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International Journal of Cardiovascular ResearchISSN: 2324-8602

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Research Article, Int J Cardiovas Res Vol: 6 Issue: 2

Early and Mid-Term Safety and Efficacy Outcomes After Mitra Clip Implantation in a Real- World Patient Cohort with High Surgical Risk – Insights from the Dresdner Mitra Clip Registry

Wiedemann S*$, Heidrich FM*$, Ebert D, Melz C, Sveric KM, Pfluecke C, Katzke S and Strasser RH
Department of Internal Medicine and Cardiology University of Dresden, heart center university hospital, Dresden, Germany
§ equally contributing authors
Corresponding authors: Dr. S. Wiedemann
Heart Center University Hospital at Technische Universität Dresden, Fetscherstraße 76, 01307 Dresden, Germany
Tel: +49351-4500
Fax: +49351-4501702
E-mail: [email protected]

Dr. F. M. Heidrich
Heart Center University Hospital at Technische Universität Dresden, Fetscherstraße 76, 01307 Dresden, Germany
Tel: +49351-4500
Fax: +49351-4501702
E-mail: [email protected]

Received: December 07, 2016 Accepted: January 06, 2017 Published: January 14, 2017
Citation: Wiedemann S, Heidrich FM, Ebert D, Melz C, Sveric KM, et al. (2017) Early and Mid-Term Safety and Efficacy Outcomes After Mitra Clip Implantation in a Real-World Patient Cohort with High Surgical Risk – Insights from the Dresdner Mitra Clip Registry. Int J Cardiovasc Res 6:1. doi:10.4172/2324-8602.1000301

 

Abstract

Background: MitraClip therapy has recently gained clinical attention after EU and US approval. The Dresdner MitraClip registry reflects real world clinical demographic findings and midterm outcomes in an older patient cohort at high or prohibitive surgical risk with mixed mitral regurgitation (MR) etiology. Methods and results: A retrospective data analysis was conducted for consecutive patients with severe MR treated with the MitraClip system in a single institution between 08/2012 and 08/2015. 160 patients (46% ischemic cardiomyopathy (ICM), 22% dilative cardiomyopathy (DCM) and 32% degenerative mitral regurgitation (DMR) participated in this study. Patients in the ICM group had a significantly higher EURO-II-Score (22 (ICM) vs. 15 (DCM) vs 13 (DMR), p<0,05), representing a more complex comorbidity profile. MitraClip implantation was successful in 97 % of patients among all groups with low peri-procedural complication rates (0,9% for stroke, myocardial infarction). No case of total clip embolization, death or conversion to open heart surgery occurred. There was a significant improvement of MR-severity in all groups when compared to baseline. About 59% of patients achieved NYHA class 2 or less. During 6-month follow up, cumulative mortality for all patients was 13,1%, with a significant higher mortality rate for patients with ICM (18,9 vs. 11,4% DCM; 5,9% DMR, p<0,05). In conclusion, in this real-world cohort of elderly patients at high surgical risk, the MitraClip procedure appears to be safe, feasible and quite effective with low major adverse event rates and positive mid-term results. Patients with reduced LVEF (<30%) and ICM are at the highest risk.

Keywords: Mitral regurgitation; Edge-to-edge-repair; MitraClip; Interventional repair

Keywords

Mitral regurgitation; Edge-to-edge-repair; MitraClip; Interventional repair

Introduction

Severe mitral regurgitation (MR) is strongly associated with progressive left ventricular (LV) dysfunction and negative LVremodeling in symptomatic and asymptomatic patients [1,2].
In patients with moderate-to-severe (3+) or severe (4+) MR which are associated with symptoms or evidence of LV dysfunction [3], symptomatic optimal medical treatment does not prevent disease progression [4] and (4)frequently leads to increased rates of rehospitalization for heart failure [2]. Although surgical correction is the standard treatment in primary severe MR, treatment in secondary MR remains controversial [5] due to a lack of evidence on a clear prognostic benefit and high rates of MR-recurrence [6]. Surgical outcomes depend on the MR-mechanism, the surgeons experience and repair-technique as well as patient’s co-morbidities. Among high-risk patients who undergo mitral valve surgery, the number of co-morbidities and age are relevant prognostic factors for patients’ morbidity and mortality. Approximately 50% of patients older than 70 years with severe symptomatic MR were denied valve surgery in a large European trial [7,8].
Percutaneous edge-to-edge mitral valve repair with the MitraClipsystem (Abbott Laboratories. Abbott Park, Illinois, U.S.A.) has emerged as an alternative to conventional surgery for selected patients with symptomatic MR and suitable anatomic criteria [9-11]. With >30,000 implantations performed worldwide, the MitraClip is a viable and less invasive interventional therapeutic option for inoperable or highrisk surgical patients [10]. In the Endovascular Valve Edge-to-Edge Repair (EVEREST) I and II studies [10,11], a majority of patients had degenerative MR and intermediate- to low risk profiles with preserved ejection fraction. However, the EVEREST II trial is the first randomized controlled trial of percutaneous versus surgical mitral valve reconstruction or replacement of severe MR. Mortality and rates of higher residual degree MR (3+ or 4+) between both groups were similar at 12 months even though the MitraClip-group had a lower primary end point for efficacy compared with surgically treated patients. Nevertheless, the efficacy and safety of percutaneous MV repair with the MitraClip-system was demonstrated in these trials. Current American and European guidelines recommend that edgeto- edge MV repair with the Mitraclip-System may be considered in patients with significant MR at high or prohibitive surgical risk in addition to optimal medical therapy [12]. Many observational studies have also demonstrated the feasibility and safety of edge-to-edge repair in the context of functional MR and/ or LV dysfunction [13-19]. However, different subgroups of MR including the very old patients or those with ischemic heart failure may be less suitable for MitraCliptherapy than other patients. In Europe and the USA, data on real world patient cohorts regarding early and mid-term outcomes are lacking. Against this background, we aimed to assess the 30-day and 6-month clinical and echocardiographic outcomes after MitraClip implantation in a real-world scenario with an older consecutive patient cohort with a higher surgical risk and with mixed MR etiology.

Materials and Methods

Patients and procedures
The non-randomized Dresdner MitraClip registry was established in 2012 to assess the safety and efficacy of the interventional catheterbased Mitraclip implantation. Consecutive patient enrollment started in July 2012 and ended in August 2015. Six month follow up data were collected during routine follow up visits in our outpatient clinic or through standardized telephone interviews.
160 patients with severe and symptomatic MR were enrolled in this single center, retrospective observational study in accordance with the Guidelines for Good Clinical Practice and the Declaration of Helsinki. The patients were recruited through screening for participation in a retrospective observational study comparing the efficacy of MitraClip in patients with severe MR. The study protocol was approved by the local ethics committee (# EK 373092013). All patients received a complete oral and written explanation of the issues in the context of the procedure. All participating patients provided written informed consent. All data were collected, managed and analyzed at the Heart Centre University hospital, University of Dresden.
Patients with symptoms or signs of LV deterioration and grade 2+ or 3 MR, which was determined by combined transthoracic and transesophageal echocardiography [20], and considered at high or prohibitive surgical risk by the clinic’s interdisciplinary heart team underwent percutaneous edge-to-edge mitral valve repair with the MitraClip system from August 1, 2012 to August 31, 2015.
The primary objective of this study was to evaluate the effect of MV repair using the MitraClip system on MR severity in various etiologic subgroups of MR in order to differentiate patients/patient subgroups that may benefit most and those who may be less suitable for MitraClip-therapy than others. Patients with functional mitral regurgitation (FMR) and normal to severely reduced ejection fraction (LV-EF<30%) were compared to controls with degenerative mitral regurgitation (DMR) and preserved or reduced left ventricular function in a real world scenario.
Severity of MR was defined according to current recommendations [21] in 3 degrees: I° mild MR, II° moderate MR and III° severe MR. Qualifying inclusion and exclusion criteria for MitraClip therapy (clinical and echocardiographic), as well as details of the procedure have been previously reported [22]. Data were collected in the MitraClip electronic database of Dresden Heart Center Hospital.
Echocardiographic data were analyzed separately by a team of 2 expert echocardiographers and reviewed by a third experienced reader for consensus when there was a disagreement. The MitraClip system received CE Mark in 2008 for interventional repair of MR.
The study groups were defined based on mitral valve etiology: ischemic (ICM), dilative cardiomyopathy (DCM) or degenerative mitral regurgitation (DMR). Baseline characteristics are summarized in Table 1. Clinical and echocardiographic outcomes prospectively collected at 30-day and 6-month follow-ups were then compared between these 3 groups. Most importantly, the Dresdner MitraClip registry is independent of industry sponsors.
Table 1: Baseline characteristics.
Endpoints
Acute device success was defined as residual MR ≤ 2+ after clip implantation, freedom from interruption of clip-procedure, conversion to open surgery or failure due to other reasons (classified by the interventional cardiology team, i.e. non-significant MR reduction, partial clip detachment).
The primary safety endpoint was the incidence of major adverse events at 30 days, defined as the composite of death, myocardial infarction, nonelective cardiovascular surgery for adverse events, stroke, renal failure, respiratory failure i.e. mechanical ventilation for >48 h, need for resuscitation, cardiac effusion or tamponade and bleeding complications with transfusion of ≥ 2 units of blood.
The primary efficacy endpoint was freedom from death or surgery fmitral valve dysfunction, or grade ≥ 2+ MR at 6-month follow-up after clip implantation, whereas the same parameters were evaluated as a secondary efficacy endpoint at 30 days.
Statistical analysis
Continuous variables following a normal distribution are presented as mean ± SD and were compared using the Student unpaired t test for comparisons between groups and paired t test for within-group comparisons. Variables that did not follow a normal distribution were compared with a Mann-Whitney U test for comparisons between groups and a Wilcoxon signed rank test for within-group comparisons. Categorical variables are presented as counts and percentages and were compared by the chi-square or the Fisher exact test. Survival curves were generated using the Kaplan-Meier method, and log-rank tests were used to evaluate differences between groups. A 2-way repeatedmeasures analysis of variance was used to evaluate the effects of time (baseline vs. 30-day follow-up vs. 6-month follow-up) and group (DMR vs FMR) on echocardiographic and clinical variables, and posthoc analysis was performed with Bonferroni correction. All p values reported are 2-sided, and p values <0.05 were considered significant. All data were processed using the Statistical Package for the Social Sciences (version 21 (SPSS Inc., Chicago, Illinois)

Results

Baseline characteristics
From July 2012 to August 2015, a total of 160 consecutive patients were included prospectively into the Dresdner MitraClip registry.
Baseline characteristics are displayed in Table 1. The mean age was 78 years (57-97 years), with an increased percentage of males in the ischemic cardiomyopathy group (69%).
Of all patients enrolled in this registry, 74 (46%) suffered from ischemic cardiomyopathy (ICM), with a mean left ventricular ejection fraction (LVEF) of 30,8% and elevated Euro-2- score of 22%. Patients with dilative cardiomyopathy (DCM) and degenerative mitral regurgitation (DMR) showed a mean LVEF of 32,5% and 55,2%, respectively. Euro-2- score in the two groups were 15% and 13%. Baseline clinical characteristics were well balanced between the groups (Table 1). However, marked differences were present in echocardiographic parameters of the DMR group compared to functional mitral regurgitation (FMR) groups (ICM, DCM) with significantly smaller dimensions of LVESD and LVEDD, as well as better LV-EF and a non-significant trend towards more severe MR grade 3+. ICM patients showed a significantly worse right ventricular systolic function (TAPSE). No differences were noted, however, in the baseline distribution of New York Heart Association (NYHA) functional classes between the groups (Table 1).
Patient assignment
Patient allocation to treatment group (open-heart surgery, percutaneous therapy or best medical therapy) was based on the decision of the local interdisciplinary heart team. Common reasons for denying surgery to patients included high surgical risk profile (log. EuroScore2>12), age and/or frailty, previous cardiac surgery or inoperability or patient`s preference.
In-hospital and 30-day outcome
Acute device success: The MitraClip procedure was successful in 97 % of patients among all groups, with success defined as a significant reduction of MR, a residual MR grade 2 or less, and an absence of disruption to the MitraClip procedure or conversion to open heart surgery. Partial clip detachment occurred in only 2 patients (one DCM, one ICM group), respectively. On average, procedural time was 60,6 ± 30,8 min, and at mean, 1,77 ± 0.63 clips per patient were implanted.
Primary safety endpoint: Specific peri-procedural complications are shown in Table 2. Overall, the procedural complication rate was very low at 0.9% for stroke and myocardial infarction. No case of total clip embolization or conversion to open heart surgery occurred. Singleleaflet clip attachment (SLCA) was observed in two cases (1,25%).
Table 2: Major adverse events within 30 days after MitraClip-implantation.
The median length of hospital stay was 10,4 days [IQR 2-42 days] and the mean length of ICU stay was 2,1 days (+-4 days). At 30 days, cumulative mortality was 1,9%, with 2 patients in the ICM group. Incidence of other complications did not differ between other groups. Specific outcome data are shown in Table 3.
Table 3: Major adverse events within 6 month.
Six month outcome
At six months, follow-up could be completed in 144 patients (90.2%) at a median of 181 days after MitraClip implantation. With regard to the missing individuals, 16 patients were omitted from the follow up due to consent withdrawal.
Cumulative mortality at 6 months for all patients was 13,1%, with a significant higher mortality rate for patients with ischemic cardiomyopathy 22% vs. 14,9% in patients with dilative cardiomyopathy and 5,8% in patients with DMR, respectively (Figures 1 and 2). The mechanism of MR did not have primary influence on primary device implant success rates, but at 6 months follow-up mortality raised up in the ICM group, even in patients with severely reduced LVEF <30%.
Figure 1: Event free survival curves in the 6 month follow up period shows an increased mortality in FMR-groups (ICM and DCM), compared with DMR group. DMR=degenerative mitral regurgitation; FMR=functional mitral regurgitation; DCM=dilative cardiomyopathy; ICM=ischemic cardiomyopathy; postop= postoperative period; d=day.
Figure 2: Event free survival curves in the 6 month follow up period shows an increased mortality in ICM-subgroup with severe LVEF.(ICM with mildto- moderate impaired LVEF >30% and ICM with severe LVEF impairment EF<30%.) ICM=ischemic cardiomyopathy; postop= postoperative period; d=day.
Most patients achieved a sufficient MR reduction to grade 2 or less at discharge and in the 6-month follow up visits, only a few patients had recurrent MR grade 3 (Tables 3 and 4). There was a significant improvement in MR severity at 6 months, compared with baseline MR. NYHA functional class improvement was similar across all subgroups in more than 73 percent of patients at 6 months compared to the baseline. Approximately 59% patients achieved NYHA class 2 or less, and about 21% were in class NYHA I. The echocardiographic parameters right ventricular systolic pressure (RVSP) and tricuspidal regurgitation (TR) were not significantly affected after MitraClip implantation (Table 4). However, we found no significant improvements in this area instead a trend towards reduced TR severity and reduced RVSP, suggesting a reduction of pulmonary congestion secondary to MitraClip implantation.
Table 4: Follow up data.

Discussion

Surgical repair or valve replacement represents the gold standard for most patients with symptomatic and severe MR. Surgical results are excellent in patients with restored left ventricular function and small LVEDD<55mm [23]. In patients with poor LV-function (LVEF<30%) or ischemic cardiomyopathy, conventional surgery is associated with higher rates of recurrent MR and increased peri-,and postoperative mortality [24,25]. Percutaneous edge-to-edge MV repair with the MitraClip system has gained attention as an alternative method for patients with increased surgical risk due to age and comorbidities or those rejected for surgery. This trans-catheter mitral valve repair technique was inspired by the surgical “Alfieri stitch”, where the two mitral leaflets were connected through a suture with durable results in short and long-term outcome [26-28].
In the Everest II study, the first randomized trial for MitraClipsystem, 279 patients with severe MR grade 3-4 were enrolled [10,11]. With a randomization to surgical or percutaneous treatment, MitraClip was compared to valve repair or replacement in mainly degenerative (primary) MR with low risk patients profile and only moderately reduced to preserved ejection fraction. MitraClip was associated with a higher rate of residual MR during first year follow up. However, occurrence of residual MR was similar to surgery during the 1-5 year follow up. Symptomatic improvement was congruent to surgical treatment; safety endpoints with the percutaneous technique were lower mostly due to higher need for blood transfusions in the surgical group. Of note, freedom from death, repeat surgery or residual MR grade 3 or 4+ at four and five years follow-up was lower in the MitraClip group (39,8% vs. 53,4%, p=0.07, respectively) [29] although the Mitraclip-group had an interventionalists learning curve in opposite to surgical treatment, which was performed only in experienced heart surgery centers.
Compared to other registries and prospective trials, the Dresdner MitraClip-registry is an industry-independent, large prospective single center cohort of real-world (“all-comers”) patients treated by edge-to-edge MV repair judged by local heart team decision with the MitraClip-system. Despite the older and sicker patient cohort treated in this registry compared to other studies, our data show that the MitraClip procedure is a safe and feasible alternative for these patients at higher or prohibitive surgical risk. The edge-to-edge repair was effective in most patients with low rates of adverse events and substantial and persistent improvement in functional status, NYHAclass and hemodynamics. Data from the Dresdner MitraClip registry could demonstrate:
The MitraClip technique is safe and feasible for older and high risk surgical patients with low 30-day incidences of MAEs and a >95% successful implantation rate. Essential preconditions for success include meticulous patient screening, high investigator experience and careful usage of MitraClip-technique. Screening for the cause of MR – ischemic, dilative or degenerative valve transformation is an essential tool for clip strategy, post-interventional follow up and medical treatment. The Dresdner MitraClip-registry offers valuable insights into current real-life patient cohorts and is as such representative for patients treated with the MitraClip system in Germany. In contrast to the EVEREST trials and other comparable registries such as GRASP, TRAMI or ACCESS-EU, patients from the Dresdner MitraClipregistry have a higher mean age (78 years), a worse LV-function (68% of patients had LV-EF<40%) and other various comorbidities (32-34). Pre-interventional perioperative mortality assessed by Euro-2-Score [30], a more precise score for perioperative mortality assessment, was 16,7 % in the entire cohort with the highest values in patients with ICM (22%) (Figure 1). These data are comparable with the EVEREST high risk study [31], in which patients had a mean age of 77, an increased surgical risk in STS-score >12% and multiple comorbidities. Compared to the Dresdner MitraClip registry, this patient cohort had a different etiology of MR (EVEREST patients had a different leading MR etiology distribution (FMR 59%)) and the number of patients included was substantially lower (78pts.).
Despite a higher age and more complex comorbidities expressed in high Euro-II Score, our data shows that the rate of adverse events within 30 days after the MitraClip procedure and in mid-term follow up remained very low, with a 30-day mortality rate as low as 1,9% in the ICM group among high risk patients. Compared with other registries [32-34], event rates of periprocedural complications in this old patients cohort with higher surgical risk were analogous with 0.9% for stroke and myocardial infarction. No case of total clip embolization or conversion to open heart surgery occurred. Single-leaflet clip attachment (SLCA) was observed in only two cases (1.25%). Mean length of hospital stay was 10.2 days, suggesting a easily tolerable procedure and quick recovery.
Note, rates of SLCA and reoperation were slightly lower (SLCA 1.25%, reoperation 0%) than in other registries. Comparable rates of pre- and post-interventional NYHA-class and MR-reduction compared to other registries were observed. The mechanism of MR did not have primary influence on primary device implant success rates and safety endpoints at 30 days. These findings imply the effectiveness of the MitraClip procedure for every MR entity [16]. Nevertheless, acute effects were abrogated in the ICM group with increased mortality rates after six months. Moreover, mortality risk in the ICM group was highest in patients with severely reduced LVEF at 6 months follow-up. Of note, this is in agreement with surgical MV repair in patient suffering ischemic heart failure with severely reduced ejection fraction <30% [5]

Study limitations

On the one hand, our data show that the results of edge-to-edge MV repair in patients at high surgical risk or inoperable patients are safe and efficient and reproducible in other registries [32-34]. All-comer“-registries like the one shown in the present study shed light into procedural performance of innovative techniques in a real world scenario, independent of sponsorship from industry. However, registries bear various limitations compared to randomized trials. Several confounding variables may have influenced the results, e.g. the risk of under-appraising complications and adverse events or worsening of MR. Parameters analyzed during the 6 month follow up could also have been influenced by survival bias, however, the low rates of adverse events and mortality may have minimized this effect. Another limitation of this registry is its relatively small sample size with a limited follow-up period. Data from long term follow ups after one year will provide more inside into adverse events and mortality. Therefore, our results like in other registries should be replicated in larger populations with longer follow-up periods. In addition, a concurrent comparator arm was lacking in this registry as was in other registries. We attempted to minimize the potential selection bias by including consecutive patients with balanced clinical characteristics in an all-comers-fashion. MitraClip-implantations were conducted by an experienced team with a high volume of clip implantations per year in a single center. Therefore, our results and adverse events should not be generalized. Echocardiography was performed by highly experienced physicians using state-of-the-art 3D transthoracal and transesophageal (TTE and TOE) imaging with longstanding experience using validated methods [22] according to current recommendations. Data were not reviewed by an independent core laboratory but were conducted in a clinical setting, reflecting the daily practice. In the future, data from two ongoing randomized trials will clarify the role of MitraClip therapy in high-risk surgical patients with functional MR. The COAPT trial (Clinical Outcomes Assessment of the MitraClip Therapy Percutaneous Therapy for High Surgical Risk Patients, NCT01626079) with an estimated inclusion of ∼1,200 patients and the RESHAPE-HF study (A Randomized Study of the MitraClip Device in Heart Failure Patients With Clinically Significant Functional Mitral Regurgitation; NCT01772108) of patients with congestive heart failure (NYHA class III or IV and severe reduced LV-function) will examine who, among the optimal patient cohort, will benefit from expanded indications of edge to edge repair with the MitraClip system.

Conclusions

Interventional edge-to-edge repair of severe symptomatic MR with the MitraClip system, routinely performed by experienced internationalists, is a safe and efficacious method that leads to significant clinical improvement in inoperable or high-risk surgical patients, with excellent results even in real-life scenarios as represented in our registry. However, patients with ischemic disease and severely reduced left ventricular ejection fraction showed highest rates of cumulative mortality. Randomized studies are necessary to prove the efficacy and equivalency of the MitraClip approach compared to surgical treatment in order to clarify which subgroups of patients benefit most from MitraClip strategy.

Disclosures

S.W. and R.H.S. received referee fees and travel expenses from Abbott Vascular Germany.

Authors’ Contributions

R.H.S. and S.W. performed most of the clinical procedures and discussed the selection of the patients in the heart team with in house surgeons. D.E. and S.W. acquired the data and conceived and designed the research, F.M. H. and S. W. performed statistical analysis and drafted the manuscript. R.H.S. and S.W. supervised the clinical maintenance of the patients and contributed critical revisions to the manuscript.

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