Percutaneous treatment of the left main coronary artery in older adults. Impact of frailty on mid-term results

INTRODUCTION

Currently, the number of percutaneous coronary interventions (PCI) involving moderate-to-severe calcified plaques is increasing due to a progressively aging population and extending procedural indications into more comorbid patients. The presence of such calcification is extremely relevant as it is strongly associated with worse outcomes, specially by means of stent underexpansion, a potent predictor of stent thrombosis or in-stent restenosis.1-3 Moreover, calcified plaques can make advancing the devices difficult and trigger stent deformation and entrapment, coronary artery dissection, or perforation.1,4-6. Currently, there is a growing interest in the assessment of plaque morphology and its modification prior to stent implantation, which has led to the development of multiple tools such as rotational atherectomy, lithotripsy, orbitational atherectomy, cutting balloons (CB) and scoring balloons (SB).7-11 The latter are easy to use and aim to create a controlled fracture of calcium deposits and plaque dilatation to facilitate stenting.12-14 However, despite their theoretical simplicity, these devices are bulky and stiff, making it difficult to cross the lesion at the first attempt, navigate the vessel, and recross the lesion once inflated. Therefore, there is a need for a more trackable and better-profiled SB to improve the uptake of these devices to treat calcified coronary artery disease.

The newly designed Naviscore SB (iVascular, Spain) seeks to address these drawbacks. Its structure is based on 125-µm thick nitinol laser cut filaments arranged in an axial pattern placed over a semi-compliant high-pressure balloon with a nominal pressure of 8 atm, a rated burst pressure of 20 atm, and a mean burst pressure of 26 atm (figure 1). A nylon compensation tube in the shaft helps to re-wrap during balloon deflation. The mechanical properties of nitinol tend to regain its original shape once the balloon has been deflated. The nylon compensation tube elongates once the balloon has been inflated and due to its elastic properties, it regains its original length when deflated (video 1 of the supplementary data). The 2 mechanisms produce a powerful re-wrapping of the entire system when the balloon has been deflated, regaining its original crossing profile, which allows for easy lesion recross and further dilatations as many times as required. Axial distribution of scoring elements provides a high push against calcified lesions. Nitinol elastic properties provide a better navigability through tortuous calcific vessels compared with rigid scoring elements, such as stainless steel. The durable hydrophilic coating of the Hydrax Plus catheter (iVascular, Spain) significantly reduces its coefficient of friction to 0.04 by increasing slip and navigability. Also, its axial design enables a far larger contact area with the vessel wall compared with other devices with spiral configuration of nitinol filaments such as the AngioSculpt catheter (Philips Healthcare, The Netherlands) (figure 2). In vitro testing (iVascular, Spain) was conducted to measure the crossing profile of different SBs using a non-contact laser meter where the profile is calculated through the shadow that has been created. This allows us to measure the profile without exerting any pressure on the device.15 The Naviscore crossing profile is 5% lower than Angiosculpt, and 31% lower than Wolverine (Boston Scientific, United States). This catheter is available in a wide range of measures from 1.5 mm up to 3.5 mm in diameter and from 6.0 mm up to 15 mm in length, all of them compatible with a 6-Fr guiding catheter.

Figure 1. Structure of the Naviscore SB. MBP, mean burst pressure; RBP, rated burst pressure.

Figure 2. In vitro model assessment of the AngioSculpt scoring surface (upper image) vs the Naviscore (lower image). The Naviscore scoring surface is 6 times larger than that of the AngioSculpt.

The present study aims to demonstrate the safety and efficacy profile associated with crossing and treating calcified coronary lesions with the Naviscore SB.

METHODS

The Naviscore first-in-man study is a multicentric and prospective registry that evaluated the device safety and efficacy profile in the treatment of calcified lesions in 85 patients from 10 centers (9 in Spain and 1 in Portugal), all from the Euro 4C Group, founded in 2018 and focused on the cardiac care of calcified and complex patients. All operators involved in this study were experts in the treatment of calcified coronary lesions and familiar with most tools designed to treat such lesions.

Inclusion criteria were the presence of de novo moderate-to-severe calcified lesions by angiographic criteria in the native coronary tree of patients with chronic coronary syndrome scheduled for a PCI due to symptom persistence despite optimal medical therapy and/or evidence of inducible ischemia. The only exclusion criterion was the presence of the patient’s hemodynamic compromise.

The study was designed to assess the safety and efficacy profile of Naviscore in terms of delivery success when used as the first device to dilate the lesion, plaque modification capabilities, and complications. Consequently, operators were asked to use the Naviscore in all cases as the first device to cross and dilate the lesion. However, in cases of failed lesion crossing, dilatation with a small balloon was recommended with subsequent re-use of the same Naviscore catheter.

Operators involved in the study had little prior experience with the Naviscore in, at least, 3 cases and were asked to include, at least, 5 patients in the study. The operators assessed the performance of the catheter in each procedure in terms of pushability, navigability, crossing, deflation time, re-wrap, recrossing capabilities and ease of retrieval, and made a subjective comparison with their routinely used SB or CB.

The baseline clinical characteristics were recorded prior to the procedure and angiographical and optical coherence tomography (OCT) images were analyzed separately by 2 different operators. Coronary angiography was performed using, at least, 2 orthogonal projections to show stenosis as it is commonly used in the routine clinical practice. The view with the most severe stenosis was selected for the quantitative analysis of the lesion before and after the PCI. Lesion calcification was angiographically categorized as none/mild, moderate (radiopacities were only noted during the cardiac cycle movement prior to contrast injection) or severe (radiopacities noted without cardiac movement prior to contrast injection involving both sides of the arterial lumen).16 Lesions were categorized as A, B1, B2 and C based on the modified ACC/AHA Task Force classification, which is in turn, based on the morphology and potential complexity of the PCI.17 Procedural success was defined as an angiographically residual percent diameter stenosis < 30% after stent implantation, absence of major complications and final Thrombolysis in Myocardial Infarction (TIMI) grade-3 flow.18 OCT analysis was performed as recommended in the routine clinical practice: lesion and proximal and distal references within 5 mm were used to estimate diameters and areas. Calcium cracks were defined as fissures involving a calcified region.19,20

Statistical analysis

Data are expressed as mean ± standard deviation for continuous variables with a normal distribution, median and interquartile range [IQR] for continuous variables with a non-Gaussian distribution, and counts and percentages for categorical data.

Statistical analyses were performed using the Stata software version 16.1 (College Station, TX, United States).

Ethical considerations

Informed consent was obtained from all the patients and the study was approved by the Research Ethics Committee. The authors declare that procedures were followed according to the regulations established by the Clinical Research and Ethics Committee and the Declaration of Helsinki of the World Medical Association.

RESULTS

From November 2021 through February 2022, a total of 85 patients—80% males—with a mean age of 71 ± 11 years were included in the present study. One center included a total of 21 patients and the remaining 9, between 5 and 10 patients each. Baseline patient and lesion characteristics are shown in table 1. Regarding comorbidities, the prevalence of diabetes mellitus, dyslipidemia, hypertension, and chronic kidney disease was 44%, 70%, 75%, and 18% respectively. Prior revascularization was present in 43% of the patients (PCI in 38% and coronary artery bypass graft in 16%). The left anterior descending coronary artery was the most common location of target lesions (41%), followed by the right coronary artery (28%), left circumflex artery (16%) and left main coronary artery (15%). Most lesions (87%) were categorized as type B2/C, 66% were severely calcified and 34% had moderate calcification by angiographic assessment. Chronic total occlusion was reported in 10% of treated lesions. Reference vessel diameter was 3.0 ± 0.5 mm; mean lesion length, 20.3 ± 9.4 mm; and diameter stenosis, 81.4 ± 12%.

Table 1. Baseline clinical and angiographic characteristics

The Naviscore catheter diameters used to dilate the lesions were 2.0 mm (21%), 2.5 mm (38%), 3.0 mm (31%), and 3.5 mm (10%). Mean number of device inflations was 2.7 ± 1.5 times.

The Naviscore crossing performance of is shown in figure 3. Despite the strong recommendation to use Naviscore as the first device, some operators decided to use Rotablator or small balloons first in 10 patients due to severely narrowed and/or calcified vessels. In all those cases, the Naviscore successfully crossed and dilated the lesion after the first attempt. In the 75 patients in whom the Naviscore was used as the first device, the lesions were crossed and treated successfully in 57 (76%) of them. In the remaining 18 (24%) patients, the Naviscore crossed the lesion after pre-dilatation with a small balloon in 16 (89%) patients. Only 2 patients had non-crossable lesions.

Figure 3. Crossing performance of the Naviscore.

PCI results and in-hospital outcomes are shown in table 2. Procedural success was achieved in 94% of cases. The mean lesion percent diameter stenosis decreased from 81.4 ± 12% at baseline to 33.3 ± 8.5% after Naviscore dilatation, with a residual percent diameter stenosis of 7.5 ± 2.6% after stent implantation. There were no in-hospital major adverse cardiovascular events or any cases of perioperative perforation or device entrapment. Coronary dissections occurred in 13% of the cases (all of them type A or B) and resolved after stent implantation.

Table 2. Angiographic and in-hospital results

Ten procedures were OCT-guided. Pre-dilatation analysis could only be performed in 5 lesions; the OCT catheter could not cross the remaining lesions. Four of those had Fujino’s scores8 of 4 and in 2 of them the nodules protruded into the lumen. After dilatation, all lesions exhibited dissections that covered the intima and the media. Fractures were seen in all calcified plaques, which were deeper and wider in non-nodular calcified regions. Enlargement of lumen area after treatment with the Naviscore and correct stent apposition and expansion was observed in all imaging-guided cases (figure 4).

Figure 4. Clinical examples of 2 different lesions treated with the Naviscore. Angiography and baseline OCT (A) after dilatation with the Naviscore catheter (B) and post-stent implantation (C). On the left side, panel A shows a severely stenotic fibrocalcific plaque on the left anterior descending coronary artery that Naviscore (B) modifies creating calcium fractures (*) and dissection (arrow) resulting in stent implantation with good apposition and expansion (C). The right side shows a severely calcified plaque on the right coronary artery (A) with an arc of calcium of 180º at its proximal edge (lateral OCT picture) and 360º at its distal edge (central OCT picture) that the Naviscore modifies (B) creating calcium fractures (*) and dissection (arrow) resulting in stent implantation with good apposition and expansion (C). OCT, optical coherence tomography.

Table 3 shows the subjective performance of the Naviscore as evaluated by the operators of the present study. The Naviscore performance including push, navigability, crossing, deflation time, re-wrap, recrossing capabilities and ease of retrieval was deemed superior to the Wolverine, NSE Alpha (Nipro Co. Ltd., Japan), AngioSculpt, and Scoreflex (OrbusNeich, China).

Table 3. Subjective performance of the Naviscore compared with traditional and scoring or cutting balloons of participant centers. Push, capacity to cross the lesion, deflation time, rewrap and recrossing capabilities were the most valued characteristics of the Naviscore

DISCUSSION

Findings of this first-in-man registry with the new SB Naviscore in moderately to severely calcified coronary lesions performed in CHIP (complex and high-risk intervention in indicated patients) by highly experienced operators on this field can be summarized as follows: a) the Naviscore was able to cross the lesions as the first device in 3 out of 4 patients in such difficult scenario; b) this device proved to be effective to treat complex coronary lesions, with procedural success rates of 94%; c) the Naviscore was safe as no major dissection, perforation, or device entrapment were observed and d) the performance of the Naviscore SB was better compared with other commercially available SB and CB as subjectively assessed by the experienced operators in this study.

Calcified coronary lesions account for up to 30% of lesions scheduled for PCI and are associated with worse clinical outcomes.1 Furthermore, these lesions are probably the most challenging ones for PCI operators. Thus, it is of paramount importance to develop specific devices for this scenario.21-23 Although several plaque-modification techniques have appeared in recent years, there are not very many head-to-head comparisons, thus complicating the choice between them. In contrast, several treatment combinations and algorithms have been published.24-27 Ablation techniques, such as rotational or orbital atherectomy, are especially indicated in uncrossable or undilatable lesions with balloon catheters. However, since there are more potential complications and a steeper learning curve associated with these therapies, developing new tools with a better crossing profile would be very positive in this scenario. The good crossability of the Naviscore SB showed in the present study is probably related to its unique nitinol structure in an axial configuration. CB such as the Wolverine or the NSE Alpha have a similar axial configuration of their cutting elements. However, the crossing profile of the Naviscore is 31% smaller than the CB. Although a comparative study on the crossing capabilities of those devices is not available, such a different profile favors the superior crossing capabilities of the Navis­core device. In fact, the operators of the present registry highlighted the ability to cross and recross lesions as one of the best features of the device compared with their usual CB or SB. Compared with the AngioSculpt—a SB that shares a nitinol structure with the Naviscore— the helical configuration of nitinol filaments in front of the axial alignment of the Naviscore nitinol filaments can make a difference. Axial alignment adds push to the device through the lesion, while the helical nitinol configuration can deform the structure under friction, thus reducing its navigability and, in some cases, cause device entrapment.28 Furthermore, as shown in figure 2, helical distribution of nitinol significantly reduces the nitinol scoring surface in front of an axial distribution.

The efficacy of the Naviscore balloon has proven to be good in the present study, with a procedural success rate of 94%. Furthermore, quantitative angiographic analysis showed a reduction of basal stenosis from 81% to 31% after Naviscore dilatation and to 7.5 ± 2.6% after stent implantation. Finally, the OCT evaluation confirmed the presence of extensive calcium fractures caused by the scoring filaments (figure 4). As the balloon gradually inflates, the radial forces concentrate along the surface of the nitinol scoring elements, resulting in a more controlled balloon expansion, increasing the force of the nitinol frame filaments to break down the calcified plaques.29 In vitro experiments comparing a simple SB (Scoreflex) with a conventional balloon catheter to dilate concentric tubes of calcium revealed that the inflation pressure required to break down the calcium tubes was consistently lower with SB. Finite element analysis revealed that the first main stress applied to the calcified plaque was, at least, 3-fold higher when inflating the balloon catheter with scoring elements.30 Naviscore has the largest scoring surface in the SB current market, being 6 times more extensive than the AngioSculpt (figure 2). Pressure concentration of the scoring elements is the mechanism of the increased ability of SB to dilate calcified lesions and facilitate stent expansion. Residual stenosis after stent placement was 7.5 ± 2.6% in our study.

Finally, the Naviscore proved to be safe in the present study, which could be justified by the mechanism of action of the device that uses nitinol filaments as the anchor to avoid balloon slippage, and allows balloon controlled expansion, minimizing the risk of barotrauma, coronary dissection, and perforation. Using OCT imaging, SB broke down the calcified lesion without the undesirable dissection of noncalcified segments, thus allowing successful stent implantation with adequate expansion.29,30

Limitations

One limitation of the study is its own design as a registry and therefore, the absence of a randomized comparator. Instead, expert operators in the treatment of calcified coronary lesions were asked to subjectively compare the device at test with their commonly used SB or CB in terms of push, cross/recross, rewrap, navigability and time of deflation. The subjective nature of this assessment, while providing valuable information, could be a limitation.

Another limitation is the sample size of the study, especially the size of the population involved in the OCT imaging analysis. Unfortunately, in our setting, the use of this technique to analyze calcified lesions, although on the rise, is still far from what would be recommended. However, and despite the limitations in terms of number, the cases analyzed with intracoronary imaging homogeneously show us the effect of the device under study—calcium fractures, dissection and increase in luminal area—as well as the optimal stent expansion.

The small sample of patients in this study does not allow for a disaggregated analysis by sex to draw any valid results.

CONCLUSIONS

The Naviscore SB is a step ahead in this field with an innovative design using a nitinol frame with axial distribution of filaments placed over a high-pressure balloon to improve current SB or CB designs. This provides a strong pushing capability and flexibility to cross the most difficult calcified lesions in 3 out of 4 patients and easily navigate through tortuous anatomy. Superior scoring surface provides strong plaque modification capabilities by facilitating calcium fractures and controlled dissections, and ultimately, optimal stent expansion. Uniform and controlled balloon expansion and the anchor effect provided by the nitinol frame minimizes the risk of uncontrolled dissections and distal embolization, thus providing an outstanding safety profile, confirmed in this study by the absence of major adverse cardiovascular events, device entrapment or flow- limiting dissections. Therefore, the Naviscore can be considered as the front-line SB, either alone or in combination with atheroablative techniques in the treatment of moderate-to-severe calcified lesions.

FUNDING

This study was partly funded by iVascular, Barcelona, Spain, who provided the devices to perform the study.

ETHICAL CONSIDERATIONS

Informed consent was obtained from all patients and the study was approved by the Research Ethics Committee. The authors declare that the procedures were followed in full compliance with the regulations set forth by the Clinical Research and Ethics Committee and Declaration of Helsinki of the World Medical Association. In accordance with the regulations of the SAGER guidelines, the small sample of patients in this study does not allow for a disaggregated analysis by sex to draw any valid results.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

No artificial intelligence has been used in the development of this paper.

AUTHORS’ CONTRIBUTIONS

A. Serra Peñaranda designed the protocol, database and study outline, participated in data collection, coordinated data analysis and interpretation, and drafted the article. E. Fernández Peregrina participated in data collection, data analysis and interpretation and drafted the article. M. Jiménez Kockar participated in data collection, data analysis and interpretation, and performed the statistical analysis. B. García del Blanco, S. Romani, J. Martín-Moreiras, E. Pinar Bermúdez, A. Rodrigues, S. Ojeda, N. Gonzalo López, A. Regueiro and A. Serrador Frutos participated in data collection and critically revised the manuscript. All authors gave their final approval to the last version for publication.

CONFLICTS OF INTEREST

S. Ojeda is an associate editor of REC: Interventional Cardiology. The journal’s editorial procedure to ensure impartial handling of the manuscript has been followed. A. Serra Peñaranda and Ander Regueiro received consulting fees from iVascular, Barcelona, Spain. The remaining authors declared no conflicts of interest whatsoever.

REFERENCES

INTRODUCTION

Percutaneous coronary intervention (PCI) has grown exponentially along with the technological evolution associated with this procedure. The continuous advancement of technology has enabled the development of stents with thinner struts, which offer a series of advantages over stents with thicker struts. One of the advantages of these new stents is the improved device profile—with increased flexibility—providing better navigability and greater lesion crossing capability. On the other hand, ultra-thin struts (UTS) cause fewer disturbances to normal laminar blood flow at target lesion level, due to the reduced protrusion of material into the vascular lumen. This seems to be associated with a lower degree of platelet activation and muscle cell proliferation,—the processes involved in stent failure—in terms of stent thrombosis (ST) and in-stent restenosis.1,2 In lesions located in small caliber vessels (≤ 2.5 mm), the use of UTS could provide additional advantages due to a higher ratio between the size of the struts and the lesion luminal area.3 Furthermore, UTS stents seem to be associated with less acute damage to the vascular endothelium during stent deployment. This reduced initial aggression could diminish the barotrauma-related inflammatory response and, therefore, prevent in-stent restenosis and promote faster device endothelialization.4,5 Studies have indicated that the use of UTS stents could be associated with lower rates of in-stent restenosis and a reduced need for new revascularizations.6,7

The Evermine 50 EES stent (Meril Life Sciences, India) is a UTS (50 μm) stent with CE marking consisting of a cobalt-chromium alloy platform with an everolimus-eluting biodegradable polymer. The aim of this study was to evaluate the 1-year safety and efficacy outcomes after UTS stent deployment in real-world patients with coronary artery disease.

METHODS

We conducted a prospective, non-randomized, multicenter study with patients who underwent UTS stent deployment at 4 different Spanish hospitals (data from the Everythin Registry). To be included in the study, patients had to be older than 18 years, with available coronary angiographies in the context of chronic or acute coronary syndrome, and have, at least, 1 target lesion with a 2 mm up to 4.5 mm reference vessel diameter on visual estimation. Overlapping stents was ill-advised and, if necessary, the overlap length should be ≤ 2 mm. PCI in multiple vessels and lesions during the same surgical act was allowed, and deferred procedures within the first 90 days since the initial procedure were also accepted. In these cases, any further procedures were not coded as an event—i.e. need for new revascularization—but as scheduled procedures. Only 1 case—1 target lesion treated with UTS stent deployment—was counted per patient. Deploying the study UTS stent was not mandatory in any of the other treated lesions, only in the target lesion/vessel.

The study followed the privacy policy of each research center, including regulations for the appropriate use of data from patient research. The study was approved by the Ethics Committee for Drug Research of the coordinating center. Moreover, the study was conducted in full compliance with the terms set forth in the Declaration of Helsinki. All patients signed specific informed consent forms prior to being included in the study.

Study device and procedure

The Evermine 50 EES (Meril Life Sciences, India) is a UTS (50 μm) stent with a cobalt-chromium platform coated with a biodegradable polymer composed of poly-L-lactic acid and poly(lactic-co-glycolic) acid. The Evermine stent—which has a hybrid design with an open cell in its central part and a closed cell at the edges—releases everolimus (1.25 μg/mm²) as the antiproliferative drug. The stent has received the corresponding CE marking and is available in several lengths from 8 mm up to 48 mm with diameters ranging from 2 mm up to 4.5 mm. The main features of the Evermine 50 EES device are illustrated in figure 1.

Figure 1. A: illustrative image of the Evermine 50 stent (Meril Life Sciences, India). B: description of the main characteristics of the stent. C: comparison of the study stent strut thickness vs major competing next-generation stents. PLGA, poly(lactic-co-glycolic acid); PLLA, poly-L-lactic acid (Images courtesy of Meril Life Sciences. Images reproduced with permission from Meril Life Sciences or its affiliates.)

PCI was performed following each center routine practice within the recommendations outlined in the clinical practice guidelines.8 The PSP algorithm (predilation, sizing [stent size selection], and postdilation) was recommended for optimal device implantation. The study protocol recommended postdilation, especially in cases where any degree of underexpansion was identified immediately after device implantation. Although the study protocol recommended the use of intravascular imaging modalities to guide the procedure, this was left to the operator’s discretion. All patients received a 300 mg loading dose of acetylsalicylic acid prior to the intervention followed by a loading dose of a second antiplatelet agent—clopidogrel, prasugrel, or ticagrelor—after the PCI, which was maintained for 3 up to 12 months and left to the discretion of the responsible investigator of the center.

Endpoints and definitions

The primary endpoint of the study was the occurrence of major adverse cardiovascular events (MACE) at 12 months. MACE were defined as the composite of cardiac death, non-fatal target vessel myocardial infarction (MI), or the need for target lesion revascularization. Secondary endpoints included each individual component of the composite endpoint, the overall mortality and ST (both definite and probable) according to the definitions of the Academic Research Consortium9 12 months after implantation. Additionally, the rates of device and procedural success were taken into consideration. Device success was defined as the deployment of the study stent in the target lesion with a final percent diameter residual stenosis < 30% by visual estimation. Procedural success was defined as the success of the device without any in-hospital complications, including death, MI, and target lesion revascularization.

Statistical analysis

Quantitative variables are expressed as mean and standard deviation or as median and interquartile range [IQR], depending on their distribution. Categorical variables are expressed as number and percentage. All analyses were performed using the statistical tool STATA 12 (StataCorp LLC, United States).

RESULTS

Demographic and baseline clinical characteristics

A total of 161 patients were included in the study from November 2020 through April 2022 whose demographic data and clinical characteristics are shown in table 1. The mean age was 64 ± 14 years, and 79% were male. A total of 66% of the patients were hypertensive; 53% had dyslipidemia; 34%, diabetes mellitus, and 59% a history of smoking. A total of 20% of the patients had experienced a prior MI, and 22% a previous PCI. The most common indication for the intervention was the diagnosis of non-ST-segment elevation acute myocardial infarction (42%), followed by ST-segment elevation myocardial infarction (STEMI) (22%) and chronic coronary syndrome (21%).

Table 1. Baseline characteristics of the study population

Angiographic and procedural characteristics

The lesion angiographic characteristics, and the results of the intervention are shown in table 2. Most patients had significant single-vessel disease (71%), being the presence of 2 or 3-vessel disease far less common (20% and 9%, respectively). The most widely treated vessel was the left anterior descending coronary artery (54%), followed by the right coronary artery (27%) and the left circumflex artery (17%). The target lesion median percent diameter stenosis by visual estimation was 90% [IQR, 75-99]. A total of 29% of the target lesions showed some degree of calcification on angiography. Intracoronary imaging modalities (7% optical coherence tomography) were used to guide the PCI in 11% of the cases. The mean number of stents deployed per lesion was 1.04 ± 0.22, with a median stent diameter of 3.0 mm [IQR 2.75-3.5] and a median stent length of 19 mm [IQR 19-24]. Pre- and postdilation were performed in 71% and 39% of the cases, respectively. The device and procedural success rates were 100%, without any procedure-related complications being reported in patients treated during the inpatient period.

Table 2. Angiographic, procedural and clinical follow-up characteristics of the cohort

Clinical outcomes at the follow-up

The 12-month follow-up was completed in 158 patients (98%). One year after implantation, 4 patients exhibited MACE (2.5%), and 3 patients died (1.9%). The cause of death was cardiac in 1 patient (due to a probable ST 7 days after the procedure) and non-cardiac in the remaining 2 (one due to lung neoplasm and the other to multiple organ failure). There were 2 non-fatal MIs (1.3%), both due to late definite ST (1 occurred 8 months after stent deployment and was associated with the study UTS stent, while the other one occurred 9 months after deployment due to a different thrombosed non-UTS stent implanted in a lesion of the target lesion same vessel. Only 2 patients required target lesion revascularization at the follow-up (1 due to ST and the other one due to in-stent restenosis).

DISCUSSION

The present study prospectively and multicentrically evaluates the safety and efficacy profile of implanting an UTS stent in a real-world population. Its main findings are that the UTS stent demonstrated a high procedural success rate, without in-hospital complications, acceptable midterm clinical outcomes, and a 2.5% rate of MACE 12 months after implantation.

The baseline characteristics of the study population are similar to the ones reported in previous studies that analyzed various stent technologies in patients with atherosclerotic coronary artery disease.10-12 However, it is noteworthy that in this study, 79% of cases were performed in the context of an acute coronary syndrome, including 22% of patients diagnosed with STEMI. In acute coronary syndrome—especially STEMI—there are factors associated with poorer outcomes of the implanted device, both in the short and long term. Firstly, the state of generalized vasoconstriction of the coronary tree and high thrombotic burden can complicate the appropriate selection of the size of the stent, thus leading to the implantation of smaller devices in relation to the actual size of the vessel, a mechanism involved in ST and in-stent restenosis. Furthermore, in the context of acute lesions, there is a higher risk of embolization and no-reflow or slow-flow phenomena, which can sometimes condition suboptimal final outcomes in terms of distal coronary flow, involving a greater risk of further ST. In our study, no ST occurred in patients with an early diagnosis of STEMI. Although it is worth mentioning that the results of the study stent were good—even in demanding contexts such as STEMI—the absolute number of STEMI patients included was low, meaning that data should be contrasted in larger series.

UTS stents provide better navigability, flexibility, and conformity to the vessel geometry. However, there may be doubts on whether the presence of UTS can lead to a reduction of the stent radial strength, which could have further implications for treating more unfavorable lesions, such as calcified lesions. Although, in the present study, 29% of the treated lesions showed some degree of calcification on angiography, the success rate of the stent reached 100%. This demonstrates the good performance of this UTS stent across different scenarios, achieving excellent radial strength even in the most challenging situations, such as calcified coronary lesions. These results are especially relevant in the specific context of the study, where, despite the recommendation for systematic postdilation, the final rate of stent postdilation was relatively low (39%).

Previous studies have consistently shown good clinical follow-up results for UTS stents with low rates of ST.13-15 The reason for this low rate of ST would be strut thickness per se, which would favor early neointimal coverage, thereby reducing the risk of ST (especially late and very ST).4 In the specific case of the study device (Evermine 50 EES), Patted et al.13 described the 6-month follow-up results of 251 patients. In this single-center, prospective experience, the authors describe a 6-month rate of MACE of 0.8%, with no ST at the follow-up. Regarding differences with respect to our series, nearly one-third of the cases were procedures in asymptomatic patients or with silent ischemia. Additionally, the rate of postdilation (57%) was higher than that of our cohort, which may have influenced the ST outcomes. The same group retrospectively described the results of 171 patients treated with the Evermine 50 EES stent,16 with 2-year rates of procedural success and MACE of 100% (same as in our study) and 2.4%, respectively. Again, the authors noted the absence of definite or probable ST at the follow-up. In this single-center cohort, the rate of stent postdilation was not reported, which may have implications for the prevention of MACE, especially ST. A meta-analysis that analyzed various types of UTS stents found no significant differences in the likelihood of stent failure, including ST across different stents with struts < 70 μm.17 In the present study, although the 1-year rate of definite ST after stent deployment was 1.3%, only 1 of these STs was attributed to the study device. The rate of ST is similar to that of other real-world experiences with second and third-generation stents,18-20 which confirms the good performance of the Evermine 50 EES in unselected real-world patients.

Limitations

The main limitations of the study are the relatively low number of patients included, and the absence of a comparator group. Furthermore, although the events reported at the follow-up were reviewed by the principal investigator of the coordinating center based on the case reports submitted by each principal investigator from the collaborating centers, these events were not allocated by an independent event adjudication committee. The fact that, in our cohort, few intracoronary imaging modalities were used to guide the PCI—reflecting real clinical practice—could be interpreted as a limitation of the study.

CONCLUSIONS

With data from a prospective, multicentric study of real-world patients, the PCIs performed with a 50 μm UTS stent, with a biodegradable polymer and everolimus elution had good clinical outcomes and a favorable safety profile at the 12-month follow-up.

FUNDING

None declared.

ETHICAL CONSIDERATIONS

The study was approved by the Drug Research Ethics Committee of the coordinating center. The study was conducted in full compliance with the terms outlined in the Declaration of Helsinki. All patients signed specific informed consent forms prior to the intervention and before being included in the study.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

No artificial intelligence was used for this work.

AUTHORS’ CONTRIBUTIONS

J. Casanova-Sandoval and M. García-Guimarães participated in the conception and design of the study, analysis and interpretation of results, and drafting the manuscript. G. Miñana Escrivà, E. Bosch-Peligero, J.F. Muñoz-Camacho, D. Fernández-Rodríguez, K. Rivera, A. Fernández-Cisnal, and D. Valcárcel-Paz participated in data acquisition and critically reviewed the content of the manuscript. All authors gave their final approval for the publication of the latest draft of the manuscript.

CONFLICTS OF INTEREST

None declared.

REFERENCES

INTRODUCTION

Aortic regurgitation (AR) results from abnormalities in the valve cusps or the structures supporting them (ie, the aortic root and annulus).1 The prevalence of AR increases with age, affecting 2% of people older than 70 years.2,3 Patients with severe AR have impaired functional capacity and increased mortality compared with the general population.2,4

If left untreated, severe AR leads to left ventricular dysfunction and heart failure in approximately 50% of patients.2 Although surgical aortic valve replacement is the recommended treatment for symptomatic severe AR,5 many elderly patients with this condition are refused surgery due to high operative risk.6

Since the introduction of transcatheter aortic valve implantation (TAVI) in 2002, it has demonstrated good safety and efficacy in various patient groups and several anatomical contexts.7-13 However, due to the high stroke volume, the lack of aortic annular calcification, and the frequent dilatation of the aortic root/annulus, TAVI for pure native AR is associated with an increased risk of adverse events including device dislocation and paravalvular regurgitation (PVR).14 The J-Valve(J.C. Medical, United States) and the JenaValve (JenaValve Technology GmbH, United States) are dedicated, next-generation, self-expanding transcatheter valves designed to address the challenges associated with native pure AR.15,16

To date, the evidence on the safety and efficacy of these technologies in native pure AR is limited. We conducted a systematic review of the current data on the safety and efficacy of TAVI using the J-Valve or JenaValve in patients with native pure AR.

METHODS

This systematic review and associated meta-analysis were conducted in accordance with the standards outlined in the PRISMA statement and the Cochrane Handbook for Systematic Reviews of Interventions (version 5.1.0).17,18 The study protocol was prospectively registered (PROSPERO registration number: CRD42023460306).

Data collection

We included studies that involved a minimum of 10 patients who underwent TAVI with the J-Valve or JenaValve for native pure or predominant AR. Studies were excluded if they involved mixed aortic valve disease (moderate to severe stenosis and regurgitation) or prior aortic valve replacement (valve-in-valve procedures).

Information sources, search strategy, and study selection

Three online databases (PubMed, Web of Science, and Cochrane Library) were searched up to March 2024 using the following search terms: ((aortic valve insufficiency OR aortic regurgitation OR regurgitant aortic valve OR aortic incompetency OR incompetent aortic valve OR NAVR OR noncalcific aortic valve) AND (transcatheter aortic valve replacement OR transcatheter aortic valve OR transfemoral aortic valve OR transaortic aortic valve OR transapical aortic valve OR transcutaneous aortic valve OR percutaneous aortic valve OR TAVI OR TAVR) AND (J-Valve OR JenaValve)). Additional relevant studies were identified through a manual search of secondary sources, including references of initially identified articles, reviews, commentaries, and archives of major cardiology conferences.

Endnote software (Clarivate Analytics, United States) was used to remove duplicates. The retrieved references were screened in 2 steps: first, all authors independently screened the titles and abstracts to determine their relevance, and second, the full-text articles of the identified abstracts were reviewed for final eligibility in the quantitative analysis. The Rayyan website was used in the selection process.19 For overlapping study populations, the most recent publication was chosen for inclusion.

Data extraction and outcomes

The data were extracted into a standardized data extraction sheet, which included: a) study characteristics, b) the patients’ baseline characteristics, c) echocardiographic and computed tomographic data, d) procedural data, and e) short-term clinical outcomes.

The main endpoints of the current investigation were device success, procedural success, and 30-day all-cause mortality. Additional outcomes of interest included bleeding, vascular complications, stroke, permanent pacemaker implantation (PPI), and PVR within 30 days.

Assessing the risk of bias

The quality of the retrieved studies was evaluated according to the Cochrane Handbook for Systematic Reviews of Interventions (version 5.1.0, updated March 2011). The risk of bias was assessed using appropriate tools based on the study design: the National Institutes of Health (NIH) tool for single-arm observational studies, the Newcastle-Ottawa Scale (NOS) for comparative observational studies, and the NIH tool for case-series studies. The individual studies were classified as ‘Low risk’ or ‘Good,’ ‘High risk’ or ‘Poor,’ and ‘Unclear risk’ or ‘Fair’ of bias.

Assessment of heterogeneity

The statistical heterogeneity among the studies was assessed using the chi-square test, specifically the Cochrane Q test. The chi-square statistic, known as Cochrane Q, was used to compute the I-squared value using the following formula: I2 = ([Q – df] / Q) × 100%. Significant heterogeneity was defined as a chi-square P value < .1. An I-squared value equal to or more than 40% was considered indicative of a significant level of heterogeneity.

Quantitative analysis

The DerSimonian and Laird meta-analysis approach was used to obtain the pooled effect size for all outcomes. Proportions and 95% confidence intervals (95%CI) were computed using R software (version 4.3.1 for Windows) and the Meta package.

A random-effects model, which gives relatively higher weight to smaller studies to account for heterogeneity, was used when heterogeneity was deemed significant. A fixed-effects model was chosen when heterogeneity was lower. Consequently, the predicted effects in our meta-analysis are conservative estimates that account for potential inconsistencies.

Certainty assessment

A certainty evaluation was performed using sensitivity analysis (leave-one-out meta-analysis) to test the robustness of the evidence. This analysis was conducted using R software (version 4.3.1 for Windows) with the Meta package and Metainf function. Sensitivity analyses were was run in several scenarios for each outcome in the meta-analysis, eliminating one study in each scenario, to ensure that the overall effect size was not dependent on any single study.

RESULTS

Literature search

Our search identified 143 results after duplicates were removed. Following title and abstract screening, 29 articles were selected for full-text review. Of these, 15 studies6,14,20-32 were included in the systematic review, with 5 studies of transfemoral TAVI being included in the quantitative meta-analysis. No further articles were included after manually searching the references of the included studies. The selection process is illustrated in a PRISMA flow diagram (figure 1). According to the NIH and NOS scales for quality assessment, the overall quality of the included studies was rated as good for all investigations, as shown in the supplementary data.

Figure 1. PRISMA flow diagram of the study.

Patient and procedural characteristics

Overall, 788 patients underwent TAVI for native pure or predominant AR (J-Valve, 357 patients; JenaValve, 431 patients). Most J-Valve procedures were performed in China, while most JenaValve procedures were conducted in Europe and North America. The average surgical risk was elevated but showed significant variability, with Log EuroSCORE at 22.8 ± 12.3, EuroSCORE II at 7.1 ± 6.6, and Society of Thoracic Surgeons - Predicted Risk of Mortality (STS-PROM) at 5.9 ± 4.7.

The mean age was 73.6 ± 7.3 years for J-Valve recipients and 75.9 ± 10.0 years for JenaValve recipients. Males comprised 61.9% of J-Valve recipients and 42.0% of JenaValve recipients. The body mass index (BMI) was 22.6 ± 3.0 for J-Valve recipients and 25.3 ± 5.7 for JenaValve recipients. The STS-PROM score was 6.7 ± 5.9 for J-Valve recipients and 4.4 ± 3.5 for JenaValve recipients. Most patients had severe symptoms, with New York Heart Association (NYHA) class III/IV dyspnea present in 75.9% of J-Valve recipients and 57.3% of JenaValve recipients. Demographic, clinical, echocardiographic, and computed tomography data from the individual studies are summarized in table 1 and table 2.

Most J-Valve implantations were performed via the transapical approach (92.4%), whereas JenaValve implantations were transapical in 36.7% of cases and transfemoral in 63.3%. The annulus diameter was 26.0 ± 2.4 mm for J-Valve and 25.6 ± 2.3 mm for JenaValve. The device size was 27.2 ± 1.9 mm for J-Valve and 26.1 ± 0.2 mm for JenaValve. The most frequently used device size was 27 mm. Further procedural data from the individual studies are summarized in table 3.

Table 1. Baseline characteristics of patients included in 15 unique studies

Table 2. Echocardiographic and computed tomographic data

Table 3. Procedural characteristics

In-hospital outcomes

Overall, in-hospital outcomes were favorable. Procedural success was achieved in 95.9% (n = 518/540). Surgical conversion was required in 1.8% (n = 12/678), device migration or embolization occurred in 3.2% (n = 17/540), and a second valve (in-valve) was required in 2.0% (n = 13/651). Only 1 patient (out of 502) experienced coronary obstruction, and no patients developed annular rupture (among 449). Details of in-hospital outcomes from the individual studies are summarized in table 4.

Table 4. In-hospital outcomes

Thirty-day outcomes

At 30 days, 95.5% of patients were alive (n = 716/750), and device success was achieved in 93.3% (n = 498/534). Mild PVR was observed in 18.0% (n = 86/478), while moderate-to-severe PVR occurred in 1.7% (n = 12/703; including 10 patients with J-Valve and 2 patients with JenaValve). PPI was required in 13.0% (n = 86/711; with 25 patients receiving J-Valve and 61 receiving JenaValve). Further 30-day outcomes from the individual studies are summarized in table 5.

Table 5. Thirty-day outcomes

Quantitative analysis of the outcomes of transfemoral TAVI for aortic regurgitation

A meta-analysis of 5 studies25-28,32 of transfemoral TAVI for AR (all with the JenaValve) included 273 patients (mean age, 77.6 years; 52.4% male). Pooled estimates were as follows: procedural success was 97.8% (95%CI, 94.4%-100%, I2 = 43%, P value = .13) (figure 2A), conversion to surgery was 0.49% (95%CI, 0.0%-1.5%, I2 = 0%, P value = .56) (figure 2B), device migration/embolization was 1.2% (95%CI, 0.0-3.3%, I2 = 47%, P value = .17) (figure 2C), and the need for a second valve was 0.46% (95%CI, 0.0%-1.44%, I2 = 0%, P value = .67) (figure 2D). Further details of in-hospital outcomes are summarized in table 6 and in the supplementary data.

Figure 2. A. Forest plot of procedural success of TF JenaValve. The bibliographical references mentioned in this figure correspond to: Adam et al.25 2023, Baumbach et al.26 2023, Ranard et al.27 2022, Baldus et al.28 2019, Vahl et al.32 2024; B. Forest plot of conversion to surgery TF JenaValve. The bibliographical references mentioned in this figure correspond to: Adam et al.25 2023, Baldus et al.28 2019, Vahl et al.32 2024; C. Forest plot of device migration/embolization TF JenaValve. The bibliographical references mentioned in this figure correspond to: Adam et al.25 2023, Vahl et al.32 2024; D. Forest plot of need for a second valve TF JenaValve. The bibliographical references mentioned in this figure correspond to: Adam et al.25 2023, Vahl et al.32 2024. 95%CI, 95% confidence interval.

Table 6. Quantitative analysis of in-hospital outcomes of transfemoral transcatheter aortic valve implantation for aortic regurgitation

At 30 days, the pooled estimate of device success was 97.0% (95%CI, 94.8%-99.2%, I2 = 0%, P value = .61) (figure 3A), and the pooled estimate of all-cause mortality was 2.0% (95%CI, 0.2%-3.7%, I2 = 0%, P value = .95) (figure 3B). The rate of PPI was 18.7% (95%CI, 13.9%-23.4%, I2 = 0%, P value = .58) (figure 3C). Mild PVR rate was 10.6% (95%CI, 1.7%-19.4%, I2 = 75%, P < .01) (figure 4A) with statistically significant heterogeneity resolved by omitting Vahl et al.32 yielding a rate of 4.7% (95%CI, 0.0%-9.5%, I2 = 38%) (supplementary data), while the rate of moderate-severe PVR was 0.47% (95%CI, 0.0%-1.47%, I2 = 0%, P- = 1.00) (figure 4B). Further 30-day outcomes are summarized in table 7 and in the supplementary data.

Figure 3. A. Forest plot of device success TF JenaValve. The bibliographical references mentioned in this figure correspond to: Adam et al.25 2023, Makkar et al.33 2023; B. Forest plot of 30-day all-cause mortality TF JenaValve. The bibliographical references mentioned in this figure correspond to: Adam et al.25 2023, Baumbach et al.26 2023, Baldus et al.28 2019, Vahl et al.32 2024; C. Forest plot of 30-day permanent pacemaker implantation TF JenaValve. The bibliographical references mentioned in this figure correspond to: Adam et al.25 2023, Baumbach et al.26 2023, Baldus et al.28 2019, Vahl et al.32 2024.

Figure 4. A. Forest plot of 30-day of mild prosthetic valve regurgitation TF JenaValve. The bibliographical references mentioned in this figure correspond to: Adam et al.25 2023, Baumbach et al.26 2023, Ranard et al.27 2022, Baldus et al.28 2019, Vahl et al.32 2024; B. Forest plot of 30-day of greater than mild prosthetic valve regurgitation TF JenaValve. The bibliographical references mentioned in this figure correspond to: Adam et al.25 2023, Baumbach et al.26 2023, Ranard et al.27 2022, Baldus et al.28 2019, Vahl et al.32 2024.

Table 7. Quantitative analysis of 30-day outcomes of transfemoral transcatheter aortic valve implantation for aortic regurgitation

DISCUSSION

In this study, we included data from 788 patients who underwent TAVI using 1 of the 2 dedicated devices specifically designed for use in pure/predominant AR: the J-Valve and the JenaValve (figure 5). Studies published up to April 2024 were included, providing a contemporary and comprehensive analysis of published data in this field to date. Overall, 357 patients received the J-Valve (in 5 studies), while 431 received the JenaValve (in 10 studies). These patients were generally at increased surgical risk. J-Valve recipients were predominantly Chinese, tended to be slightly younger, had a smaller BMI, wand showed a clear male predominance compared with JenaValve recipients.

Figure 5. Central illustration. Features of the contemporary generations of 2 TAVI systems dedicated to aortic regurgitation.

The use of the 2 technologies (J-Valve and JenaValve) was influenced by their geographical availability, leading to differences between the populations treated with each device. Moreover, as mentioned earlier, the 2 groups differed in age, sex, and STS-PROM scores. Additionally, most of the transfemoral implantations involved the JenaValve, while the vast majority of J-Valve implantations were transapical. Consequently, direct statistical comparison between the 2 devices and the 2 access routes was deemed inappropriate. For similar reasons, we avoided pooling data from all JenaValve procedures (mixing transapical and transfemoral implantations) and from all transapical procedures (mixing J-Valves and JenaValves). This approach minimized the risk of drawing invalid conclusions by mixing heterogeneous data or comparing outcomes without accounting for important independent confounders. Patients receiving the JenaValve via the transfemoral approach constituted a homogeneous subgroup, allowing for pooled/quantitative analysis. The findings of this latter analysis are particularly important, as transfemoral access currently dominates the TAVI field.

Our systematic review combines prospective and retrospective studies, which share common limitations such as small sample sizes and nonrandomized designs. Therefore, the findings should be regarded as preliminary and require validation in larger randomized studies. From the available data, our major observations can be summarized as follows: first, TAVI using AR-dedicated devices demonstrated a high success rate with a reassuring early safety profile. Second, the rates of surgical conversion, device dislocation, and second valve implantation were low (2%-3%). Third, both dedicated devices effectively eliminated or reduced AR, with only 1% to 2% of patients having ≥ moderate residual AR. Fourth, the results of transfemoral TAVI for AR using the JenaValve were particularly encouraging, although the PPI rate was still relatively high. Taken together, these initial findings suggest that transcatheter treatment of AR, especially through transfemoral access, may be a safe and effective alternative to surgery in appropriately selected patients.

Treating AR with TAVI using the first/older generations of transcatheter heart valves has been associated with suboptimal results.35,36 However, subsequent studies showed that next/newer generation transcatheter heart valves can improve outcomes, bringing them closer to those achieved in patients with AS.13 With the introduction of dedicated devices, several key outcomes have shown further improvement, yielding very high procedural and device success rates and low rates of conversion to surgery, device migration or embolization, the need for a second valve, and PVR. Although annular injury is a concern given the frequent association of AR with aortopathy, no cases of annular rupture were reported with the 2 self-expanding dedicated devices. We also observed low rates of acute kidney injury, bleeding, vascular complications, and in-hospital mortality. Whether this low rate of early complications will translate into improved long-term clinical outcomes remains to be determined and should be explored in longitudinal prospective studies.

A major challenge associated with TAVI for native pure/predominant AR is the risk of device migration/embolization and paravalvular leakage. This risk arises from the absence of calcification in the landing zone, the large size of the aortic annulus, and the high stroke volume in AR patients. The design of the 2 AR-dedicated TAVI devices aims is to mitigate this risk (figure 5).

The JenaValve device features an natomically-oriented design with ‘supporting arms’ that can be positioned in the sinuses of the aortic root, ensuring precise placement of the valve stent. Additionally, the fixation of the oriented device to the native valve leaflet through clip attachment provides an extra axial expansion force, enabling secure fixation even in the absence of leaflet calcifications.37

The J-Valve device is characterized by its U-shaped grasper that captures the aortic valve leaflets, achieving ‘axial’ fixation, which complements the ‘radial’ fixation, which is less reliable in the absence of calcification. Furthermore, the dual-phase release mechanism of this device (the graspers are initially released, followed by the valve) can aid in precise placement of the graspers prior to valve deployment and decrease the likelihood of damage to the native valve.38

Our data suggest that these innovative designs are associated with very low rates of device dislocation and paravalvular leakage, which in turn results in low rates of second valve requirement and surgical conversion. Importantly, these benefits did not come at the expense of increased risk of annular injury or coronary obstruction. However, a relatively high rate of PPI was observed with JenaValve, reaching nearly 19% in 5 studies of its updated transfemoral version. This may reflect a tendency for a relatively deeper implantation, a common issue with early experience of nearly all TAVI systems that tends to improve over time and typically portends a decline in PPI rates.39-42

While the current review includes preliminary single-arm, observational, small-scale studies, several randomized trials are have been conducted on J-Valve and JenaValve.43-47 While the results of these trials are pending, our data suggest a positive outcome.

In the currently available data, there is a dominance of transapical access procedures among J-Valve implantations. However, with the trend toward more minimalistic TAVI procedures, the transapical approach may only be a precursor, with the transfemoral approach expected to eventually become the standard, as already observed with the JenaValve. The most recent data, presented in 2023, on transfemoral J-Valve procedures (from the compassionate use experience in North America) is particularly reassuring.20

Study limitations

The scope of our investigation was restricted to observational studies, abstracts, and conference presentations;, none of which were randomized controlled trials. This inherently limits the quality of the evidence produced. Additionally, the present findings may have been influenced by publication bias favoring TAVI for native pure or predominant AR, which was mitigated by our. However, we sought to mitigate this bias through an exhaustive review of the available literature and the meticulous exclusion of overlapping or duplicate data. The total patient population remained relatively small, and follow-up was restricted to 30-day outcomes, so the findings should be interpreted with these limitations in mind.

CONCLUSIONS

This systematic review provides a comprehensive and up-to-date analysis of data on TAVI with dedicated devices for native pure/predominant AR. The initial experience discussed in the present review demonstrates the safety and favorable early outcomes of TAVI using J-Valve and JenaValve in patients with pure/predominant AR, especially when the transfemoral approach is used. Nevertheless, PPI requirement remains frequent.

FUNDING

None.

ETHICAL CONSIDERATIONS

The present article is a literature review and, as such, ethics approval was not required. The study did not involve patient recruitment or access to disaggregated information on individuals and therefore informed consent was not required. Possible sex/gender biases have been taken into account in the preparation of this article.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

No artificial intelligence was used in the preparation of this article.

AUTHORS’ CONTRIBUTIONS

A. Hassan, M. Abdelshafy, and R.A. Diab performed the literature review, data analysis, and initial manuscript drafting. H. Wienemann, M. Adam, S. García, and M. Saad critically reviewed the manuscript. M. Abdelghani conceived the idea, designed and supervised data collection and analysis, and finalized the manuscript.

CONFLICTS OF INTEREST

M. Adam reports personal fees and speaker honoraria from Abbott, Boston Scientific, Edwards Lifesciences, JenaValve, and Medtronic. S. Garcia reports institutional grants from J.C. Medical and JenaValve. All other authors have no conflict of interest to report.

SUPPLEMENTARY DATA

REFERENCES

INTRODUCTION

The use of the transradial approach for coronary interventions has become increasingly widespread in interventional cardiology due to its numerous advantages.1 As a result, current guidelines recommend it as the first-line approach.2

However, the benefits of this technique are tempered by the risk of radial artery occlusion (RAO), with reported rates ranging from 5% to 30%.3,4 The aim of this study was to assess the incidence and predictors of RAO following transradial catheterization using Doppler ultrasound for evaluation.

METHODS

Patient population

This longitudinal, single-center prospective study was conducted in the cardiology department of the Military Central Hospital in Algiers. After applying exclusion criteria (hemodynamic instability and ST-segment elevation myocardial infarction), we included 427 consecutive patients undergoing transradial coronary procedures between January 2019 and March 2020. The study adhered to the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practices and was approved by the local ethics committee. All patients provided written informed consent.

Radial artery cannulation and retrograde radial arteriography

After radial artery (RA) puncture, a radial hydrophilic sheath (Radiofocus II, TERUMO Medical, Japan, or Prelude, MERIT Medical, United States) was introduced. An antispastic cocktail was then administered into the RA through the sheath, consisting of a saline solution, a vasodilator (1 mL of nicardipine), and a bolus of unfractionated heparin, which was administered either intravenously or directly into the RA as part of the spasmolytic cocktail, depending on the operator’s preference. In patients on vitamin K antagonists, these medications were not discontinued prior to the procedure.

Retrograde radial arteriography was performed by injecting a mixture of 4 mL of contrast and 4 mL of isotonic saline through the sheath. Radiographic images were then obtained in an anteroposterior projection.

Transradial coronary procedure

The standard approach was conventional right radial access. For coronary angiography, 5-French (Fr) hydrophilic sheaths and catheters were usually used. If the patient required revascularization, an ad hoc percutaneous coronary intervention was performed, using 6-Fr guiding catheters after exchanging the sheath from 5-Fr to 6-Fr. The usual dose of heparin is 5000 IU (2500 IU for oral anticoagulation with a vitamin K antagonist).

Hemostasis procedure

At the end of the procedure, the sheath was removed, and hemostasis was achieved using a hemostatic compression device (TR BAND, TERUMO Medical, Japan). A reverse Barbeau test5 was systematically performed. The hemostasis device was removed by nurses in the hospitalization unit. No standardized protocol for the duration of hemostasis was followed.

Assessment of postprocedural radial artery patency

Radial Doppler assessments were conducted before and after each transradial procedure. To evaluate RAO, pulsed Doppler was performed bilaterally on the radial and ulnar arteries. Normal arterial flow was indicated by a biphasic or triphasic signal, reflecting good perfusion. In cases of RAO, 2 additional ultrasonographic examinations were performed at 1 and 3 months, following the same protocol. Artery patency was assessed by an independent operator.

Classifications and definitions

RAO was defined as the absence of anterograde flow in the RA on ultrasound (figure 1). The location of the radial occlusion was identified using color and pulsed Doppler. We delineated 3 anatomical territories: the distal third, extending from the radial styloid to approximately 7 to 10 cm proximally; the proximal third, from the elbow folds to approximately 7 to 10 cm distally; and the middle third, located between the previous 2 regions (middle part of the forearm).

Figure 1. Radial artery with occlusion in the distal third. Pulsed Doppler flow targets a stop flow indicating radial occlusion.

The type of hemostasis, whether occlusive or patent, was assessed: patent hemostasis was indicated by the presence of a plethysmographic signal in the RA during the reverse Barbeau test,5 which involves compression of the ulnar artery. The operator did not intervene during this process but simply recorded whether the artery remained patent or not.

The internal luminal diameter of the RA was defined as the distance between the leading edges of the intima-lumen interface on the superficial wall and the lumen-intima interface on the deep wall.6

The R/S ratio (radial/sheath) was calculated by dividing the luminal diameter of the RA by the external diameter of the sheath (Radiofocus II: 5-Fr = 2.29 mm, 6-Fr = 2.62 mm, 7-Fr = 2.97 mm; Prelude: 5-Fr = 2.52 mm, 6-Fr = 2.83 mm). This ratio was categorized qualitatively as < 1 or ≥ 1.

RA anatomical variations of clinical relevance were classified according to definitions provided in the literature.7,8 A high origin (high bifurcation) of the RA (figure 2) was defined with reference to the intercondylar line of the humerus. A radioulnar loop was characterized by the presence of a complete 360° loop of the RA, while radial tortuosity was identified by a curvature greater than 45°.

Figure 2. Anatomic variations of the radial artery. A: high origin of the radial artery. The radial and ulnar arteries separate at the level of the middle third of the humerus (arrow). B: radioulnar loop was defined as a complete 360° loop of the radial artery distal to the bifurcation of the brachial artery (arrow).

A blood pressure profile was obtained on the same side as the radial access. Forearm hematomas were classified according to the “EASY” study9: type I: < 5 cm in diameter; type II: < 10 cm; type III: > 10 cm but not extending to the elbow; type IV: extending beyond the elbow; type V: resulting in an ischemic lesion.

Statistical analysis

The statistical analysis was performed using IBM SPSS Software version 25. Parameters of interest are reported with their 95% confidence intervals (95%CI). For all tests, a significance threshold of 5% was retained. All tests were performed bilaterally. The following tests were used to compare groups: the chi-square test was used to compare 2 qualitative variables; the Student t-test or analysis of variance was used to compare a quantitative variable with a qualitative variable, with the Fisher test being applied when variances were unequal; and logistic regression was used to identify predictors of RAO.

RESULTS

Clinical and procedural characteristics of the study population

During the study period, 441 patients were screened. Of these, transradial access failed in 14 patients, who were excluded from the study, resulting in an eligible sample of 427 patients (mean age 61.9 ± 11.1 years, 67.4% male). Among the patients, 260 had hypertension (60.9%), and nearly half had diabetes (48.9%).

Table 1 summarizes the procedural data. The sheaths used were mainly 6-Fr (83.6%), and heparin was injected intra-arterially in 63.5% of patients. The mean heparin dose was 5669 ± 1394 IU, with a higher dose given when percutaneous coronary intervention was performed (4940 ± 339 IU vs 7491 ± 1368 IU; P < .001).

Table 1. Procedural data

Incidence and characteristics of radial artery occlusion

RAO occurred in 48 patients (11.24%). Of these, 89.6% were asymptomatic, and the radial pulse remained palpable in 14 patients (29.2%). At 1 month, 2 patients were lost to follow-up. Among the remaining 46 patients, spontaneous recanalization occurred in 13 patients (28.3%). At the 3-month follow-up, the recanalization rate increased to 32.6% (15 cases).

The site of RAO was the distal third in 7 patients (14.6%), the middle third in 21 patients (43.8%), and the proximal third in 20 patients (41.7%).

Predictors of radial artery occlusion

Patients with RAO were significantly younger (table 2). The mean periprocedural systolic blood pressure in the RAO group was significantly lower (138.04 mmHg ± 21.92, vs 145.84 mmHg ± 21.10; P = .017). Type A Barbeau test was associated with a higher risk of RAO compared with types B and C, and patients with occlusion had a smaller RA diameter (2.34 mm ± 0.40 vs 2.61 mm ± 0.37; P < .001) (figure 3).

Table 2. Comparison of patients with and without RAO

Figure 3. Radial artery diameter as a predictor of occlusion. A: the radial diameter is significantly smaller if there is RAO. B: less than 2.5 mm, the risk of occlusion becomes greater.

RAO procedural factors are listed in table 2. An R/S ratio < 1 was found in 35 patients in the RAO group vs 153 patients in the non-RAO group (72.9% vs 40.3%, P < .001). The mean heparin dose was significantly lower in patients with RAO (5007 ± 1352IU vs 5754 ± 1378 IU; P < .001), and the dose adjusted to weight was also significantly lower in the RAO group (62.31 ± 17.82 IU/kg vs 75.73 ± 22.57 IU/kg; P < .001). In addition, the RAO rate decreased significantly when the heparin dose exceeded 70 IU/kg.

Forty-two patients in the RAO group had occlusive hemostasis vs 241 in the non-RAO group (87.5% vs 63.5%; P = .001). Surprisingly, two-thirds of our patients (283 [66.3%]) had occlusive hemostasis. The mean duration of hemostasis was longer if there was RAO (5.15 h ± 1.41 vs 4.29 h ± 1.22; P < .001).

On multivariate logistic regression analysis (figure 4), the following factors were independent predictors of RAO: young age (odds ratio [OR], 0.642; 95%CI, 0.480-0.858; P = .031), low periprocedural systolic blood pressure (OR, 0.598; 95%CI, 0.415-0.862; P = .007), type A Barbeau test (OR, 0.441; 95%CI, 0.198-0.981; P = .045), small RA diameter (OR, 0.371; 95%CI, 0.323-0.618; P = .031), insufficient anticoagulation (OR, 0.287; 95%CI, 0.163-0.505; P < .001), occlusive hemostasis (OR, 0.128; 95%CI, 0.047-0.353; P < .001), and a long hemostasis duration (OR, 1.786; 95%CI, 1.428-2.039; P < .001).

Figure 4. Independent factors predictive of radial artery occlusion. Multiple logistic regression analysis revealed that the independent factors predictive of radial occlusion were young age, low periprocedural systolic blood pressure, type A Barbeau test, small radial artery diameter, insufficient anticoagulation, occlusive hemostasis, and long hemostasis duration. 95%CI, 95% confidence interval; PSBP, periprocedural systolic blood pressure; RAO, radial artery occlusion.

Anatomic variations of the radial artery

The mean radial diameter was 2.58 mm ± 0.39, and the diameter was larger in men (2.69 mm ± 0.37 vs 2.36 mm ± 0.31; P < .001) and smaller in patients with diabetes (2.53 mm ± 0.38 vs 2.64 mm ± 0.38; P = .003). The mean radial diameter was significantly larger than the mean ulnar diameter (2.58 mm ± 0.39 vs 2.22 mm ± 0.43; P < .001).

Radial anatomical variations affected 63 patients (14.8%). The most common variation was a high origin of the RA, observed in 63.5% of cases (40 patients), followed by radial tortuosity in 28.6% (18 patients), radioulnar loop in 7.9% (5 patients). Anatomical variations were more frequent in women (23% vs 10.8%; P = .001) and in older patients, with a mean age of 66.3 years ± 10.2 vs 61.2 years ± 11.2 in those without variations (P = .001).

Periprocedural complications

Radial spasm occurred in 72 patients (16.9%). This complication was more frequent in women (29% vs 10.1%; P < .001), patients with diabetes (22.5% vs 11.5%; P = .002), and when 6-Fr catheters were used (14% vs 24%; P = .035). Forearm hematoma occurred in 25 patients (5.85%). According to the EASY classification,9 most hematomas were type I (17 patients, 68%), followed by type II (6 patients, 24%), with type III occurring in only 2 patients (8%).

DISCUSSION

The rate of RAO remains relatively high in some institutions.10,11 In the PROPHET study, the acute incidence of RAO (12%) was almost halved in 28 days (7%).3 Recanalization occurs as a result of activation of primary fibrinolysis.12 In the present study, the rate of radial recanalization at 3 months was 32.6%. The only predictor of recanalization was radial diameter: the larger the diameter, the higher the rate of spontaneous recanalization.

Zankl et al.13 found that RAO was located in the distal third of the forearm in 49% of patients, in the distal and middle third in 13.7%, and in the entire forearm (proximal third) in 37.3%. Dissections of the media also occur in the proximal RA, likely due to catheter progression or manipulation without protection of the sheath.14 In our opinion, this would explain the location of RAO in the proximal part of the artery.

Among our patients with RAO, 29.2% had a radial pulse. According to Uhlemann et al.,4 in 19.5% of patients with RAO on Doppler, the RA pulse was still palpable. This was likely due to retrograde filling of the RA by collaterals. Therefore, the diagnosis of RAO should be confirmed using a more objective method, such as Doppler ultrasound.

Young age is a predictor of RAO, possibly due to higher sympathetic reactivity in younger individuals, which increases their risk of spasm. However, this characteristic does not influence the rate of recanalization, likely because prolonged radial spasm leads to the formation of a permanent intra-arterial thrombus.

Low mean systolic blood pressure was also a predictor of radial occlusion. We speculate that hypertension and arterial stiffness may prevent complete interruption of flow during compression, thereby helping to maintain radial patency.15

There was a higher incidence of occlusion with type A Barbeau test. We believe that in cases with well-developed ulnar circulation, the ulnar artery generates a competitive retrograde flow that opposes the radial flow, promoting occlusion and hindering recanalization.

The likelihood of developing RAO is related to the size of the sheath,16 or more precisely, the R/S ratio.17 A prospective registry showed that 5-Fr sheaths reduced the rate of RAO by up to 55% compared with 6-Fr.4

A study by Pancholy et al.,18 demonstrated that intravenous heparin is as effective as intra-arterial heparin in reducing the incidence of RAO, suggesting that the systemic effect of heparin is more important than its local effect. A recently published meta-analysis identified higher heparin doses as the most significant measure for decreasing RAO.12 This results is in line with our finding that a dose of less than 70 IU/kg seems to promote the occurrence of RAO. The high prevalence of RAO and the benefit of higher doses of unfractionated heparin (≥ 50 IU/kg) in this setting were also highlighted by a meta-analysis of 112 studies.19 In a randomized superiority trial comparing high-dose (100 IU/kg) and standard-dose (50 IU/kg) heparin, the RAO rate was significantly lower in the high-dose group.20 Recent evidence suggests that a small dose of rivaroxaban, given orally after a transradial procedure, may decrease the occurrence of RAO at 1 month.21,22

Using the reverse Barbeau test, Sanmartin et al.23 found that 60% of patients had an absence of radial flow during compression. These observations led to the concept of nonocclusive hemostasis (patent hemostasis). In the PROPHET study,3 RAO was significantly less frequent in the group that underwent nonocclusive hemostasis than in the control group.

The duration of hemostatic compression has been studied in large, randomized trials.24-26 The authors concluded that compression duration was a strong predictor of RAO.

In a meta-analysis by Rashid et al.,27 the incidence of RAO after diagnostic coronary angiography was notably higher compared with percutaneous coronary intervention, possibly due to the use of higher anticoagulation doses during interventions.12 However, opposite findings have been reported by other studies.

In our sample, the mean radial diameter was 2.58 mm ± 0.39 and was significantly larger in men. Velasco et al.28 reported a mean arterial diameter of 2.22 ± 0.35 mm, while a Polish study found a mean diameter of 2.17 ± 0.53 mm for the right RA and 2.25 ± 0.43 mm for the left RA.29 The ulnar artery is also used in interventional cardiology,30 although there is no consensus on its size compared with the RA.

Autopsy studies of arterial anatomic variations of the upper extremity have reported frequencies between 4% and 18.5%.8 In the literature, the most frequent anatomic variation of the RA is high bifurcation. Yoo et al.31 reported a 2.4% incidence of high radial origin in 1191 Korean patients. Tortuosity of the RA frequently affects patients with high radial origin, possibly due to the elongated course of the RA predisposing it to tortuosity, which is considered one of the most common causes of procedural failure, along with radial spasm.32

Radioulnar loop is the most common cause of procedural failure with experienced operators.33 Angiographic evaluation of the radioulnar anastomosis is mandatory in such cases, as there is often a negotiable anastomosis between the radial and ulnar arteries.

In our study, radial spasm was the leading cause of procedural failure, occurring in 50% of the 14 patients who experienced such failures. Ruiz-Salmerón et al.34 found that RA anatomic variations were strongly associated with radial spasm in a multivariate analysis. The relationship between radial spasm and anatomic variations is mainly explained by the strong correlation with high radial origin and the radioulnar loop.

Study limitations

Since this study is a prospective registry and not a randomized trial, selection bias cannot be excluded. Our study represents a single-center experience with a limited number of patients, despite being one of the largest prospective registries of vascular ultrasound in radial catheterization to date. Among the other limitations of the study, we note the lack of standardized protocols for both heparin use and compression.

CONCLUSIONS

With the increasing number of transradial procedures and the greater age of patients undergoing these interventions, leading to more complex procedures, it is essential to maintain the patency of the RA for future access. Although predictors of RAO after cardiac catheterization have been identified, implementing preventive measures in practice remains a challenge. The main modifiable predictors associated with the risk of RAO are insufficient heparinization and occlusive hemostasis. Therefore, preventive strategies should primarily focus on addressing these 2 factors.

FUNDING

None.

ETHICAL CONSIDERATIONS

The study was conducted in accordance with the provisions of the Declaration of Helsinki and with the International Conference on Harmonization Good Clinical Practices and was approved by the local ethics committee. All patients included in the study provided written informed consent, which is archived and available. Our study population included both sexes. Gender had no influence on the occurrence of radial occlusion.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

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

AUTHORS’ CONTRIBUTIONS

All authors meet the criteria for authorship as defined by the International Committee of Medical Journal Editors. M.S. Lounes, A. Meftah, C. Belhadi, K. Allal, H. Boulaam, A. Sayah, I. Hafidi, and E. Tebache contributed to the acquisition and analysis of data for this article. M.S. Lounes, A. Bedjaoui, A. Allali, and S. Benkhedda were responsible for the study design and the writing of the article. M.S. Lounes, A. Allali, and S. Benkhedda contributed to writing and critical revision of the content. All authors have read and approved the final version of the article and agree to be accountable for all aspects of the work, including the accuracy and integrity of all its parts.

CONFLICTS OF INTEREST

None.

REFERENCES