, and the system automatically outlines the contours of the detected vessel. If the traced vessel trajectory deviates from the normal lumen, the necessary manual modifications will be performed. The artificial intelligence-assisted software combines the intravascular imaging information with the estimated vessel flow to obtain the IMRangio. All the angiography images will be analyzed by an independent core lab to obtain the IMRangio.

Study population and enrolment criteria

Patients will be screened to ensure they meet the inclusion criteria and none of the exclusion criteria prior to study enrolment. Inclusion criteria consist of an indication to undergo PCI for a de novo lesion according to current guidelines (with no restrictions regarding vessel size).5 Inclusion and exclusion criteria are summarized in table 1.

 

Table 1. Inclusion and exclusion criteria

Inclusion criteria	Exclusion criteria
Patient with CAD undergoing PCI with DCB with no limitation to vessel size	Age < 18 years
	Cardiogenic shock
	ST-segment elevation myocardial infarction
	Use of mechanical circulatory support
	Complex coronary lesions* including chronic total occlusions, bifurcation lesions, left main coronary artery disease, severe calcified lesions, graft interventions and in-stent restenosis
	Inability to provide informed consent
	Unable to understand and follow study-related instructions or unable to comply with study protocol
	Currently participating in another trial
	Pregnant women
CAD, coronary artery disease; DCB, drug-coated balloon; PCI, percutaneous coronary intervention. * Complex coronary lesions as defined in Lawton et al.11

 

Sample size

Because of the exploratory nature of this study, no formal sample size calculation is required. Based on previous pilot studies with similar designs,12 a sample of 30 lesions is planned to evaluate the impact of DCB on coronary healing and the microcirculatory territory.

Study endpoints

The primary endpoint is the change in percentage atheroma volume evaluated by IVUS from baseline to 3 months of follow-up. Secondary endpoints will include a) lumen change from baseline to 3 months of follow-up (minimum, maximum, average areas), b) the percentage of progressors and percentage of regressors, c) external elastic membrane (EEM) change from baseline to post DCB-PCI (average), d) EEM change post-DCB-PCI to the 3-month follow-up (average), e) the percentage of remodeling types (neutral, negative, and positive), f) IMRangio change from baseline to post- DCB-PCI, g) IMRangio change from post-DCB-PCI to the 3-month follow-up.

An independent clinical event committee, consisting of cardiologists not participating in the trial, will review and adjudicate all major adverse cardiac events according to the study protocol.

Considering the luminal area as the area delimited by the luminal border, the minimal luminal area is defined as the smallest lumen area within the length of the treated lesion.13,14 The atheroma or plaque burden is defined as the ratio of atheroma area to the vessel EEM and is calculated by dividing the sum of plaque and media cross-sectional area (CSA) by the EEM CSA.13,14 As the atheroma area can be calculated in each frame, the total atheroma volume is obtained by taking the sum of the differences between the EEM CSA area and the luminal CSA for all available images.15 The percent of the volume of the EEM occupied by atheroma is called the percentage atheroma volume.15,16

Serial arterial remodeling types will be classified as usual: neutral if there is no change in EEM, negative if there is a decrease in the EEM and positive if vice versa.

Statistical considerations

Continuous variables will be described as mean ± standard deviation or median [interquartile range]. Categorical variables will be described as percentages. The paired t-test will be used to compare continuous variables measured before and after treatment in the same patient, and differences in proportions will be tested with the chi-square or Fisher exact test. A P value less than .05 (typically ≤ .05) will be considered statistically significant. Statistical analyses will be performed using Stata software version 13.1 (StataCorp LP, United States).

DISCUSSION

Although the use of DES remains predominant in the performance of PCI, complications such as stent thrombosis and in-stent restenosis led to the development of DCB. DCB have the theoretical benefit of not leaving metallic material in the vascular lumen, thereby reducing the possibility of mechanical complications such as malapposition, stent fracture, and stent thrombosis. This could potentially reduce neointimal proliferation and shorten the duration of dual antiplatelet therapy.6 Current guidelines assign a level IA recommendation to the treatment of in-stent restenosis.5 While the use of DCB in de novo lesions seems promising, it is not yet widespread. In addition, PCI is not without risks, as it involves a certain degree of injury to the artery wall from balloon inflations and stent struts.17,19 The vascular response to endothelial cell and smooth muscle cell injury represents a complex network of biochemical responses that involve the immune system. All these factors regulate the processes of neointimal hyperplasia, vascular remodeling, and normal reendothelialization of the arterial wall.17

The pathophysiology of restenosis and lumen loss after angioplasty is a complex process involving various factors and is not limited to neointimal hyperplasia.19 Acutely, plain old balloon angioplasty (POBA) generates an increase in luminal area that is mainly due to an expansion of the EEM, mainly attributed to the elastic properties of the vessel rather than to plaque compression or removal.20 Subsequently, within the first few minutes after PCI, there is an “acute recoil” due to the elastic properties of the arterial wall. In the chronic phase, IVUS data indicate that luminal loss is mainly due to a progressive reduction in EEM rather than an increase in atherosclerotic plaque volume. Unlike the acute phase where loss of area is solely due to elastic properties, “chronic recoil” leading to the loss of area also involves a combination factors such as fibrosis, apoptosis, and changes in the extracellular matrix.19,21 Interestingly, not all patients show negative remodeling with a decrease in EEM; around 25% show a persistent increase in EEM, which is correlated with a reduced restenosis rate. Consequently, restenosis appears to be primarily due to the direction and magnitude of changes in arterial remodeling,19 although neointimal hyperplasia also plays a role .

Nevertheless, the existing evidence is based on analysis after the use of traditional balloons. With DCB-PCI, late lumen enlargement has been observed compared with POBA.20 Although this finding has been partly attributed to the inhibition of neointimal proliferation by antiproliferative drugs,22 the role of plaque modification or vessel healing phenomena in influencing this process cannot be excluded. A previous study showed that late lumen enlargement was higher in areas with the highest plaque burden; however, that study was a retrospective assessment and used a quantitative coronary angio­graphy protocol.23 It could be hypothesized that, by inducing controlled damage to the artery wall, together with the antiproliferative effect of DCB, positive vessel remodeling might be achieved, reducing restenosis rates without the need for DES. Therefore, with DCB-PCI, we are able to treat coronary stenosis not only from a mechanical point of view, but can also change the natural history of the disease and restenosis. In this regard, IVUS analysis will be essential to evaluate the reasons behind the gain or loss of luminal area. The dynamic changes produced after PCI are depicted in figure 3.

Figure 3. Central illustration. Schematic representation of timeline of DCB-PCI and lumen variation. A: pre-DCB-PCI de novo lesion. B: DCB-PCI (blue), generating injury to the vessel wall and an increase in lumen and EEM CSA. C: acute recoil. D, chronic recoil with decrease in EEM and neointimal hyperplasia. E. LLE due to maintenance of EEM area and no neointimal hyperplasia. The dotted lines represent the variations of the luminal area throughout the process. The image exemplifies how changes in luminal area, as well as plaque burden, are mainly due to variations in EEM rather than plaque compression. CSA, cross-sectional area; DCB-PCI, drug-coated balloon percutaneous coronary intervention; EEM, external elastic membrane; LLE, late lumen enlargement.

 

The DCB that will be used in our study, paclitaxel, has been extensively analyzed as a balloon-coating drug due to its lipophilic properties and its ability to elute into the vessel wall.24 Moreover, the available paclitaxel-DCB have shown good results in patients undergoing PCI for native vessel disease.25 In contrast, because of the hydrophobic characteristics of sirolimus, maintaining an adequate percentage in the wall over the mid-term poses technical challenges. However, advances in the formulation of the new generation of sirolimus DCB are anticipated to address this issue by facilitating adequate drug release into the vessel wall.24

As previously mentioned, the coronary microcirculation is closely related to proper coronary functioning and the pathophysiology of coronary artery disease. While it is believed that the performance of PCI, as well as the injury and healing of the coronary artery, may affect the coronary microcirculation, the evidence regarding DCB-PCI is scarce. Moreover, the plaque rupture, intimal dissections and thrombus formation that occur during balloon angioplasty are a potential source of embolism to the microvascular bed.

Since direct visualization of the microcirculation is not feasible in clinical practice,26 its assessment relies on parameters reflecting its functional status, usually coronary flow reserve and the IMR. Coronary flow reserve is defined as the ratio between hyperemic flow in response to nonendothelial vasodilation and resting blood flow. It is crucial to exclude epicardial stenosis before using coronary flow reserve, as it provides an integrated measurement of both epicardial and coronary microcirculation.26 IMR is calculated as the product of distal coronary pressure at maximal hyperemia multiplied by the hyperemic mean transit time.

In our study, we will perform a noninvasive, nonhyperemic assessment of the coronary microcirculation using IMRangio. This approach aims to characterize the baseline status of the microcirculation and assess the microvasculature changes induced by PCI and their variation over a 3-month period.

By monitoring IMRangio before and after treating the stenotic epicardial lesion, we will be able to assess the effects of acute fracture of the atherosclerotic plaque and injury to the arterial wall in the microvascular bed. We also aim to investigate whether these collateral harmful changes provoked during angioplasty remain consistent or vary significantly at 3 months of follow-up. In this same context, the analysis of IVUS during follow-up will allow us to correlate the changes in the arterial wall and atherosclerotic plaque after DCB-PCI with microcirculation physiology. To date, no insights into the anatomical and physiological process of healing of the injured arterial wall after DCB-PCI have been available in the published literature.

CONCLUSIONS

The PLAMI study is a first-in-man pilot study that aims to provide new information on the modification of atherosclerotic plaque assessed by intracoronary imaging in patients with de novo lesions undergoing PCI with DCB.

FUNDING

None reported.

ETHICAL CONSIDERATIONS

The study has been approved by the hospital ethics committee on research involving medical products. Eligible patients will be informed about the study and must provide written informed consent prior to inclusion in the study. Possible gender/sex biases have been considered.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

No artificial intelligence has been used in the preparation of this article.

AUTHORS’ CONTRIBUTIONS

J.A Sorolla Romero, A.Teira Calderón, J. Sanz Sánchez and H.M. Garcia-Garcia contributed to the conception, design, drafting and revision of the article. J.P. Vílchez Tschischke, P. Aguar Carrascosa, F.Ten Morro, L. Andrés Lalaguna, L. Martínez Dolz and J.L. Díez Gil contributed to the critical revision of the intellectual content.

CONFLICTS OF INTEREST

None declared.

REFERENCES