Transcatheter Mitral Valve Repair With MitraClip: Comparison of NT, NTr, and XTr Devices

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J INVASIVE CARDIOL 2024. doi:10.25270/jic/24.00020. Epub April 8, 2024.

Objectives. Transcatheter edge-to-edge repair (TEER) has become an established minimally invasive treatment for significant mitral regurgitation. Ongoing refinements and the availability of different clipping devices have expanded the indications for and effectiveness of TEER, but comprehensive comparative data on this issue are lacking. In this study, we compared NT, NTr, and XTr MitraClip devices (Abbot) for TEER.

Methods. Details on patient, imaging, and procedural details, as well as short- and long-term outcomes, were sought from a national prospective clinical registry on TEER with MitraClip. The primary outcome of interest was discharge after procedural success without major clinical complications.

Results. A total of 2236 patients were included, 1228 (54.9%) in whom NT implantation only was attempted, 233 (10.4%) in whom NTr but not XTr implantation was attempted, and 775 (34.7%) in whom XTr implantation was attempted. Clinical and imaging features differed substantially across the groups, reflecting expanding indications with NTr and XTr devices. In-hospital outcomes were largely similar among the 3 groups, including death. Long-term unadjusted estimates of effect showed significant differences in several outcomes, including death, rehospitalization, and their composite, which demonstrated that NT was associated with more unfavorable outcomes compared with the other devices (all P < .05). However, most differences depended on baseline features, as adjusted analysis showed no significant differences for early as well as long-term outcomes, including long-term death, rehospitalization, and their composite (all P > .05).

Conclusions. New-generation MitraClip devices are associated with favorable procedural and clinical outcomes, despite being used in patients with more adverse features, when compared with patients treated with previous devices.

Mitral regurgitation is the most prevalent valvular heart disorder, and it is associated with significant morbidity and mortality.^{1, 2} Transcatheter edge-to-edge mitral valve repair (TEER) with the MitraClip (Abbott) device and, more recently, the Pascal (Edwards Lifesciences), has revolutionized mitral regurgitation treatment.^3-8 Indeed, TEER is now a recommended intervention in all patients with significant mitral regurgitation who are considered at increased surgical risk, as long as adequate valve features are present.⁹

Successive device iterations, such as the availability of the Mitraclip NT, NTr, and XTr clipping systems, have brought about critical enhancements in design and functionality, including ease and reliability of deployment, promising improved patient outcomes, optimized procedural results, and long-term event rate.^4-6 The NT was similar to the first-generation MitraClip device, but boasted nitinol grippers for increased grasping ease and gripper opening up to 120 degrees. The NTr included refinements in delivery catheter features to increase stability, whereas the XTr boasted a longer total clip length of 18 mm with a coaptation length of 12 mm while maintaining a 120-degree gripper angle, suitable to reach a total diameter of 22 mm.¹⁰ Due to these refinements, more patients have become eligible for TEER, and acute and long-term results have remarkably improved, at least according to small series and reports focusing on the short-term outlook.¹¹

However, whether the ongoing refinements in the MitraClip may actually translate into eligibility for TEER and improvements in clinical outcomes remains unclear, as no formal and dedicated comparative effectiveness study has been reported on this important topic to-date. Thus, we sought to leverage the Italian multicenter GIse registry Of Transcatheter treatment of mitral valve regurgitation (GIOTTO), an established prospective observational cohort study that includes thousands of patients treated over several years with MitraClip, to formally compare patient, procedural, and outcome features of TEER using the MitraClip NT, NTr, and XTr devices.^12-14

This work was designed as a secondary analysis of the Italian prospective multicenter observational GIOTTO registry on TEER with MitraClip, which has been sponsored over several years by the Italian Society of Invasive Cardiology (GISE – Società Italiana di Cardiologia Interventistica, Milan, Italy).¹² The study is registered online (NCT03521921), all participating institutions have obtained ethical approval, as appropriate, and all patients provided written informed consent for inclusion.

The details on the study methods have been provided already in detail elsewhere.^12-17 Briefly, all patients in whom TEER with MitraClip was attempted were included, and detailed baseline, imaging, procedural, and outcome data were entered into a dedicated electronic case report form, which was developed and is maintained by Air-Tel. Given the pragmatic nature of the registry, no formal clinical monitoring was conducted, but data were routinely verified for consistency and completeness.

We divided patients according to attempted implantation of a given device. Accordingly, patients in whom neither NTr nor XTr implantation was attempted were entered into the NT group (which also also first-generation MitraClip devices), whereas patients in whom XTr implantation was attempted were entered into the XTr group. Accordingly, patients in whom NTr but not XTr had been attempted were included in the NTr group.

For the purposes of this work, we focused on clinical and procedural outcomes. Notably, procedural outcomes included attempted, failed, and successful implantation of the different types of MitraClip devices, as well as  device success, procedural success, partial device detachment, and device embolization. Among the short-term clinical outcomes, we focused on procedural death, bailout mitral valve surgery, any bleeding, minor bleeding, major bleeding, disabling bleeding, red blood cell transfusion, any vascular complication, minor vascular complication, major vascular complication, vessel perforation, femoral pseudoaneurysm, stroke, transient ischemic attack, cardiac tamponade, myocardial infarction, in-hospital death, and total hospital stay. Imaging outcomes included severity of mitral regurgitation, mitral gradient, left ventricular ejection fraction, and systolic pulmonary artery pressure. To determine long-term outcomes, we collected details on death, cardiac death, mitral valve surgery, heart transplantation, endocarditis, rehospitalization, rehospitalization for heart failure, heart failure, death or rehospitalization, cardiac death or rehospitalization for heart failure, and New York Heart Association class; we also considered mitral regurgitation grade, mitral gradient, tricuspid regurgitation, left ventricular ejection fraction, and systolic pulmonary artery pressure. Definitions abided by the guideline recommendations that were available and applicable during the pertinent study conduct.

The descriptive analysis was based on the computing mean ± standard deviation for continuous variables and count (%) for categorical variables. Inferential analysis was based on the computing analysis of variance and post-hoc unpaired t tests for continuous variables, and Fisher exact tests and logistic regression for categorical variables. Survival analysis was based on the Kaplan-Meier method and computing log-rank tests and hazard ratios stemming from the Cox proportional hazard analysis. Inverse probability of treatment weighting was used to perform adjusted head-to-head comparisons between the NT, NTr, and XTr groups. Statistical significance was set at the 2-tailed 0.05 level, without multiplicity adjustments, and no missing data imputation was carried out. Computations were performed with Stata 13 (StataCorp, College Station).

A total of 2236 patients undergoing TEER between January 2016 and June 2023 were included; of these patients, there were 1228 (54.9%) in whom NT implantation only was attempted, 233 (10.4%) in whom NTr but not XTr implantation was attempted, and 775 (34.7%) in whom XTr implantation was attempted (Table 1, Supplemental Table 1). Significant differences were found in the baseline features, including age, etiology of mitral valve disease, functional class, surgical risk score, prior pacemaker implantation, prior implantable cardioverter defibrillator implantation, diabetes mellitus, dyslipidemia, hypertension, smoking history, aortic valve disease, prior myocardial infarction, prior hospitalization for heart failure, history of coronary artery disease, prior coronary revascularization, prior coronary artery bypass grafting, prior mitral valve repair, presence of a hostile chest, and frailty (all P < .05). These differences typically favored the NT group, such that the patients in the XTr group and, to a lesser extent, those in the NTr group, had worse baseline profiles than those in in the NT group.

As expected, similarly significant differences were found in the other baseline features, including frequency of left bundle branch block at electrocardiogram, measures of left ventricular dimensions and ejection fraction, presence of tethering, leaflet prolapse, tricuspid regurgitation at echocardiography, and extent of coronary artery disease at coronary angiography (all P < .05; Table 2, Supplemental Table 2). A comparative analysis of these features suggested a more complex scenario, with some adverse characteristics more common in the NT group (eg, tethering) and others more frequent in the NTr and XTr group (eg, left main disease and leaflet prolapse, respectively). Indeed, while the NT was used earlier than the NTr and XTr for market access reasons, once available, the NTr and XTr enabled an expansion of indications in terms of valve dysfunction.

Procedural features are detailed in Table 3 and Supplemental Table 3. As expected, several differences in such details were found among the 3 groups, including the total number of MitraClip devices eventually implanted, which was 1. 8± 0.7 in the NT group, 1.5 ± 0.6 in the NTr group, and 1.6 ± 0.6 in the XTr group (P < .001). Nevertheless, mitral regurgitation at the end of the procedure was similarly reduced, with residual 3+ or 4+ grade in 62 (5.1%), 9 (3.9%), and 38 (4.9%, P = .612) patients from the NT, NTr, and XTr groups, respectively. Table 4 and Supplemental Table 4 detail in-hospital outcomes, which were largely similar among the 3 groups, including in-hospital death, overall, and according to etiology and COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) trial eligibility (Figure 1). However, total hospital stay was shorter and the discharge left ventricular ejection fraction greater in the XTr group, whereas mitral regurgitation 3+ or 4+ was less prevalent in the NTr group, especially when considering COAPT ineligible patients (all P < .05). Discharge therapy, which varied across the years and thus among the groups under study, is presented in Supplemental Table 5.

Long-term outcomes were collected over several months of follow-up, which varied substantially (the average follow-up range from 10-24 months among the 3 groups) given the introduction of different devices over the years (Table 5, Supplemental Table 6). Unadjusted estimates of effect showed significant differences in several outcomes, including death, cardiac death, rehospitalization, rehospitalization for heart failure, heart failure, death or rehospitalization, cardiac death or rehospitalization for heart failure, functional class, and left ventricular ejection fraction, which all indicated more unfavorable outcomes in the NT group (all P < .05). Figure 2 shows the Kaplan-Meier failure curves for death (all P > .05), and Figure 3 shows the Kaplan-Meier failure curves for death or rehospitalization (all P > .05).

Adjusted effect estimates suggest that most of the differences quoted beforehand depend on baseline features (Supplemental Table 7), as no significant differences after inverse probability of treatment weighting were found for device success, procedural success, in-hospital death, long-term death, cardiac death, rehospitalization, rehospitalization for heart failure, heart failure, death or rehospitalization, and cardiac death or rehospitalization for heart failure (all P > .05).

TEER with MitraClip, despite its remarkable safety in most anatomic and clinical scenarios, has seen many iterative refinements aimed at maximizing procedural ease and, most importantly, expanding indications and optimizing acute and long-term results.^18-22 Changes to the clip itself have been substantial, as evidenced by the NTr and XTr devices, which, along with the NT device, offer the opportunity for improved leaflet capture and coaptation, and eventually better outcomes, at least in terms of procedural results.^4-6,10 However, limited data are available on  the comparative performance of NT, NTr, and XTr MitraClip devices.

Our study, using data from a national registry, shows that both the NTr and XTr are often used in patients undergoing TEER. Access to NTr and XTr devices has occurred concomitantly with expanded patient access to TEER. Accordingly, patients treated with NTr and XTr devices presented on average a worse clinical risk profile and a higher prevalence of high-risk features compared with  individuals treated with the NT device. With the improvements in materials, delivery systems, and the improved grasping and coaptation surface of the XTr because of its longer clip arm length, the MitraClip can now be used to treat patients with more severe mitral regurgitation, with the XTr typically reserved for patients with more advanced disease and severe valve features.

Imaging features were also strikingly different between the 3 groups under investigation, albeit with a more complex pattern of non-univocal interpretation. Despite some apparent differences in procedural features, including fewer devices being implanted in the NTr and XTr groups, adjusted comparisons did not show any significant difference between the 3 groups in early and long-term outcomes. These findings can be interpreted as a demonstration of the safety of NTr and XTr devices, and thus support their expanded use. Most importantly, by adopting a broader perspective and considering the baseline differences and similar outcomes at adjusted analysis, our study shows that the availability of the NTr and XTr devices may lead to a significant expansion of eligibility and indication for TEER with MitraClip, without paying a price in terms of procedural success and early or long-term outcomes.^23-25 The need for multiple MitraClip devices in the same individual is also worth mentioning. This event was relatively uncommon, and typically occurred in patients with worse regurgitation severity and proportionality, larger mitral valve area, and presence of flail leaflet, as also previously reported.¹⁵

Limitations. Despite the strengths of the GIOTTO registry, which has been already the subject of several peer-reviewed publications and the meticulous analysis conducted for the present study, this work has several limitations. First, the decision to attempt implantation of the NT, NTr or XTr devices was operator-dependent and not based on randomized allocation. Thus, despite careful adjusted analyses, we cannot rule out the potential effect of unmeasured confounders. Furthermore, enrolment in GIOTTO has continued over several years, and this implies that management strategies have changed over the course of time, ranging from procedural aspects to ancillary pharmacologic therapy. In this case as well, multivariable adjustment techniques have a distinct yet imperfect inferential role. By design, the GIOTTO study did not include any patient receiving last-generation MitraClip devices (ie, NTW and XTW).^26-27 While a novel Italian registry dedicated to such Generation 4 MitraClip devices is currently underway, appraisal of their comparative effectiveness is clearly beyond the scope of our present work. Among other limitations, mitral valve area after MitraClip implantation was not systematically measured, and thus we were not able to analyze or report on that factor. Finally, lack of independent clinical monitoring and imaging core lab analysis should be acknowledged, as well as the follow-up, which is not yet sufficient to gauge the long-term impact of different MitraClip generation devices.

New-generation MitraClip devices are associated with favorable procedural and clinical outcomes despite being used in patients with more adverse features than in the past. These findings support expanding the indications for TEER with MitraClip and lowering the threshold for its use in clinical practice

From the ¹Unità Operativa di Interventistica Cardiovascolare, Pineta Grande Hospital, Castel Volturno, Italy; ²Unità Operativa di Emodinamica, Santa Lucia Hospital, San Giuseppe Vesuviano, Italy; ³Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy; ⁴Cardiology Unit, Santa Maria Goretti Hospital, Latina, Italy; ⁵Department of Cardiac Surgery, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy; ⁶Department of Cardiology, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy; ⁷Centro Cardiologico Monzino, IRCCS, Milan, Italy, and Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy; ⁸Division of Cardiology, Department of Medical and Surgical Sciences, "Magna Graecia" University; ⁹Division of Interventional Cardiology, Azienda Ospedaliera S. Camillo Forlanini, Rome, Italy; ¹⁰Cardiac Catheterization Laboratory and Cardiology, ASST Spedali Civili di Brescia, and Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health University of Brescia, both in Brescia, Italy; ¹¹Interventional Cardiology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy; ¹²Heart Department, University Hospital 'Scuola Medica Salernitana', Salerno, Italy; ¹³Department of Cardiac, Thoracic and Vascular Science, Interventional Cardiology Unit, University of Padua, Padua, Italy; ¹⁴Division of Cardiology, IRCCS Ospedale Galeazzi - Sant'Ambrogio, Milan, Italy; ¹⁵Interventional Cardiology, Department of Cardio-Thoracic and Vascular Sciences, Ospedale dell'Angelo, AULSS3 Serenissima, Mestre, Venezia, Italy; ¹⁶Divisione di Cardiologia, A.O. dei Colli, Ospedale Monaldi, Napoli; ¹⁷Cardiac Surgery Unit and Valve Center, Poliambulanza Foundation Hospital, Brescia, Italy; ¹⁸Division of Cardiology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy; ¹⁹Cardiovascular Department, Papa Giovanni XXIII Hospital, Bergamo, Italy; ²⁰Interventional Cardiology Unit, GVM Care & Research, Maria Cecilia Hospital, Cotignola, Italy; ²¹Division of Cardiology, Centro Alte Specialità e Trapianti (CAST), Azienda Ospedaliero-Universitaria Policlinico-Vittorio Emanuele, University of Catania, Catania, Italy.

Disclosures: Dr Biondi-Zoccai has consulted for Amarin, Balmed, Cardionovum, Crannmedical, Endocore Lab, Eukon, Guidotti, Innovheart, Meditrial, Microport, Opsens Medical, Terumo, and Translumina, outside the present work. Dr Adamo has received speaker fees from speaker fees from Abbott Structural Heart. Dr Montorfano received consultant fees from Abbott, Boston Scientific, Kardia, and Medtronic.  The remaining authors report no financial relationships or conflicts of interest regarding the content herein.

Funding: The GIOTTO (GIse registry Of Transcatheter treatment of mitral valve regurgitaTiOn) registry is sponsored by the Italian Society of Invasive Cardiology, with an unrestricted grant by Abbott Vascular.

Address for correspondence: Giuseppe Biondi-Zoccai, MD, MStat Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy. Email: giuseppe.biondizoccai@uniroma1.it; X: @gbiondizoccai