Single or dual antiplatelet therapy after transcatheter aortic valve implantation. A meta-analysis of randomized controlled trials

INTRODUCTION

Percutaneous coronary intervention (PCI) is the first-line therapy in patients with ST-segment-elevation myocardial infarction (STEMI).1 The STEMI-related culprit vessel is usually considered as one of the most important prognostic factors in STEMI patients.2,3 This assumption comes from previous studies –conducted in the pre-reperfusion or thrombolysis era– which showed that left anterior descending artery (LAD)-related STEMIs were associated with worse clinical outcomes compared with right coronary (RCA) and left circumflex artery (LCX)-related lesions.4-9

However, in the contemporary era of primary PCI there are limited data about the prognostic impact of LAD as the STEMI-related culprit vessel especially in a very long follow-up.10,11

Therefore, the aim of this study was to investigate the impact of the LAD as the STEMI-related culprit vessel on very long-term clinical outcomes in STEMI patients undergoing primary PCI enrolled in the EXAMINATION-EXTEND study (10-year follow-up of the EXAMINATION trial).

METHODS

Study design and patients

The EXAMINATION trial (NCT00828087) was an all-comer, multicenter, prospective, 1:1 randomized, 2-arm, single-blind, controlled trial conducted at 12 centers across 3 countries to assess the superiority of EES (Xience V) vs BMS (Multilink Vision, Abbott Vascular) in STEMI patients regarding the primary endpoint of all-cause mortality, any myocardial infarction, and any revascularization at 1 year. The study had broad inclusion criteria and few exclusion criteria to ensure an all-comer STEMI population representative of the routine clinical practice. The study outcomes have been reported up to the year 5.12,13 After that, it was reinitiated as the EXAMINATION- EXTEND study to evaluate patient- and device-oriented composite endpoints at 10 years. The latter is registered at ClinicalTrials.gov (NCT04462315) as an investigator-driven extension of follow-up of the EXAMINATION trial. An independent study monitor (ADKNOMA, Barcelona, Spain) verified the adequacy of the extended follow-up and events reported. All events were adjudicated and classified by an independent event adjudication committee blinded to the therapy groups (Barcicore Lab, Barcelona, Spain). The 10-year primary endpoint results of the EXAMINATION-EXTEND study have been previously published.14 For the aim of this study, baseline, procedural characteristics and outcomes were stratified according to the STEMI-related culprit vessel (LAD vs others). All centers participating in the EXAMINATION trial received the approval of their Medical Ethics Committee, and all enrolled patients who had already signed their written informed consent forms. Medical ethics committee approval for EXAMINATION- EXTEND was granted at the institutions of the principal investigators (Hospital Clínic and Hospital Bellvitge, Barcelona, Spain), and the requirement to obtain informed consent to gather information on 10- year events was waived. The study complied with the Declaration of Helsinki.

Study endpoints

The primary endpoint of this study was the patient-oriented composite endpoint of all-cause mortality, any myocardial infarction, or any revascularization at 10 years. Secondary endpoints were each individual components of the primary endpoint, device-oriented composite endpoint (cardiac death, target-vessel myocardial infarction, target lesion revascularization), its individual components and stent thrombosis. Detailed descriptions of the study endpoints and definitions have been published previously.15

Statistical analysis

Continuous variables are expressed as median (interquartile range; IQR), and categorical variables as absolute and relative frequencies (percentages).

Baseline clinical, angiographic, and procedural characteristics were compared between the groups stratified by the STEMI-related artery (LAD vs other vessels) using the Wilcoxon rank sum test, the chi-square, or Fisher’s exact test, where appropriate.

Time-to-event curves for POCE and all-cause death were plotted using the one minus the Kaplan-Meier estimate and the cumulative incidence function for other outcomes. The incidence of events at the follow-up was compared between groups using log-rank or Grey’s test. Landmark analyses were also performed, setting landmark points at 1 and 5 years.

The association between LAD as a STEMI-related culprit vessel and events was analyzed in univariable and multivariable cause-specific Cox regression models. Covariates were added to the multivariable model in 2 blocks. The first model included all clinically relevant baseline characteristics variables with P < .1 in the between-groups comparison (LAD vs other vessels), i.e., sex, smoking status, peripheral vascular disease, previous PCI, previous CABG, previous MI, and Killip class. The second model (expanded adjustment) included both the baseline characteristics and the left ventricular ejection fraction (LVEF) at discharge.

Two-tailed P-value < .05 was considered statistically significant. All statistical analyses were performed using R (R Core Team (2022). R: a language for statistical computing. R Foundation for Statistical Computing, Austria) with the following packages: survival, tidycmprsk, jskm, and gtsummary.

RESULTS

Patient characteristics

In 631 (42%) out of the 1498 STEMI patients included in the EXAMINATION EXTEND trial, the LAD was the culprit vessel (LAD-STEMI group), whereas in 867 patients (58%) it was not (non- LAD-STEMI group). Patients’ inclusion flowchart is shown in figure 1.

Figure 1. Study flowchart. A total of 1498 patients were initially recruited. At 10 years, clinical follow-up was obtained in 95.2% of the patients. LAD, left anterior descending artery; STEMI, ST-elevation myocardial infarction.

LAD-STEMI group had a higher incidence of active smokers, advanced Killip class and more depressed LVEF vs the non-LAD-STEMI group, which, however, exhibited a higher incidence of peripheral vascular disease, previous MI and previous PCI (table 1). Also, although non-statistically significant, the frequency of late comers and bailout PCI was numerically higher in the LAD-STEMI group.

Table 1. Baseline clinical characteristics

Regarding procedural data, LAD-STEMI group received smaller stent diameter (3.12 mm vs 3.26 mm; P = .001) and had a lower incidence of ST-segment resolution than the non-LAD-STEMI group (73%, vs 50%; P = .001) (table 2). The use of GP IIb/IIIa inhibitors was numerically lower in the LAD-STEMI group, although the differences between groups were not statistically significant. Of note, almost half of the patients (46%) with LAD-STEMI had the lesion in the proximal LAD compared with 44% of them who had it in the mid/distal LAD.

Table 2. Angiographic and procedural characteristics

Ten-year outcomes

At the 10-year follow-up, POCE did not differ between LAD-STEMI and non-LAD-STEMI group (adjusted HR, 0.95; 95%CI, 0.79-1.13; P = .56) (figure 2). Moreover, no differences were found in terms of each individual component of POCE (all-cause mortality, MI, any revascularization) (figure 3) and other secondary endpoints (figure 1 of the supplementary data). Furthermore, when the expanded adjustment was performed and LVEF was included in the multivariable analysis, there were no inter-group differences between (table 3).

Figure 2. Central illustration. Outcomes of patients with ST-segment elevation myocardial infarction according to the culprit vessel at the 10-year follow-up. LAD, left anterior descending coronary artery; STEMI: ST-segment elevation myocardial infarction; POCE: patient-oriented composite endpoint.

Figure 3. Time-to-event curves for the patient-oriented composite endpoint (A), all-cause mortality (B), myocardial infarction (C), and any revascularization (D) in patients stratified according to the culprit vessel. LAD, left anterior descending coronary artery; MI, myocardial infarction; STEMI, ST-segment elevation myocardial infarction; POCE, patient-oriented composite endpoint.

Table 3. Ten-year outcomes

Landmark analyses

POCE landmark analysis showed no differences between the 2 groups across different time points. (figure 4A). Looking specifically at the various POCE individual components, the LAD-STEMI group exhibited a higher rate of all-cause mortality within the first year vs the non-LAD-STEMI group (p = 0.041), but this difference disappeared thereafter (figure 4B). Between years 0 and 1, there was also a trend toward a lower rate of myocardial infarction in the LAD-STEMI group vs the non-LAD-STEMI group (p = 0.081), which disappeared after year 1 (figure 4C). No differences were ever found regarding any revascularization (figure 4D) or other secondary endpoints between the 2 groups (figure 2 of the supplementary data).

Figure 4. Landmark analysis for the patient-oriented composite endpoint (A), all-cause mortality (B), myocardial infarction (C), and any revascularization (D) in patients stratified according to the culprit vessel. LAD, left anterior descending coronary artery; MI, myocardial infarction; STEMI, ST-segment elevation myocardial infarction; POCE, patient-oriented composite endpoint.

DISCUSSION

The main findings of this study can be summarized as follows: a) STEMI patients with LAD as the culprit vessel have a different baseline clinical profile vs STEMI patients with other culprit vessels; b) in the contemporary era of primary PCI, LAD as the STEMI-related culprit vessel did not bring worse very long-term outcomes compared with other coronary vessels; c) nevertheless, between years 0 and 1 the LAD-STEMI group exhibited a higher all-cause mortality rate, which disappeared thereafter compared with non-LAD-STEMI group.

Cardiology community knows (as reflected by the ESC guidelines on the management of acute coronary syndromes) that STEMI with LAD involvement as culprit vessel is a clinical marker of high risk of further events.1 LAD-related STEMI represents, approximately, 40% up to 50% of all STEMIs,12,16 and its worse prognosis has been related to the large myocardium covered by the LAD flow compared with the myocardium supplied by other coronary vessels. Of note, those studies were performed in the pre-reperfusion4-7 and early thrombolysis/PCI era,8,9 when PCIs were still not widely available. In the PCI era, there are very few studies (with short or mid-term follow-ups ranging from 1 to 3 years) reporting that LAD-STEMI is associated with an increased risk of stroke, heart failure, all-cause mortality10,17 and cardiovascular death11 after the PCI.

In our analysis, conducted in a cohort where the PCI was extensively performed, LAD as the STEMI culprit vessel did not appear to confer a worse prognosis to patients at the 1- or even 10-year follow-up. Of interest, LAD-STEMI patients exhibited the classical clinical features related to LAD, such as advanced Killip class at the time of presentation, lower ST-segment resolution and lower LVEF, which is similar to previous studies.8-11,17 All these unfavorable clinical characteristics are indeed related to the large amount of myocardium damaged in a LAD-STEMI with subsequent heart failure and ventricular arrhythmias.17-19 Nevertheless, this did not translate into a worse, very long-term clinical outcome. Significantly, even after accounting for variations in LVEF (which we addressed separately in our model due to its perceived role in the outcome cascade) the results showed no differences. This observation stands in contrast to earlier evidence, where the higher mortality rate in this cohort had been partially attributed to the subsequent decline in LVEF after STEMI.9,10

Several explanations may be claimed to understand our main finding. It may be hypothesized that worse outcome related to anterior STEMI may have been overcome by the introduction of the PCI with quick myocardial reperfusion. Pharmacological treatment has been also improved from thrombolysis to the PCI era, not only in terms of antiplatelet agents, but also in terms of secondary prevention (high intensity statins and angiotensin converting enzyme inhibitors/angiotensin receptor blockers or angiotensin receptor/neprilysin inhibitors for left ventricular dysfunction).20-23 Furthermore, in our study, the LAD-STEMI group had a higher proportion of active smokers. Smoking cessation remains the most critical preventive measure for coronary artery disease. The relationship between smoking and cardiovascular outcomes has been a matter of discussion, as some studies have suggested improved cardiovascular outcomes, even in the long term, among smokers who experienced STEMI.24 However, many of these studies were observational registries conducted in the pre-PCI era. Recent evidence indicates that smoking is associated with more post-PCI long-term adverse outcomes.25 Therefore, the so-called “smoker’s paradox” might be better explained by factors such as younger age and a lower prevalence of other risk factors among smokers. Indeed, in our study, while the LAD-STEMI group had a higher proportion of smokers, they had a lower prevalence of other risk factors, such as peripheral vascular disease and a history of prior PCI or MI.

Last, but not least, in landmark analysis we found that between years 0 and 1, all-cause mortality was more common in the LAD-STEMI group. Notably, in this period, there was a numerically higher number of cardiac deaths (although not statistically significant, P = .12), a similar finding to other existing evidence that found a higher relatively short-term mortality in the LAD-STEMI group within the first 30 days. In these studies, the elevated short-term mortality was associated with acute sequelae, such as heart failure and was also speculated to be connected to other lethal complications, such as ventricular arrhythmias, cardiogenic shock or mechanical complications.10,11 In our cohort, we found a trend towards a higher rate of reinfarction in the non-LAD-STEMI group (P = .081) that was largely unrelated to TLR, TVMI, or stent thrombosis. This observation contrasts with previous literature that reported a more common occurrence of reinfarction at the follow-up in patients with the SVG as the culprit vessel26 as well as the LAD,8 but not in LCx or the RCA.9-11

Our 10-year follow-up revealed similar clinical event rates between LAD-STEMI and non-LAD-STEMI group, indicating absence of long- term divergence. Previous studies showed a favorable post-acute phase prognosis for LAD-STEMI patients,10,11 which is consistent with our findings. In fact, non-cardiac factors seem to impact long-term mortality more than infarct location does.19 Thus, patients with STEMI should receive uniform management focused on secondary prevention strategies, regardless of the culprit vessel. Unfortunately, insufficient long-term data collection limits deeper insights into these outcomes (such as the presence of heart failure, optimal medical therapy, or other comorbidities).

Limitations

This study presents several limitations. First, this is a non-prespecified post-hoc analysis of the EXAMINATION-EXTEND study and therefore its conclusions must be considered only hypothesis generating. The association between infarction and outcomes may be driven by confounders which have not been recorded in the study. Then, several clinical and procedural characteristics were not available for the analysis, such as specified in-hospital or follow-up clinical data, like optimal medical treatment or compliance to medication at the follow-up.

CONCLUSIONS

In a contemporary cohort of STEMI patients, there were no differences in POCE between LAD as the STEMI-related culprit vessel and other vessels at the 10-year follow-up. However, within the first year after STEMI, all-cause death was more common in the LAD-STEMI group. Our results should be considered as hypothesis-generating. Further studies are needed to specifically assess the relationship between infarction location and outcomes in a contemporary setting where interventional and medical treatments are optimized.

FUNDING

The EXAMINATION-EXTEND study was funded by an unrestricted grant of Abbott Vascular to the Spanish Society of Cardiology (promoter). P. Vidal Calés has been supported by a research grant provided by Hospital Clínic at Barcelona, Spain.

ETHICAL CONSIDERATIONS

The study fully complied with the Declaration of Helsinki and was approved by our Institutional Review Committee. All patients signed a written informed consent form before being included in this study. The clinical ethics committee gave its approval for the analysis of the data collected. In this work, SAGER guidelines regarding sex and gender bias have been followed.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

No artificial intelligence tools were used during the preparation of this work.

AUTHORS’ CONTRIBUTIONS

The authors declare they meet the full criteria and requirements for authorship and have reviewed and agree with the content of the article. P. Vidal Calés, K. Bujak, R. Rinaldi, A. Salazar Rodríguez, S. Brugaletta and M. Sabaté contributed to conceptualization, design, data analysis and drafting of the manuscript. L. Ortega-Paz, J. Gómez-Lara, V. Jiménez-Diaz, M. Jiménez, P. Jiménez-Quevedo, R. Diletti, P. Bordes, G. Campo, A. Silvestro, J. Maristany, X. Flores, A. De Miguel-Castro, A. Íñiguez, A. Ielasi, M. Tespili, M. Lenzen, N. Gonzalo, M. Tebaldi, S. Biscaglia, R. Romaguera, J.A. Gómez-Hospital and P. W. Serruys reviewed and edited the manuscript.

CONFLICTS OF INTEREST

M. Sabaté declares he has received consulting fees from Abbott Vascular and iVascular outside the submitted work. R. Romaguera is associate editor of REC: Interventional Cardiology. The journal’s editorial procedure to ensure impartial handling of the manuscript has been followed. The rest of the authors declared no conflicts of interest whatsoever.

SUPPLEMENTARY DATA

REFERENCES

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