Author + information
- Received March 1, 2016
- Revision received March 25, 2016
- Accepted March 29, 2016
- Published online June 28, 2016.
- Georg Nickenig, MDa,∗ (, )
- Robert Schueler, MDa,
- Antonio Dager, MDb,
- Pedro Martinez Clark, MDb,
- Alexandre Abizaid, MDc,
- Tomasz Siminiak, MDd,
- Pawel Buszman, MDe,
- Marcin Demkow, MDf,
- Adrian Ebner, MDg,
- Federico M. Asch, MDh and
- Christoph Hammerstingl, MDa
- aDepartment of Cardiology, Heart Center Bonn, University Hospital Bonn, Bonn, Germany
- bAngiographia de Occidente, Cali, Colombia
- cInstitute Dante Pazzanese de Cardiologia, São Paulo, Brazil
- dCentrum Medical Center HCP, Poznan, Poland
- eAmerican Heart of Poland, Bielsko-Biala, Poland
- fNational Institute of Cardiology, Warsaw, Poland
- gSanatorio Italiano, Asuncion, Paraguay
- hMedstar Heart Institute at the Washington Hospital Center, Washington, DC
- ↵∗Reprint requests and correspondence:
Dr. Georg Nickenig, Department of Cardiology, Heart Center Bonn, University Hospital Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.
Background Current surgical and medical treatment options for functional mitral regurgitation (FMR) are limited and additional interventional approaches are required.
Objectives This study sought to report the safety and performance data from the feasibility study with a novel direct annuloplasty system.
Methods Seventy-one patients with moderate to severe FMR (mean 67.7 ± 11.3 years of age, left ventricular [LV] ejection fraction 34.0 ± 8.3%), on stable medical heart failure medication were prospectively enrolled.
Results Device success rate was 70.4% (n = 50 of 71). No intraprocedural death occurred. In patients receiving implants, 4 patients (8.9%) experienced cardiac tamponade. Thirty-day (n = 45) and 6-month (n = 41) rates for all-cause mortality, stroke, and myocardial infarction were 4.4%, 4.4%, and 0.0% and 12.2%, 4.9%, and 0%, respectively. At 6 months, nonurgent mitral surgery was performed in 1 patient (2.4%) and nonurgent percutaneous repair in 7 patients (17.1%). Echocardiographic core analysis after 6 months showed mitral regurgitation reduction in 50% of treated patients by a mean of 1.3 grades. Concerning mitral valve (MV) annular geometry, we found significant reduction of anterior-posterior (–0.31 ± 0.4 cm) and septal-lateral dimensions (–0.21 ± 0.3 cm), a decreased MV-tenting area (–0.57 ± 1.1 cm2) and increase in MV coaptation length (0.13 ± 0.2 cm). Transthoracic echocardiography indicated reverse LV remodeling with reduction of LV end-diastolic diameter (–0.20 ± 0.4 mm) and volume (–22 ± 39 ml). Treatment was associated with significant improvement in 6-min walking distances (56.5 ± 92.0 m) and improvements in New York Heart Association functional class III/IV at 6 months from 53.3% to 23.3%.
Conclusions Percutaneous direct annuloplasty is feasible and safe in high-risk FMR patients. This treatment initiates LV reverse remodeling, and provides clinical improvement during 6 months after treatment. (Mitralign Percutaneous Annuloplasty First in Man Study; NCT01852149).
Mitral regurgitation (MR) is a common disease affecting >4 million patients either in the United States or the European Union (1,2). Degenerative MR (DMR) represents approximately one-third of all MR cases. It is caused by damage from either acute or chronic deterioration of the mitral leaflets or other parts of the mitral valve (MV) apparatus, and is typically treated with either surgical reconstruction of the MV or valve replacement (3).
In the majority of symptomatic MR patients, however, MV disease is not based on a direct damage of the MV apparatus itself but on an indirect deficiency of MV function caused by ischemic or nonischemic dilated left heart disease (4). This functional MR (FMR) is caused by left ventricular (LV) and/or MV annular dilation and papillary muscle displacement (4,5). The progression of LV dilation in such patients aggravates MV leaflet malcoaptation and thereby induces further LV dilation (6–8). FMR exacerbates heart failure–related symptoms, and increased hospitalization and mortality rates (9,10). Current medical treatment is limited, as it targets only heart failure symptoms and not the underlying cause of disease and—in contrast to DMR—the prognostic and clinical benefit of surgical treatment is controversial (3,11). The interventional adoption of the surgical edge-to-edge technique with percutaneous MV repair therapy (MitraClip system, Abbott Vascular, Santa Clara, California) has been shown noninferior to open heart surgery for the treatment of selected patients with mostly DMR (12). In clinical practice, however, the majority of patients undergoing interventional MR repair have functional MV disease (13,14). The durability of interventional FMR repair with the MitraClip is a matter of debate due to its limited approach by targeting the MV leaflets only. Interventional therapies mimicking the surgical gold standard for FMR treatment aiming to reduce annular dimensions may be the preferred treatment option in this setting (15).
To our knowledge, 3 catheter-based direct annuloplasty devices are currently used in early phase clinical trials: the GDS Accucinch (Guided Delivery Systems, Santa Clara, California), the Cardioband (Valtech, Or Yehuda, Israel), and the Mitralign system (Mitralign, Tewksbury, Massachusetts). For the Accucinch procedures, original publications are yet to be published. The Cardioband reached CE mark certification in 2015. We report here on feasibility, safety, and efficacy data of the direct percutaneous annuloplasty Mitralign system.
Trial design and endpoints
We report data from a prospective, multicenter single-arm feasibility study. Participating centers and recruitment numbers are listed in Online Table 1. The study complies with the Declaration of Helsinki. The institutional ethics committee at each site before study participation approved the protocol, and informed written consent was obtained from all patients. The safety of the study was monitored by an independent medical monitor. An independent data management group performed data management and statistical analysis. Echocardiography was performed according to the recommendations of the American Society of Echocardiography following a pre-defined study protocol with core lab evaluation of echocardiographic results (Medstar Research Institute/Cardiovascular Core Lab Washington Hospital Center, Washington, DC).
Detailed patient inclusion and exclusion criteria are given in Online Table 2. Table 1 shows eligibility criteria for study inclusion. In brief, symptomatic patients with chronic FMR on stable guideline directed heart failure medication and/or device therapy were eligible for study inclusion when echocardiography confirmed FMR grade ≥2, and LV ejection fraction (LVEF) ≥20%.
Main exclusion criteria were interventional/surgical revascularization within 3 months before study inclusion, and contraindications for transfemoral interventional procedures such as LV thrombus or severe peripheral vascular disease.
All patients were under stable optimal medical therapy, which was determined by the investigator. Compliance incidence was observed during the study for the following medications: angiotensin-converting enzyme inhibitor/angiotensin II blocker (baseline 95.8%), beta-blocker (baseline 97.2%), and diuretics (98.6%). Compliance was observed at baseline and all subsequent follow-up periods.
Study endpoints and follow-up procedures
Primary endpoints of this study were to assess safety and performance of the direct annuloplasty with the percutaneous annuloplasty system (Online Table 3).
Safety was defined as the 30-day composite of death, stroke, myocardial infarction, or emergent surgery or intervention.
Performance was defined with as need of MV-related cardiac surgery/intervention, device and/or procedure-related death, and changes in echocardiographic parameters on LV reverse remodeling during 6 months of follow up.
Secondary endpoints were assessed with clinical and echocardiographic evaluation before discharge and at 30 days and 6 months after the procedure including changes in echocardiographic measures on severity of MR, clinical outcome measures concerning New York Heart Association functional class, 6-min walking distance, and quality of life assessed with the Minnesota Living with Heart Failure Questionnaire.
Figure 1 gives an overview of the interventional strategy and material. The procedure is performed under general anesthesia, guided by 2-dimensional/3-dimensional transesophageal echocardiography and fluoroscopy, with an activated clotting time of 250 s maintained throughout the procedure.
After femoral access, the 14-F deflectable guiding catheter is introduced into the left ventricle and directed towards the posterior annulus (Figure 1A). Through the guide catheter, an articulating wire delivery catheter is advanced to steer a crossing wire to the targeted position of the posterior mitral annulus (Figure 1A). An insulated 0.019-inch interventional crossing wire with radiofrequency facilitates the crossing of the wire through the annulus into the left atrium. Over the first wire, a bident catheter, with an appropriate span (10, 14, 17, or 21 mm) is advanced to the annulus and a second crossing wire is introduced through the bident arm for annular crossing with radiofrequency energy (Figure 1B).
Thereafter, a pledget delivery catheter is introduced over each wire across the annulus into the left atrium. One-half of the polyester pledget is delivered at the atrial site, and the ventricular pledget part is delivered after pledget delivery catheter removal (Figure 1C). Finally, the pledgets are released and attached leaving 2 sutures exiting the guide catheter (Figure 1D).
Over the sutures a dedicated plication lock device is advanced. Once the required plication is achieved, a stainless steel lock is placed, maintaining the plication of the mitral annulus (Figure 1D). Last, the sutures are cut approximately 4 mm from the lock. If a second pair of pledgets is needed, the steps are repeated in the P1 and P3 scallop regions of the posterior mitral annulus (Figure 1D). Post-procedural antithrombotic regimen consists of aspirin for a minimum of 6 months and clopidogrel 75 mg for a minimum of 30 days.
Continuous and categorical variables are reported as mean ± SD and percentage, respectively. Statistical testing was done with the paired Student t test for continuous variables. The Friedman test was used for categorical variables. A value of p < 0.05 was considered statistically significant.
Baseline characteristics and FU procedures
Seventy-one symptomatic patients with moderate or severe FMR and impaired LVEF were prospectively enrolled in the trial (25.1% with MR 2+, 74.9% with MR >2+), of whom 50 patients (70.4%, treatment group) were treated successfully; the reasons for unsuccessful implant are given in Online Table 4. Seventeen of the 71 (23.9%) patients had an implantable cardioverter-defibrillator/pacemaker before enrollment. There were no reports of implantable cardioverter-defibrillator, pacemakers, or cardiac resynchronization therapy devices implanted within 6 months post-procedure. There are 2 reports of implantable cardioverter-defibrillator/pacemakers implanted at 724 and 802 days post-procedure.
After recruitment of the first 20 patients to the study the delivery system underwent technical refinements and the following 51 patients were intended to be treated with a second-generation delivery system.
Baseline characteristics and 30-day safety results are presented on 45 patients treated with implantation of 1 (n = 20) or 2 pair of pledget devices (n = 25). Five patients were excluded from 30-day analysis because they withdrew informed consent (n = 1), underwent surgery (n = 1), or underwent interventional treatment of MR with the percutaneous annuloplasty system (n = 3). With regard to arterial access, there were 6 bleeding complications reported. Three of the complications required transfusion and 3 did not.
Six-month data are reported for 41 of the 45 successfully implanted patients; 1 patient withdrew informed consent and 3 patients were lost to follow-up procedures. Five patients that were successfully implanted did not reach the 6-month timeframe at the time of data analysis and thus are excluded (Figure 2).
Mean age of the patients receiving implants was 67.9 ± 12.5 years, 68.9% were male and 60.0% of the patients were in NYHA functional class III to IV heart failure state. Chronic kidney disease was present in 28.9%, and atrial fibrillation/flutter in 28.9% of the individuals and LVEF was at 34.7 ± 8.2%. Stable optimal medical treatment for at least 3 months was a prerequisite to enter the study, which was determined by the investigator. Compliance incidence was observed during the study for the following medications: angiotensin-converting enzyme inhibitor/angiotensin II blocker (baseline 95.8%), beta-blocker (baseline 97.2%), and diuretics (98.6%). Compliance was observed at baseline and all subsequent follow-up periods. We found no relevant difference between the overall cohort and the final treatment group (Table 2).
Thirty-day outcomes of patients with implants
There were no intraprocedural death and no necessity for acute conversion to open heart surgery. Pericardial tamponade occurred in 4 patients (8.0%) and was managed uneventfully with pericardiocentesis. Three of the 4 tamponades were related to catheter manipulation within the ventricle. One of the tamponades led to the exclusion of LV end-diastolic diameter <5.0 cm. While the other 2 were a function of early learning curve and first-generation devices. Thus, the exclusion of LV end-diastolic diameter <5.0 cm and second-generation catheter systems have mitigated potential risks of tamponade. Second, all tamponades were resolved on table with pericardiocentesis and no need of emergency cardiac surgery. With regard to arterial access, there were 6 bleeding complications reported. Three of the complications required transfusion and 3 did not. All were managed conservatively without need for surgery or interventional repair/stent placement.
All-cause mortality through 30 days was 4.4%, 2 patients died of cardiogenic shock or decompensated heart failure at 14 and 18 days post-procedure (Table 3). When separating patients with implants (n = 45) from subjects without treatment (n = 21), 30-day mortality rates were 4.4% in treated patients and 14.3% in untreated patients (p = 0.2). Online Table 5 gives additional information on differences in clinical endpoints and LV remodeling in these patient groups during 30 days and 6 months of follow up.
Safety and performance data at 6 months after treatment with implants
All-cause mortality was 12.2%, nonemergent MV surgery was performed in 1 patient (2.4%), and alternative catheter-based MV intervention with the MitraClip was performed in 7 patients (17.1%) within the 6-month follow-up (Table 3).
Five deaths were reported through the 6-month follow up. Only 2 of these deaths were considered related to either procedure or device and procedure. Both of these deaths occurred at 14 and 18 days, respectively. The other 3 deaths occurred between 45 and 165 days post-procedure. No deaths were reported during the procedure.
Two strokes were reported during the study. The occurrence of the strokes was reported at days 78 and 137 days post procedure. The events were medically adjudicated and deemed not related to device or procedure.
Echocardiographic core lab analysis found evidence for reverse LV remodeling after the percutaneous annuloplasty procedure, as shown by significant decrease in LV end-diastolic diameter and LV end-diastolic volume (both p values <0.05). LVEF remained unchanged after follow up (Table 4).
Changes in MV geometry and severity of MR
Analysis of core lab data showed significant changes in MV annular geometry with reduction of the anterior-posterior and septal-lateral dimensions of the mitral annulus. Concerning valve-specific echo data, coaptation length of the MV leaflets increased and tenting distance showed significant differences as compared to baseline data (Table 5). There was a trend toward a reduction in MR grade and semiquantitative variables on MR severity, which did not reach statistical significance (Table 4, Figure 3).
Overall, severity of MR improved in 50% of treated patients by a mean of 1.3 grades; in 34.6% of cases MR was stabilized or unchanged and it worsened in 15.4% after 6 months. When comparing patients treated with 1 or 2 pairs of pledgets, the benefit of the percutaneous annuloplasty procedure in terms of MR severity reduction was pronounced in those patients who were successfully treated with 2 pairs of pledgets (Figure 3B).
Clinical performance of treated patients after 6 months
Heart failure symptoms improved over time, with 53.3% of patients presenting with NYHA functional class ≥III before annuloplasty as compared to 23.3% after follow-up (p = 0.02) (Figure 4). Six-minute walking distance significantly increased during follow-up by 56 m (p = 0.01) (Figure 5), and there was a trend toward improved quality of life after treatment.
In this study we were able to show that minimal invasive, percutaneous direct mitral annuloplasty is feasible with a dedicated annuloplasty system. Following this minimal invasive approach, procedural complication and 6-month mortality rates were low; thereby, the percutaneous annuloplasty system met its pre-specified endpoints on device safety and performance. The results of this feasibility study on a new interventional annuloplasty system must be interpreted in the light of the available evidence and treatment options for high-risk FMR patients.
FMR in failing hearts, does it really matter?
Due to its underlying pathophysiology, FMR affects up to 25% to 65% of heart failure patients with ischemic or dilative cardiomyopathy (9,10). Chronic FMR usually is a progressive disease resulting in malignant LV volume overload and thereby further accelerates the progression of chronic heart disease (16). Several studies demonstrated the negative prognostic impact of FMR in heart failure patients and current guidelines propose early treatment of FMR if effective regurgitant orifice area exceeds 20 mm2 (17). Reduction of FMR in heart failure patients makes sense; it reduces LV filling pressures, decreases post-capillary pulmonary congestion and potentially prevents or even reverses cardiac remodeling. This may not only relieve heart failure symptoms and decrease hospitalization rates but also reduce cardiovascular mortality.
Available treatment options
Patients with significant FMR typically present in advanced stages of chronic heart failure, which is commonly complicated by severe comorbidities and advanced age (3). In contrast to primary MR the benefits of MV surgery are uncertain in such patients and recurrence of FMR after surgical treatment is reported up to 20% during 12 months after surgery (18). More importantly, in daily routine only 15% of FMR patients are referred for surgical valve replacement or reconstruction (19) and there is still an unmet need for true low-risk alternatives to open heart surgery.
Interventional edge-to-edge repair with the percutaneous MV repair MitraClip system has been introduced in clinical routine since 2008, and the technique has been rapidly adopted for MR treatment with >30,000 implants worldwide. The safety and efficacy of this system, however, has been demonstrated in clinical studies on predominantly DMR patients (12) and the durability of this approach focused on the MV leaflets might be limited in true FMR. Data on reverse LV remodeling after successful clip for the treatment of FMR are inconsistent (14) and 1 potential drawback of this device is that the MitraClip procedure requires interatrial transseptal puncture with advancement of a 24-F steerable sheath in the left atrium. Persistent atrial septal defects after the procedure might have a negative impact on the clinical outcomes of chronic heart failure patients (20).
The Carillon Mitral Contour System (Cardiac Dimensions, Kirkland, Washington) has been tested aiming to reduce FMR with indirect annuloplasty by an interventional approach via the coronary sinus (21). The published data on the mitral contour device showed promising clinical results on patient outcomes and reverse LV remodeling and MR reduction over time, which are similar to the reported results with direct annuloplasty.
In this context, an interventional annuloplasty system offers several potential advantages:
It is a direct annuloplasty device for dedicated use in FMR patients. By reducing MV annular dilation, this technique directly addresses the underlying pathology of FMR and transseptal puncture is not needed during this procedure. Annuloplasty with the system led to reverse LV remodeling as demonstrated by a significant reduction of LV volumes and diameters comparable to the indirect acting mitral contour system (21). Despite only moderate effects on MR severity with interventional annuloplasty, which seems better with interventional edge-to-edge repair, the herein reported clinical outcomes are comparable to registry data on FMR patients treated with the MitraClip device (14) and study data on the mitral contour system (16) (Central Illustration).
The observed reduction of LV dimensions could be of potential importance for the long-term outcomes in heart failure patients as shown by clinical data on cardiac resynchronization therapy (22). When putting this into perspective with identical clinical outcome data achieved with the MitraClip system, future studies are needed to compare the true importance of (a) direct mitral annuloplasty inducing reverse remodeling as compared to (b) acute reduction of MR by a direct approach on the MV leaflets without measurable effects on LV performance.
Future perspectives of interventional annuloplasty with the system
The reported results of this feasibility trial on a new interventional annuloplasty device must be interpreted with cautions, taking into account several important procedural aspects.
Similar to other complex structural heart interventions, interventional annuloplasty with a new device requires a learning phase. The early learning curve is included in the presented analysis, which might have led to the relative high incidence of 8.9% of patients with cardiac tamponade. All patients were treated uneventfully with pericardioscentesis, however, this safety aspect must be addressed with improved implantation strategies. The device underwent refinements over time and future development of this technique will have to prove its applicability in larger patient cohorts.
Early learning phase and the use of a first-generation device leads to the fact that stable reduction to MR 2+ or less was achieved in only 13 of 71 (18%) of cases by intention-to-treat analysis. Patients who received 2 pairs of pledgets demonstrated a pronounced reduction of MR defining parameters in addition to changes in MV annular dimensions (Central Illustration). It seems reasonable to assume that the results would have been more favorable if every patient had received device treatment with multiple pairs of pledgets.
Twenty-one patients did not receive implants after successful screening for study inclusion and 2 deaths within 30 days occurred in patients with an ejection fraction below 30%. Refinement of patient selection seems an important issue for future studies.
It cannot be excluded that in line with surgical annuloplasty recurrence of MR may occur over time in patients treated with a direct annuloplasty or other catheter-based devices. The percutaneous annuloplasty system does not prevent other clinical options, as demonstrated by the ability to perform a percutaneous intervention, surgical repair, or even valve replacement if the initial treatment was ineffective. Due to its very small footprint, it could be surmised the percutaneous annuloplasty system can be used as the front line treatment for MR, if necessary in conjunction with other percutaneous MV repair technologies or replacement devices in the future.
We report on data from an early feasibility study, which are clearly limited by its small patient population and a relatively short follow-up. However, both patient number and follow-up period are similar to other early studies with new transcatheter devices (16). This prospective single-arm study has no randomization or control group and the reported treatment effects must be proven in larger patients cohorts. Blood pressure was not recorded at the time of baseline and follow up transthoracic echocardiography, therefore we cannot exclude that reported findings in MR severity might be influenced by relevant changes in patients’ blood pressures at clinical presentation.
Percutaneous annuloplasty with the percutaneous annuloplasty system is feasible and safe in high-risk FMR patients. The treatment initiates LV reverse remodeling, and provides clinical improvement during 6 months after treatment.
COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: Surgical therapy of FMR related to LV dilation is associated with high rates of recurrent MR, and in an initial experience, a catheter-directed annuloplasty system improved clinical symptoms with a low rate of procedural complications.
TRANSLATIONAL OUTLOOK: Larger-scale studies in patients with heart failure and FMR are needed to establish the long-term efficacy of transcatheter direct annuloplasty.
For supplemental tables, please see the online version of this article.
The study was funded by Mitralign Inc (Tewksbury, Massachusetts). Dr. Dager is a proctor for Medtronic. Dr. Martinez Clark has served as a consultant for Mitralign. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- degenerative mitral regurgitation
- functional mitral regurgitation
- left ventricular
- left ventricular ejection fraction
- mitral regurgitation
- mitral valve
- New York Heart Association
- Received March 1, 2016.
- Revision received March 25, 2016.
- Accepted March 29, 2016.
- American College of Cardiology Foundation
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