Author + information
- Received February 9, 2015
- Revision received June 10, 2015
- Accepted June 18, 2015
- Published online September 1, 2015.
- Felix Kreidel, MD∗∗ (, )
- Christian Frerker, MD∗,
- Michael Schlüter, PhD†,
- Hannes Alessandrini, MD∗,
- Thomas Thielsen, MD∗,
- Stephan Geidel, MD‡,
- Ulrich Schäfer, MD∗ and
- Karl-Heinz Kuck, MD∗
- ∗Department of Cardiology, Asklepios Klinik St. Georg Hospital, Hamburg, Germany
- †Asklepios Proresearch, Hamburg, Germany
- ‡Department of Cardiac Surgery, Asklepios Klinik St. Georg Hospital, Hamburg, Germany
- ↵∗Reprint requests and correspondence:
Dr. Felix Kreidel, Asklepios Klinik St. Georg, Department of Cardiology, Lohmühlenstrasse 5, 20099 Hamburg, Germany.
Objectives The goal of this study was to assess procedural details and outcomes of repeat MitraClip therapy.
Background MitraClip implantation is a safe and efficacious percutaneous approach to treat significant mitral regurgitation (MR).
Methods Of 410 inoperable or high surgical risk patients treated with the MitraClip at our institution, 17 (4.1%) patients, as well as 4 patients initially treated at external institutions, underwent repeat MitraClip procedures. Mean age of the 21 patients (14 men [67%]) was 77 years; 15 patients (71%) had functional MR.
Results Repeat procedures performed at a median of 6.3 months (range 0.7 to 34 months) after the index intervention were successful (discharge MR grade ≤2+) in 13 patients (62%), with a pronounced difference in success rate observed between the 13 patients with adequate leaflet insertion at the time of the repeat intervention and the 8 patients in whom loss of leaflet insertion (LLI) (leaflet tear/perforation or partial clip detachment) was present (11 of 13 [85%] vs. 2 of 8 [25%], respectively). The 21 patients were followed for a median of 8.5 (interquartile range: 2.3 to 18.6) months; 13 patients (62%), 8 with adequate leaflet insertion and 5 with LLI, died during follow-up.
Conclusions Repeat MitraClip intervention for significant recurrent MR appears to be a viable therapeutic approach in patients in whom leaflet insertion into the MitraClip is not compromised. LLI is strongly associated with repeat procedural failure.
- mitral regurgitation
- partial clip detachment
- percutaneous mitral valve repair
- repeat intervention
In recent years, transcatheter mitral valve repair using the MitraClip (Abbott Vascular, Abbott Park, Illinois) has become a prevalent approach to treat significant mitral regurgitation (MR) in patients deemed inoperable or at high surgical risk (1–3). The technique emulates the surgical “edge-to-edge” suture (4) by using 1 or more transseptally introduced clips to approximate the mitral leaflets at the origin of the regurgitant jet. Although the reduction in MR severity achieved by MitraClip implantation has been shown to persist in the majority of patients, recurrence of significant MR has been reported (2,3,5).
Different mechanisms may account for MR recurrence. On the one hand, progression of the underlying disease that originally gave rise to (functional or degenerative) MR may lead to recurrent regurgitation despite initially successful MitraClip therapy. On the other hand, loss of leaflet insertion (LLI) into the clip imperatively causes a relapse of MR. LLI may be the consequence of insufficient leaflet grasping, which predisposes the affected leaflet to slip out of the clip if only a few millimeters of leaflet tissue are captured (the distance between the distal barb of the gripper and the end of the clip arm is approximately 1.5 mm [cf. Figure 2 in (6)]); in cases of initially adequate grasping of both leaflets, LLI is conceivable as a consequence of leaflet tear or perforation (7–9).
The complete loss of connection between a clip and 1 leaflet has mostly been referred to as “partial clip detachment” (PCD) (10–12). The less frequently used terms “single leaflet detachment” (13), “single leaflet device attachment” (2), and “single leaflet clip attachment” (12,14) describe the same pathology. The disconnection of a clip from both leaflets, that is, clip embolization, has not been reported to date.
Defining the adequate treatment for MitraClip failure is challenging, particularly in inoperable or high surgical risk patients who constitute the vast majority of “real-life” patients undergoing MitraClip therapy in Europe. Other than in the EVEREST II (Endovascular Valve Edge-to-Edge Repair Study) patient cohort (15), surgery is typically no option in post-MitraClip patients who were already poor surgical candidates (or no surgical candidates at all) pre-MitraClip. Thus, a repeat MitraClip intervention appears to be a reasonable therapeutic option. Apart from a few case reports on PCD (10–13), data on the outcomes of repeat intervention after MitraClip failure are lacking. Therefore, we have retrospectively assessed procedural details and factors impacting the acute outcome of, as well as long-term survival after, repeat MitraClip intervention.
Between September 2009 and May 2014, 410 patients had been treated at our institution with MitraClip implantation for significant MR. All patients were considered inoperable or at high surgical risk by heart team consensus of interventional cardiologists and cardiac surgeons. Index procedures were successful (discharge MR grade ≤2+) in 365 of 402 patients (90.8%, 95% confidence interval [CI]: 87.5% to 93.4%) in whom discharge echocardiograms were available. Repeat MitraClip interventions were performed in 17 (4.2%) of the 402 patients as well as in 4 patients initially treated at external institutions (Figure 1). The majority (n = 15 [71%]) of these 21 patients suffered from functional MR. In-house index procedures had been regarded as initially successful (discharge MR severity ≤2+) in 14 (82.4%) of the 17 patients, with repeat intervention indicated because of recurrent symptomatic severe MR; the indication for the 3 other in-house repeat interventions (17.6%) was failure of the index procedure. All repeat interventions were performed by 2 experienced operators (K.-H.K. and U.S.). Baseline characteristics of the 21 patients are listed in Table 1.
Index procedures were adjudicated as failures also in 34 (9%) of the 385 patients who did not undergo repeat MitraClip treatment. Nineteen (56%) of those 34 patients were subsequently managed medically, and 8 (24%) underwent surgical conversion within a median of 12 days. With 4 patients dying shortly after conversion and another 7 patients dying without surgical intervention, a total of 11 patients (32%) died within a median of 21 days after a failed MitraClip intervention.
The procedural details of percutaneous mitral valve repair using the MitraClip have been described before (15). In the present study, procedural success was defined as MR severity ≤2+ at discharge.
All patients underwent 2-dimensional transthoracic echocardiography before and after the repeat intervention. Two- and 3-dimensional (3D) transesophageal echocardiography (TEE) was performed during index and repeat procedures with commercially available echocardiographic systems (iE33, Philips Medical Systems, Andover, Massachusetts or Vivid E9, GE Vingmed Ultrasound AS, Horten, Norway). Standard parameters of left ventricular dimension, as well as left and right ventricular function, were assessed according to American Society of Echocardiography guidelines (16). MR grading was based on a previously reported technique (17).
The anatomic location of the clips was determined by TEE in the intercommissural view and, if available, also in the 3D en face view of the mitral valve. Clip locations at the lateral (P1) and medial (P3) scallops of the posterior leaflet were defined as lateral and medial, respectively. A clip location involving the central scallop (P2) was defined as central (a purely central position) or, if the clip was located close to either P1 or P3, as centrolateral or mediocentral, respectively.
The 3 echocardiographic scenarios encountered at the time of the repeat intervention are shown schematically in Figure 2. They comprise insertion of both the anterior mitral leaflet (AML) and the posterior mitral leaflet (PML) into the clip (Figure 2A); LLI suggestive of leaflet tear/perforation (Figure 2B); and LLI clearly representing PCD (Figure 2C).
Leaflet length and leaflet insertion into the MitraClip were retrospectively examined at 3 time points: before MitraClip implantation, at the end of the index procedure, and at the beginning of the repeat procedure. All measurements were taken in diastole using TEE intercommissural and long-axis views in a simultaneous biplane manner. Leaflet lengths at baseline were measured from hinge point to leaflet tip at the anatomic site of later clip implantation (Figures 3A, 3D, and 3G). At the end of the index procedure (Figures 3B, 3E, and 3H) and at the beginning of the repeat procedure (Figures 3C, 3F, and 3I), leaflet length outside the MitraClip was measured either between the hinge point and the contact point of the leaflet with the MitraClip or, if no contact point was seen at the beginning of the repeat procedure, between the hinge point and the tip of the leaflet. At the latter 2 time points, the length of leaflet captured inside the clip was determined by subtracting the leaflet length outside the clip from the corresponding leaflet length at baseline. “Adequate leaflet insertion” was considered present if the length of leaflet captured inside the clip was ≥5 mm and both leaflets inserted into the atrial aspect of the closed clip arms (Figure 3B, 3E, and 3H).
LLI was established at the beginning of the repeat procedure if a leaflet inserted no longer into the atrial aspect of the clip, but was seen during diastole to move along the clip arm toward its ventricular tip, with a regurgitant jet originating from the leaflet tip. If the leaflet tip did not deviate by >2 mm from the edge of the MitraClip, leaflet tear/perforation was diagnosed (Figure 3F); in the case of complete diastolic disconnection of one of the leaflets from the clip, PCD was diagnosed (Figure 3I).
Vena contracta area (VCA) has been shown to be a measure of the severity of MR, with a cutoff value of 41 mm2 differentiating optimally between moderate and severe MR (18). VCA of the regurgitant jet was measured by plane-corrected planimetry in a 3D color Doppler full volume (QLAB-Version 8.0, Philips Medical Systems) just before and after repeat MitraClip implantation.
Written informed consent was obtained from all patients.
Continuous variables are described as mean ± SD if normally distributed, or as median plus range or interquartile range (IQR) if not. Categorical variables are described as absolute and relative frequencies.
Patients and procedures
In this cohort of 21 elderly patients who had received either a single clip (n = 13 [61.9%]) or 2 clips (n = 8 [38.1%]), for a total of 29 clips, during the index procedure, the median time between index and repeat procedure was 6.3 (range 0.7 to 33.7) months. Of the 21 repeat interventions, 13 were eventually successful and 8 failed. There was no association between operator and repeat procedural failure rate (4 of 10 vs. 4 of 11).
The repeat procedural success rate of 61.9% (95% CI: 38.4% to 81.9%) was markedly lower than the 90.8% (95% CI: 87.5% to 93.4%) index procedural success rate. No apparent baseline differences in surgical mortality risk or prevalence of comorbidities were noted between the 13 patients with a successful repeat intervention and the 8 patients with a failed repeat intervention (Table 2). During repeat interventions, a total of 29 additional clips were implanted, with multiple clips relatively more often implanted in patients in whom the repeat procedure eventually failed (Table 3). Total device time, that is, the time from transseptal puncture to withdrawal of the clip delivery system from the left atrium, was 55 (IQR: 36 to 85) minutes; it tended to be longer in patients with a failed repeat intervention than in those with a successful repeat intervention. Four patients (2 procedural successes, 2 procedural failures) had increased mean transmitral pressure gradients at discharge (6 mm Hg in 1 patient, 7 mm Hg in 3 patients).
Index clips were mostly implanted in the medial to central location, with only 1 clip implanted centrolaterally; new clips implanted during the repeat intervention were also placed predominantly in the medial to central position; a substantial percentage (n = 8 [28%; 95% CI: 13% to 47%]) of new clips were placed centrolaterally.
Echocardiography before the repeat intervention did not identify any quantitative variable predictive of procedural outcome (Table 4). However, it revealed LLI in 8 patients, with 3 of these meeting the criterion for PCD. The latter 3 patients had all been treated initially for functional MR, as had 3 other patients with LLI; the condition was observed in only 2 patients initially treated for degenerative MR.
Leaflet insertion at the end of the index procedure was found to be adequate in all patients. The 8 patients with LLI underwent the repeat intervention at a median of 6.2 (range 0.7 to 33.7) months after the index procedure, which was not different from patients with adequate leaflet insertion at the time of the repeat intervention (6.3 [0.7 to 28.1] months). LLI affected the anterior mitral leaflet in 3 cases and the posterior mitral leaflet in 5 cases.
TEE measurement of leaflet lengths at beginning and end of the index procedure, as well as at beginning of the repeat procedure, is shown in Figure 3 for a patient without LLI, for 1 with leaflet tear/perforation, and for a patient with PCD. Results for 7 of the 8 patients with LLI (no index procedure echocardiography was available in 1 external patient) are given in Table 5. At the end of the index procedure, a median length of 7 mm was captured inside the clip in leaflets later affected by LLI, as well as in leaflets later not affected by LLI, indicative of acute procedural success. In the time between the index and repeat procedures, the lengths of both affected and unaffected leaflets had essentially not changed (minor, 1-mm differences in AML length were measured in 3 patients [Table 5]). Therefore, a slipping of the affected leaflet out of the clip as the underlying mechanism of LLI was ruled out in our patients.
Transthoracic echocardiography in in-house patients initially treated for functional MR revealed that left ventricular volumes tended to be markedly larger, at both the index and the repeat procedure, in patients with LLI than in those with adequate leaflet insertion (Table 6). In the latter patients, median volumes had noticeably increased during the period between index and repeat interventions, presumably reflecting progression of the underlying ventricular disease. By contrast, median ventricular volumes were hardly different at the 2 time points in patients with LLI.
As shown in Table 4 and Figure 4, LLI impacted the outcome of the repeat intervention such that its absence was associated with a success rate of 84.6% (95% CI: 54.6% to 98.1%), whereas its presence entailed a success rate of only 25.0% (95% CI: 3.2% to 65.1%). The 2 successfully treated among the latter patients had both presented with leaflet tear/perforation; no patient with PCD could be treated successfully. Compared with the index procedural success rate of 90.8%, the repeat procedural success rate was on the same order of magnitude in the 13 patients with adequate leaflet insertion (90.8% vs. 84.6%), yet clearly lower in the 8 patients with LLI (90.8% vs. 25.0%).
Total repeat procedural device time tended to be lower in patients with adequate leaflet insertion (48 [30 to 88] min) than in patients with LLI (68 [45 to 84] min).
LLI was present in 5 (38.5%) of the 13 patients initially implanted with 1 clip and 3 (37.5%) of the 8 patients initially implanted with 2 clips. Repeat procedural success rates in patients initially implanted with 1 and 2 clips were 53.8% and 75.0%, respectively.
Vena contracta area
VCA was available before and after repeat MitraClip therapy in 12 patients. Before the repeat intervention, median VCA was 66 (IQR: 40 to 96) mm2, clearly indicating the severity of the recurrent MR. VCA tended to be lower in the 7 patients in whom the repeat intervention was eventually successful than in the 5 patients in whom the repeat intervention failed (Table 4). After the repeat intervention, the median VCA of 68 mm2 in patients with a failed repeat intervention was clearly indicative of inadequate MR reduction and markedly larger than in patients with a successful repeat intervention (22 mm2). VCA after the repeat intervention was >40 mm2 in all 5 patients with repeat procedural failure, yet in none of the 7 patients with repeat procedural success (Table 4). Of note, LLI was present in all of the former patients, yet in only 1 of the latter.
The 21 patients were followed for a median of 8.5 (IQR: 2.3 to 18.6) months after the repeat MitraClip intervention. Four patients (3 with LLI, among them 1 with PCD; and 1 with adequate leaflet insertion) underwent mitral valve surgery at a median of 20 (range 6 to 57) days after the failed repeat intervention; a fifth patient (with adequate leaflet insertion) underwent mitral valve surgery for recurrence of significant MR 43 days after an initially successful repeat procedure. Thirteen patients (62%) died at a median of 3.0 (IQR: 0.7 to 7.9) months after the repeat MitraClip intervention, among them all 3 patients with functional MR who had undergone mitral valve surgery. The 2 patients with degenerative MR who underwent mitral valve surgery were alive at 13 and 32 months after the repeat intervention.
New York Heart Association (NYHA) functional class was assessed at a median of 28 (IQR: 14 to 45) months after the repeat intervention in 7 of the 8 surviving patients and revealed NYHA class I/II (n = 2) and IV (n = 1) in the 3 patients initially treated for degenerative MR (of whom 2 had LLI) and NYHA class III in all 4 patients (none with LLI) initially treated for functional MR.
In this report from a single center with a large experience in MitraClip treatment of inoperable or high surgical risk patients, repeat MitraClip interventions were rare (4.2% incidence) and occurred at a median of 6.3 months after the index procedure. Of note, the overall repeat procedural success rate of 62% contrasted starkly with the procedural success rate of 91% achieved in 402 index procedures. LLI at the time of the repeat intervention was strongly associated with interventional outcome, such that only 25% of repeat procedures could be successfully completed when LLI was present, as opposed to 85% repeat interventional success when leaflet insertion was adequate. Despite the placement of up to 3 new clips in patients with LLI, the regurgitant orifice as reflected by the VCA could mostly not be reduced sufficiently to qualify the repeat intervention as a procedural success. In the long term, repeat procedural success appeared to impart a beneficial effect on survival in patients initially treated for functional MR.
Index clips had mostly been placed in the central, mediocentral, and medial valvular region, probably reflecting the predominance of a central regurgitant jet in patients with mostly functional MR and the tendency of the investigators to preferentially treat this condition with centrally and/or mediocentrally placed clips. During the repeat intervention, the majority of new clips were also implanted in the central to medial valvular region; however, almost 30% of new clips were implanted centrolaterally, possibly indicating a substantial prevalence of “new” regurgitant flow originating lateral to a central index clip.
Recurrence of symptomatic MR after initially successful MitraClip therapy or aggravation of symptoms requiring treatment after failed MitraClip therapy may prompt interventional cardiologists to attempt a repeat MitraClip intervention, because mitral valve surgery had not been an option in these patients in the first place. The present study has shown that repeat MitraClip implantation is feasible, particularly in patients with adequate leaflet insertion at the time of the repeat intervention. In such patients, a repeat procedural success rate on the order of 85% can be expected. However, in our study, in patients who presented with an echocardiographic pattern of LLI at the time of the repeat intervention, the chance of repeat procedural success dropped to 25%.
Our findings suggest that sufficient leaflet coaptation is hard to restore if one of the leaflets is torn or perforated—be it “only” with the clip still attached to the affected leaflet, or be it that the part of the leaflet captured by the index clip is completely ripped out. In our experience, the former scenario may lend itself to successful repeat MitraClip intervention, whereas we did not succeed in repairing any of the 3 PCDs. This is in apparent contradiction to previous case reports of successful PCD treatment (10–13). However, it is not known whether PCDs in those reports were associated with leaflet tear or perforation (it is conceivable that PCD may also occur as a consequence of inadequate leaflet capture with the gripper barbs not imbedded in leaflet tissue), nor is it known how many PCDs those authors encountered that could not be treated successfully.
Despite the fact that LLI had an adverse impact on the outcome of the repeat intervention, we did not find that it directly affected survival, at least not out to 1 year. Indirectly, though, LLI as a predictor of a negative procedural outcome did appear to affect survival: a failed repeat intervention entailed poorer survival than a successful one, at least in patients with functional MR.
Repeat MitraClip intervention is apparently a rare event. Therefore, the number of patients we were able to analyze was small. As a consequence, predictors of repeat procedural success in patients with LLI could not be determined. Strict adherence to a separation of MR etiologies, with respect to the prevalence of LLI and repeat procedural outcome would have been desirable.
Repeat MitraClip intervention for significant recurrent MR appears to be a viable therapeutic approach in patients in whom leaflet insertion into the MitraClip is not compromised. Loss of leaflet insertion as manifested by leaflet tear/perforation or PCD is strongly associated with repeat procedural failure.
WHAT IS KNOWN? In Europe, MitraClip implantation has become the therapy of choice for patients with significant MR who are considered inoperable or at high operative risk. Reduction in MR severity persists in the majority of successfully treated patients; repeat MitraClip intervention may be considered in cases of significant MR recurrence.
WHAT IS NEW? This study of 21 patients has shown that repeat MitraClip therapy has a high chance of success if leaflet insertion into the MitraClip is not compromised. However, LLI, be it leaflet tear/perforation at the site of the clip or complete detachment of one of the leaflets from the clip, likely entails repeat procedural failure.
WHAT IS NEXT? Larger numbers of patients undergoing repeat MitraClip intervention are required to assess both the prevalence of LLI in different MR etiologies and predictors of repeat procedural outcome.
Dr. Schäfer has received research funding from Abbott Vascular. Dr. Kuck has received research funding from Abbott Vascular and consulting fees/honoraria from Medtronic, Boston Scientific, St. Jude Medical, and Biosense Webster. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Kreidel and Frerker contributed equally to this work.
- Abbreviations and Acronyms
- anterior mitral leaflet
- confidence interval
- interquartile range
- loss of leaflet insertion
- mitral regurgitation
- New York Heart Association
- partial clip detachment
- posterior mitral leaflet
- transesophageal echocardiography
- vena contracta area
- Received February 9, 2015.
- Revision received June 10, 2015.
- Accepted June 18, 2015.
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