- Email: [email protected]
Long-Term Outcomes After MitraClip Implantation According to the Presence or Absence of EVEREST Inclusion Criteria
Long-Term Outcomes After MitraClip Implantation According to the Presence or Absence of EVEREST Inclusion Criteria Hasema Lesevic, MDa,*, Michael Karl, MDa, Daniel Braun, MDb, Petra Barthel, MDc, Martin Orban, MDb, Jürgen Pache, MDd, Martin Hadamitzky, MDe, Julinda Mehilli, MDb,f, Lynne Stecher, PhDg, Steffen Massberg, MD, PhDb,f, Ilka Ott, MDa, Heribert Schunkert, MDa,f, Adnan Kastrati, MDa,f, Carolin Sonne, MDa, and Jörg Hausleiter, MDb Numerous patients are treated with the MitraClip, although they do not fulfill the stringent inclusion criteria of the Endovascular Valve Edge-to-Edge Repair Study (EVEREST) trials. The outcome of those patients is not well known. Therefore, we compared the long-term outcome after MitraClip treatment between patients who matched (group 1) and did not match (group 2) the EVEREST criteria. One hundred thirty-four consecutive patients were treated from September 2009 to July 2012: 59 patients (44%) in group 1 versus 75 patients (56%) in group 2. Investigated end points were acute procedural success (for group 1 vs 2: 97% vs 95%; p [ 0.694), all-cause mortality (28% vs 27%; p [ 0.656), reintervention (RI) rate (11% vs 37%; p [ 0.010), and improvement in mitral regurgitation (MR) (L1.3 – 1 vs L1.5 – 1, p [ 0.221) and in New York Heart Association functional class (L0.7 – 1 vs L0.9 – 0.8, p [ 0.253) during the follow-up of 33 months (27.9 to 38.3). The morphologic extent of a flail leaflet was an independent predictor for RI. In conclusion, although the overall outcome was comparable between both groups, recurrent symptomatic MR with need for RI was higher in group 2, mainly because of complex valve pathologies: especially flail width >15 mm and gap ‡10 mm. Improvements in the interventional strategy are warranted for reducing the need for RI in patients with primary MR. Ó 2017 Elsevier Inc. All rights reserved. (Am J Cardiol 2017;119:1255e1261) Numerous elderly patients with symptomatic severe mitral regurgitation (MR) are not considered for mitral valve (MV) surgery—the gold standard of treatment—because of their age and/or left ventricular (LV) dysfunction.1,2 These issues have led to the development of several less-invasive transcatheter treatment options for MV repair. The most established technique is the transcatheter edge-to-edge MV repair (TMVR) using the MitraClip system (Abbott Vascular, Abbott Park, Illinois). The 5-year results of the first and only randomized controlled trial comparing surgery for MR versus TMVR showed a higher procedural success rate for the surgical approach and a higher rate of surgery because of residual/recurrent MR in patients with TMVR but with sustained and comparable improvement in
a Department of Cardiology, Deutsches Herzzentrum München, cDepartment of Cardiology, Klinikum Rechts der Isar, eDepartment of Radiology, Deutsches Herzzentrum München, and gElse Kröner-Fresenius-Center for Nutritional Medicine, Technische Universität München, Munich, Germany; b Department of Cardiology, Campus Grobhadern, Ludwig-MaximiliansUniversität München, Munich, Germany; dDepartment of Cardiology, Schön Klinik Starnberger See, Berg, Germany; and fDZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany. Manuscript received September 30, 2016; revised manuscript received and accepted December 14, 2016. Drs Sonne and Hausleiter contributed equally to this work. See page 1261 for disclosure information. *Corresponding author: Tel: (þ49) 89-1218-0; fax: (þ49) 89-1218-4013. E-mail address: [email protected] (H. Lesevic).
0002-9149/17/$ - see front matter Ó 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2016.12.027
functional class.3e5 All patients included in the EVEREST II (Endovascular Valve Edge-to-Edge Repair Study) trial were primarily candidates for surgery and had “ideal” anatomic criteria.3 Nevertheless, in everyday clinical practice, numerous patients are treated with TMVR who would have primarily been excluded from the EVEREST II trial and are still outside currently considered “good candidates” for TMVR. Recommendations for patient selection with ideal, moderate, and not suitable anatomic criteria for TMVR have been published.6 Such factors are also considered prognostic for procedural success.6 Two previous studies showed comparable results in patients with and without EVEREST criteria basically in secondary MR.7,8 Although this was limited by a small sample size and a short duration of follow-up. Thus, we analyzed our patient population treated with TMVR according to the presence or absence of EVEREST inclusion criteria and compared the procedural success and long-term outcome, repair durability, and prognostic factors. Methods This observational cohort study was conducted from September 2009 to July 2012. All included patients gave written informed consent before entering the study that complies with the Declaration of Helsinki and was approved by the institutional ethics committee. Consecutive patients with symptomatic MR and placement of at least 1 clip were included in these analyses—after discussion with the heart team. www.ajconline.org
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Figure 1. Key anatomic inclusion criteria of the EVEREST trials modified after Feldman et al.9 A2/P2 ¼ central segment of the anterior/posterior MV leaflet; LVEF ¼ left ventricular ejection fraction; LVESD ¼ left ventricular endsystolic diameter; MVOA ¼ mitral valve orifice area.
All those patients who would have been eligible for the EVEREST II trial (see also Figure 19) formed group 1 and were assigned as EVEREST patients. The remainder of patients, who were not conform to the anatomic inclusion criteria were allocated as non-EVEREST patients (group 2). Full inclusion and exclusion criteria of the EVEREST trials have been reported previously.3,10 Exclusion criteria used by this team were MV orifice area 2 cm2, active endocarditis and thrombus. All patients underwent 2-dimensional (2D) transthoracic and 2D and 3D transesophageal echocardiography before intervention to assess valve morphology, MR severity, and suitability for TMVR. MR quantification was performed according to international guidelines and graded from 1 þ to 4þ.11e13 All procedures were performed with transesophageal echocardiography and fluoroscopic guidance as previously described.3,14e16 After TMVR, TTE was conducted before discharge and at regular appointed follow-up visits. The clinical outcome was assessed by New York Heart Association (NYHA) functional class and 6-minute walking test (6mWT). If a return visit was not possible, a telephone follow-up was performed. End points included all-cause mortality, reintervention (RI, i.e., second TMVR and/or MV surgery), MR severity, NYHA class, and distance in the 6mWT at the latest follow-up visit.
Categorical data are reported as absolute numbers or percentages and were compared between the groups using chi-square test or Fisher’s exact test. Continuous variables are presented as mean SDs and were compared between the groups using t tests. Time to the occurrence of an end point and each of the individual components were analyzed using Kaplan-Meier method. The log-rank test was used to compare the time-to-event end points between the groups. The events are presented as Kaplan-Meier estimates in percentage and in absolute numbers. A Cox proportional hazards model was used for assessing the independent factors associated with RI and logistic regression for independent factors associated with MR 3þ at follow-up. All p values reported are 2 sided and a p value of <0.05 was considered statistically significant. Data analysis was performed with IBM SPSS Statistics, version 22, and R 2.15.1 package (The R foundation for Statistical Computing, Vienna, Austria). Results One hundred thirty-four consecutive patients were treated by TMVR (Figure 2). In 6 patients, a sufficient MR reduction of grade I or more could not be achieved. Consequently, the primary success rate was 95.5% (97% in
Valvular Heart Disease/MitraClip Outcome According to EVEREST Criteria
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Figure 2. Study flow chart.
group 1 vs 95% in group 2, p ¼ 0.694). Baseline demographic and clinical characteristics are listed in Table 1. Reasons of non-EVEREST conformity are specified in Table 2. The number of implanted clips did not differ between the groups: in group 1 one clip per procedure was placed in 42 (71%), 2 clips in 16 patients (27%), and 3 clips in 1 patient (2%); whereas in group 2 one clip was placed in 52 (69%), 2 clips in 22 patients (29%), and 3 clips in 1 patient (1%), respectively (p ¼ 0.95). A similar mean acute MR reduction was seen in both groups (2.3 0.9 vs 2.2 1, respectively; p ¼ 0.497). One hundred thirty-one patients (97.8%) were followed up to 3.5 years with a median of 992 days (836 to 1,148). During the follow-up, 32 patients died: 5 patients during hospital stay after index procedure, whereas 27 deaths occurred >30 days after index TMVR and were not adjudicated as procedure related (further details in Figure 2). There was no significant difference in the survival rate (Figure 3, Table 3) and in residual/recurrent MR defined as MR 3þ at follow-up—although by trend more frequent in group 2 (14 of 50 patients presented with MR 3þ in group 1 vs 27 of 60 patients in group 2; p ¼ 0.066, OR 0.48 [0.21 to 1.06]). Repeat TMVR was increased by trend, whereas MV surgery was significantly increased in group 2 (Table 3). Combining these 2 end points as RI, there are significantly more RI in group 2 (Figure 3). Altogether, 21 patients needed an RI during follow-up: 17 patients presented with primary MR (81%)
and 4 patients (19%) with secondary MR (p ¼ 0.031). In group 1, all 4 patients with RI displayed a primary MR, whereas in group 2, 13 patients presented with primary and 4 patients with secondary MR. Table 4 lists the distribution of the anatomic criteria of all non-EVEREST patients with and without RI. Variables with a p value 0.05 were entered into Cox proportional hazards model. Flail width was found to be an independent predictor for RI, whereas flail gap 10 mm displayed a strong trend (flail width: adjusted hazard ratio 11.2, 95% confidence interval 2.6 to 48.3; p ¼ 0.001; flail gap: adjusted hazard ratio 3.1, 95% confidence interval 0.9 to 11.5; p ¼ 0.077). When entering the variables into logistic regression analyses for identifying independent factors associated with MR 3þ at follow-up, only flail gap 10 mm displayed a trend (p ¼ 0.082). A significant MR reduction (Figure 4) and an improvement in NYHA class (Figure 5) were maintained in most of the patients. The walking distance in the 6mWT extended significantly in both cohorts but without a difference regarding EVEREST conformity (in group 1: from 299 123 m to 353 131 m, p ¼ 0.014, vs in group 2: from 305 94 m to 348 124 m, p ¼ 0.032; p ¼ 0.715 for difference). Discussion This is the first study investigating the prognostic effect of the EVEREST inclusion criteria on acute and long-term
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Table 1 Baseline characteristics Variable
EVEREST (n¼59)
non-EVEREST (n¼75)
Age (years) 72.8 10.4 73.8 10.2 Women 18 (31%) 34 (45%) Systemic hypertension 47 (80%) 63 (84%) Diabetes mellitus 8 (14%) 13 (17%) Coronary artery disease 30 (51%) 40 (53%) Previous myocardial 12 (20%) 14 (19%) infarction Previous percutaneous 24 (41%) 35 (47%) coronary intervention Previous coronary11 (19%) 13 (17%) artery bypass grafting Atrial fibrillation 34 (58%) 46 (61%) Left ventricular ejection 47.5 15.8 43.4 19.3 fraction (%) Implanted electrical device 12 (20%) 29 (39%) (pacemaker/ implantable cardioverter defibrillator/ cardiac resynchronization therapy device) Impaired renal function 16 (27%) 19 (25%) Pulmonary disease 24 (41%) 24 (32%) Previous stroke 7 (12%) 9 (12%) New York Heart Association functional class II 8 (14%) 3 (4%) III 35 (59%) 50 (67%) IV 16 (27%) 22 (29%) Mitral regurgitation / etiology primary 36 (61%) 44 (59%) secondary 23 (39%) 31 (41%) Mitral regurgitation / severity III/IV 26 (44%) 28 (37%) IV/IV 33 (56%) 47 (63%) Logistic EuroSCORE I, %; 12.9 (4.0 e 28.2) 14 (6.6 e 25.5) median (25th e 75th percentile) STS mortality score, %; 10.7 (3.7 e 12.8) 10.1 (3.9 e 20.8) median (25th e 75th percentile)
p value
Table 2 All non-EVEREST patients according to EVEREST exclusion criteria (n¼75) EVEREST exclusion criteria
0.510 0.108 0.651 0.636 0.862 0.829 0.599 1.000 0.724 0.217 0.025
0.845 0.365 1.000 0.152
0.860
0.480
0.728
0.967
Data are given as mean SD, unless otherwise stated. EuroSCORE I ¼ European System for Cardiac Operative Risk Evaluation I; STS ¼ Society of Thoracic Surgery.
outcome and on repair durability up to 3.5 years after TMVR—both in primary and secondary MR. We could demonstrate a significant reduction of MR severity with a primary success rate of 95.5%—regardless of the EVEREST criteria and MR etiology. Although 56.9% of our patient population would have been excluded from the EVEREST II trial, we achieved comparable acute results in both groups. Nevertheless, non-EVEREST patients were significantly more likely to be treated by RI due to MR recurrence. This is probably because of complex MV pathologies. Taking those 17 patients into account who were non-EVEREST
Main pathology in P1- and/or A1-segment (prolapse þ/- flail) Main pathology in P3- and/or A3-segment (prolapse þ/- flail) Morbus Barlow with flail gap < 10 mm with flail gap 10 mm with bileaflet flail Flail gap 10 mm Flail width > 15 mm with MVOA < 4 cm2 MVOA < 4 cm2 with prolapse þ flail gap < 10 mm with LVEF 20% Prior mitral valve surgery with prolapse þ flail gap < 10 mm with prior Alfieri suture þ MVOA < 4 cm2 with prior annuloplasty Coaptation length < 2 mm Cleft LVEF < 25 % and/or LVESD > 55 mm
Number of patients 11 (15%) 9 (12%) 5 (7%) 2 1 1 6 (8%) 3 (4%) 1 3 (4%) 1 1 2 (3%) 1 1 14 (19%) 4 (5%) 18 (24%)
A1/A3 ¼ anterior mitral valve leaflet - lateral/medial segment; LVEF ¼ left ventricular ejection fraction; LVESD ¼ left ventricular endsystolic diameter; MVOA ¼ mitral valve orifice area; P1/P3 ¼ posterior mitral valve leaflet - lateral/medial segment.
and needed an RI, only 4 patients displayed a secondary MR—2 of those with a coaptation length <2 mm. The remaining 13 patients presented with complex primary MV pathologies. Of note, the presence of flail width >15 mm was predictive for need for RI, whereas flail gap 10 mm indicated a strong trend. Moreover, all the EVEREST patients who needed an RI displayed a primary MR. Thus, our results support the assumption of previous studies that selected patients especially with secondary MR can benefit more from TMVR.3e5,14,16 Furthermore, high-risk patients with advanced LV dysfunction not amenable to surgery may derive particular benefit from TMVR8,16,17 and should not be precluded from this treatment option even if the coaptation length is <2 mm. Similarly, Adamo et al8 suggested an extension of the use of TMVR to patients with secondary MR including patients with a coaptation length <2 mm. Moreover, Adamo et al did not observe a significant reverse remodeling in their study population which might be because of a more advanced stage of disease (i.e., more dilated left ventricle and lower LV ejection fraction).8 Therefore, an earlier intervention in secondary MR might be of prognostic relevance in clinical outcome and in terms of sufficient MR reduction. Attizzani et al7 demonstrated similar rates of safety and efficacy in their patient population according to EVEREST criteria through a 12-month follow-up. They reported only 2 second clip procedures with no MV surgery. This very low RI rate might be associated with the high amount of secondary MR included (>80% had secondary MR),7 whereas in our cohort 59.7% of the patients presented with primary MR. However, even primary MR with medial and lateral MV
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Figure 3. (A) End point with death of any cause. Kaplan-Meier estimates freedom from death of any cause. Blue line indicates EVEREST patients (n ¼ 59), red line indicates non-EVEREST patients (n ¼ 75). (B) End point with RI. Kaplan-Meier estimates freedom from RI composed of MV surgery and second TMVR. Blue line indicates EVEREST patients (n ¼ 59) and red line indicates non-EVEREST patients (n ¼ 75).
Table 3 Long-term clinical outcome
Table 4 Comparison of all non-EVEREST patients with and without reintervention
Variable
EVEREST non-EVEREST (n¼59) (n¼75)
Hazard Ratio [95 % CI]
p value
Death of any cause Reintervention second clip procedure mitral valve surgery
14 (28%)
18 (27%)
0.85 [0.42-1.72]
0.656
4 (11%) 1 (2%)
17 (37%) 7 (13%)
0.24 [0.08-0.71] 0.16 [0.02-1.29]
0.010 0.085
3 (9%)
11 (28%)
0.27 [0.08-0.98]
0.047
Events are presented as absolute numbers and Kaplan-Meier estimates in percentage. CI ¼ confidence interval.
pathologies can be successfully treated by TMVR with comparable long-term results to the “ideal” central pathology, but it is technically more challenging. Altogether, high-risk patients with suboptimal anatomic criteria should not be deprived of TMVR and there is a need for establishing new eligibility criteria—particularly in the hands of experienced TMVR users. Nonetheless, it is very important to carefully select the patients and to have an interdisciplinary approach by a “heart team” for developing the ideal treatment plan and for identifying the high-risk/inoperable patients in whom TMVR is feasible—especially if a patient’s anatomy is not in accordance with the EVEREST inclusion criteria. In particular, improvements in the interventional strategy are warranted for reducing the need for RI. In our study, there was no significant difference in the number of clips implanted comparing EVEREST to non-EVEREST patients (most often 1 clip per procedure was placed). Previous studies have shown that especially in primary MR often >1 clip per procedure is needed.18,19 There are actually some case reports presenting treatment strategies with
EVEREST II exclusion criteria
Main pathology in P1-/A1- and/or P3-/A3-segment Barlow’s disease Flail gap 10 mm Flail width > 15 mm MVOA < 4 cm2 Prior mitral valve surgery Coaptation length < 2 mm Cleft LVEF < 25 % and/or LVESD > 55 mm
Reintervention
p value
Yes (n¼17)
No (n¼58)
3 (18%)
16 (28%)
0.407
3 (5%) 4 (7%) 0 4 (7%) 2 (4%) 12 (21%) 3 (5%) 18 (31%)
0.338 0.051 0.001 0.883 0.438 0.406 0.909 0.114
2 4* 3 1
(12%) (24%) (18%) (6%) 0 2 (12%) 1 (6%) 2 (12%)
A1/A3 ¼ anterior mitral valve leaflet - lateral/medial segment; LVEF ¼ left ventricular ejection fraction; LVESD ¼ left ventricular endsystolic diameter; MVOA ¼ mitral valve orifice area; P1/P3 ¼ posterior mitral valve leaflet - lateral/medial segment. * One patient had a second clip procedure within 49 days due to partial clip detachment, within 849 days after index procedure there was again a partial clip detachment detected, consequently the patient was transferred to surgery for mitral valve replacement.
“multiple-clip-placements” or “zipping-by-clipping.”20,21 Therefore, one may consider >1 clip placement in primary MR to “stabilize” the initial/acute MR reduction in regard to the long-term success. Because most of the patients treated with TMVR are high-risk patients and not amenable to surgery, the “several clip strategy” may become a very important issue in secondary MR as well. Particularly, in patients with LV dilation, which might progress over years and, thus, cause further mitral annulus dilation, thus again emphasizing the ideal/earlier timing for TMVR to achieve LV remodeling. Alternative approaches may
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Figure 4. MR severity comparing baseline to longest available follow-up. MR compared from baseline to last available FUV (longest FUV) with a median of 381 days. Results are matched for baseline to longest FUV. The analysis was performed on patients alive and free from RI at each time point. Difference between EVEREST to non-EVEREST patients: p ¼ 0.221. FUV ¼ follow-up visit.
Figure 5. NYHA functional class comparing baseline to longest available follow-up. NYHA functional class compared from baseline to last available FUV (longest FUV) with a median of 652 days. Results are matched for baseline to longest FUV. The analysis was performed on patients alive and free from RI at each time point. Difference between EVEREST to non-EVEREST patients: p ¼ 0.253. FUV ¼ follow-up visit.
include the combination of percutaneous MV annuloplasty with TMVR and interventional MV replacements. One limitation of the study is the relatively small number of enrolled patients, although our study displays one of the largest, published single-center experiences yet. Moreover, our study population consisted of a very heterogeneous
group with patients not amenable to surgery and others denying surgery after detailed education considering the available and recommended therapy options. Finally, no imputation for the deceased patients’ data was performed. This might have led to an overestimation of the positive effects caused by TMVR.
Valvular Heart Disease/MitraClip Outcome According to EVEREST Criteria
Disclosures Prof. Mehilli and Prof. Hausleiter received speaker honoraria from Abbot Vascular. Dr. Sonne and Dr. Lesevic received speaker honoraria and travel grants from Abbott Vascular. Dr. Orban received speaker honoraria from Roche and travel grants from Abbott Vascular, Bayer, and Roche. Prof. Schunkert received lecture fees from AstraZeneca, Bayer Vital, Brahms GmbH, Medtronic, Mitsubishi Pharma, MSD SHARP and DOHME, Novartis, Servier, Takeda, Cordis, Genzyme, and Synlab, speaker honoraria from Sanofi-Aventis and Daiichi-Sankyo and grants from BristolMyers Squibb. Prof. Kastrati received lecture fees from Daiichi-Sankyo and lecture fees and fees for advisory board activities from Astra-Zeneca. All other authors have no conflicts of interest to declare.
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functional mitral regurgitation and missing leaflet coaptation: is it still an exclusion criterion? Eur J Heart Fail 2016;18:1278e1286. Feldman T, Kar S, Rinaldi M, Fail P, Hermiller J, Smalling R, Whitlow PL, Gray W, Low R, Herrmann HC, Lim S, Foster E, Glower D; EVEREST Investigators. Percutaneous mitral repair with the MitraClip system: safety and midterm durability in the initial EVEREST (Endovascular Valve Edge-to-Edge REpair Study) cohort. J Am Coll Cardiol 2009;54:686e694. Mauri L, Garg P, Massaro JM, Foster E, Glower D, Mehoudar P, Powell F, Komtebedde J, McDermott E, Feldman T. The EVEREST II trial: design and rationale for a randomized study of the evalve mitraclip system compared with mitral valve surgery for mitral regurgitation. Am Heart J 2010;160:23e29. Lancellotti P, Tribouilloy C, Hagendorff A, Popescu BA, Edvardsen T, Pierard LA, Badano L, Zamorano JL; Scientific Document Committee of the European Association of Cardiovascular Imaging. Recommendations for the echocardiographic assessment of native valvular regurgitation: an executive summary from the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 2013;14: 611e644. Foster E, Wasserman HS, Gray W, Homma S, Di Tullio MR, Rodriguez L, Stewart WJ, Whitlow P, Block P, Martin R, Merlino J, Herrmann HC, Wiegers SE, Silvestry FE, Hamilton A, Zunamon A, Kraybill K, Gerber IL, Weeks SG, Zhang Y, Feldman T. Quantitative assessment of severity of mitral regurgitation by serial echocardiography in a multicenter clinical trial of percutaneous mitral valve repair. Am J Cardiol 2007;100:1577e1583. Zoghbi WA, Enriquez-Sarano M, Foster E, Grayburn PA, Kraft CD, Levine RA, Nihoyannopoulos P, Otto CM, Quinones MA, Rakowski H, Stewart WJ, Waggoner A, Weissman NJ; American Society of Echocardiography. Recommendations for evaluation of the severity of native valvular regurgitation with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr 2003;16:777e802. Franzen O, van der Heyden J, Baldus S, Schluter M, Schillinger W, Butter C, Hoffmann R, Corti R, Pedrazzini G, Swaans MJ, Neuss M, Rudolph V, Surder D, Grunenfelder J, Eulenburg C, Reichenspurner H, Meinertz T, Auricchio A. MitraClip(R) therapy in patients with end-stage systolic heart failure. Eur J Heart Fail 2011;13:569e576. Puls M, Lubos E, Boekstegers P, von Bardeleben RS, Ouarrak T, Butter C, Zuern CS, Bekeredjian R, Sievert H, Nickenig G, Eggebrecht H, Senges J, Schillinger W. One-year outcomes and predictors of mortality after MitraClip therapy in contemporary clinical practice: results from the German Transcatheter Mitral Valve Interventions registry. Eur Heart J 2016;37:703e712. Swaans MJ, Bakker AL, Alipour A, Post MC, Kelder JC, de Kroon TL, Eefting FD, Rensing BJ, Van der Heyden JA. Survival of transcatheter mitral valve repair compared with surgical and conservative treatment in high-surgical-risk patients. JACC Cardiovasc Interv 2014;7: 875e881. De Bonis M, Taramasso M, Lapenna E, Denti P, La Canna G, Buzzatti N, Pappalardo F, Di Giannuario G, Cioni M, Giacomini A, Alfieri O. MitraClip therapy and surgical edge-to-edge repair in patients with severe left ventricular dysfunction and secondary mitral regurgitation: mid-term results of a single-centre experience. Eur J Cardiothorac Surg 2016;49:255e262. Alegria-Barrero E, Chan PH, Foin N, Syrseloudis D, Tavazzi G, Price S, Lindsay AC, Duncan A, Moat N, Di Mario C, Franzen OW. Concept of the central clip: when to use one or two MitraClips(R). EuroIntervention 2014;9:1217e1224. Paranskaya L, D’Ancona G, Bozdag-Turan I, Akin I, Kische S, Turan GR, Divchev D, Rehders T, Westphal B, Schubert J, Nienaber CA, Ince H. Percutaneous mitral valve repair with the MitraClip system: perioperative and 1-year follow-up results using standard or multiple clipping strategy. Catheter Cardiovasc Interv 2013;81:1224e1231. Safian RD. Percutaneous mitral valve repair for mitral regurgitation: zipping-by-clipping. Catheter Cardiovasc Interv 2013;81:1232e1233. Singh GD, Smith TW, Rogers JH. Multi-MitraClip therapy for severe degenerative mitral regurgitation: “Anchor” technique for extremely flail segments. Catheter Cardiovasc Interv 2015;86:339e346.
a Department of Cardiology, Deutsches Herzzentrum München, cDepartment of Cardiology, Klinikum Rechts der Isar, eDepartment of Radiology, Deutsches Herzzentrum München, and gElse Kröner-Fresenius-Center for Nutritional Medicine, Technische Universität München, Munich, Germany; b Department of Cardiology, Campus Grobhadern, Ludwig-MaximiliansUniversität München, Munich, Germany; dDepartment of Cardiology, Schön Klinik Starnberger See, Berg, Germany; and fDZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany. Manuscript received September 30, 2016; revised manuscript received and accepted December 14, 2016. Drs Sonne and Hausleiter contributed equally to this work. See page 1261 for disclosure information. *Corresponding author: Tel: (þ49) 89-1218-0; fax: (þ49) 89-1218-4013. E-mail address: [email protected] (H. Lesevic).
0002-9149/17/$ - see front matter Ó 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2016.12.027
functional class.3e5 All patients included in the EVEREST II (Endovascular Valve Edge-to-Edge Repair Study) trial were primarily candidates for surgery and had “ideal” anatomic criteria.3 Nevertheless, in everyday clinical practice, numerous patients are treated with TMVR who would have primarily been excluded from the EVEREST II trial and are still outside currently considered “good candidates” for TMVR. Recommendations for patient selection with ideal, moderate, and not suitable anatomic criteria for TMVR have been published.6 Such factors are also considered prognostic for procedural success.6 Two previous studies showed comparable results in patients with and without EVEREST criteria basically in secondary MR.7,8 Although this was limited by a small sample size and a short duration of follow-up. Thus, we analyzed our patient population treated with TMVR according to the presence or absence of EVEREST inclusion criteria and compared the procedural success and long-term outcome, repair durability, and prognostic factors. Methods This observational cohort study was conducted from September 2009 to July 2012. All included patients gave written informed consent before entering the study that complies with the Declaration of Helsinki and was approved by the institutional ethics committee. Consecutive patients with symptomatic MR and placement of at least 1 clip were included in these analyses—after discussion with the heart team. www.ajconline.org
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Figure 1. Key anatomic inclusion criteria of the EVEREST trials modified after Feldman et al.9 A2/P2 ¼ central segment of the anterior/posterior MV leaflet; LVEF ¼ left ventricular ejection fraction; LVESD ¼ left ventricular endsystolic diameter; MVOA ¼ mitral valve orifice area.
All those patients who would have been eligible for the EVEREST II trial (see also Figure 19) formed group 1 and were assigned as EVEREST patients. The remainder of patients, who were not conform to the anatomic inclusion criteria were allocated as non-EVEREST patients (group 2). Full inclusion and exclusion criteria of the EVEREST trials have been reported previously.3,10 Exclusion criteria used by this team were MV orifice area 2 cm2, active endocarditis and thrombus. All patients underwent 2-dimensional (2D) transthoracic and 2D and 3D transesophageal echocardiography before intervention to assess valve morphology, MR severity, and suitability for TMVR. MR quantification was performed according to international guidelines and graded from 1 þ to 4þ.11e13 All procedures were performed with transesophageal echocardiography and fluoroscopic guidance as previously described.3,14e16 After TMVR, TTE was conducted before discharge and at regular appointed follow-up visits. The clinical outcome was assessed by New York Heart Association (NYHA) functional class and 6-minute walking test (6mWT). If a return visit was not possible, a telephone follow-up was performed. End points included all-cause mortality, reintervention (RI, i.e., second TMVR and/or MV surgery), MR severity, NYHA class, and distance in the 6mWT at the latest follow-up visit.
Categorical data are reported as absolute numbers or percentages and were compared between the groups using chi-square test or Fisher’s exact test. Continuous variables are presented as mean SDs and were compared between the groups using t tests. Time to the occurrence of an end point and each of the individual components were analyzed using Kaplan-Meier method. The log-rank test was used to compare the time-to-event end points between the groups. The events are presented as Kaplan-Meier estimates in percentage and in absolute numbers. A Cox proportional hazards model was used for assessing the independent factors associated with RI and logistic regression for independent factors associated with MR 3þ at follow-up. All p values reported are 2 sided and a p value of <0.05 was considered statistically significant. Data analysis was performed with IBM SPSS Statistics, version 22, and R 2.15.1 package (The R foundation for Statistical Computing, Vienna, Austria). Results One hundred thirty-four consecutive patients were treated by TMVR (Figure 2). In 6 patients, a sufficient MR reduction of grade I or more could not be achieved. Consequently, the primary success rate was 95.5% (97% in
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Figure 2. Study flow chart.
group 1 vs 95% in group 2, p ¼ 0.694). Baseline demographic and clinical characteristics are listed in Table 1. Reasons of non-EVEREST conformity are specified in Table 2. The number of implanted clips did not differ between the groups: in group 1 one clip per procedure was placed in 42 (71%), 2 clips in 16 patients (27%), and 3 clips in 1 patient (2%); whereas in group 2 one clip was placed in 52 (69%), 2 clips in 22 patients (29%), and 3 clips in 1 patient (1%), respectively (p ¼ 0.95). A similar mean acute MR reduction was seen in both groups (2.3 0.9 vs 2.2 1, respectively; p ¼ 0.497). One hundred thirty-one patients (97.8%) were followed up to 3.5 years with a median of 992 days (836 to 1,148). During the follow-up, 32 patients died: 5 patients during hospital stay after index procedure, whereas 27 deaths occurred >30 days after index TMVR and were not adjudicated as procedure related (further details in Figure 2). There was no significant difference in the survival rate (Figure 3, Table 3) and in residual/recurrent MR defined as MR 3þ at follow-up—although by trend more frequent in group 2 (14 of 50 patients presented with MR 3þ in group 1 vs 27 of 60 patients in group 2; p ¼ 0.066, OR 0.48 [0.21 to 1.06]). Repeat TMVR was increased by trend, whereas MV surgery was significantly increased in group 2 (Table 3). Combining these 2 end points as RI, there are significantly more RI in group 2 (Figure 3). Altogether, 21 patients needed an RI during follow-up: 17 patients presented with primary MR (81%)
and 4 patients (19%) with secondary MR (p ¼ 0.031). In group 1, all 4 patients with RI displayed a primary MR, whereas in group 2, 13 patients presented with primary and 4 patients with secondary MR. Table 4 lists the distribution of the anatomic criteria of all non-EVEREST patients with and without RI. Variables with a p value 0.05 were entered into Cox proportional hazards model. Flail width was found to be an independent predictor for RI, whereas flail gap 10 mm displayed a strong trend (flail width: adjusted hazard ratio 11.2, 95% confidence interval 2.6 to 48.3; p ¼ 0.001; flail gap: adjusted hazard ratio 3.1, 95% confidence interval 0.9 to 11.5; p ¼ 0.077). When entering the variables into logistic regression analyses for identifying independent factors associated with MR 3þ at follow-up, only flail gap 10 mm displayed a trend (p ¼ 0.082). A significant MR reduction (Figure 4) and an improvement in NYHA class (Figure 5) were maintained in most of the patients. The walking distance in the 6mWT extended significantly in both cohorts but without a difference regarding EVEREST conformity (in group 1: from 299 123 m to 353 131 m, p ¼ 0.014, vs in group 2: from 305 94 m to 348 124 m, p ¼ 0.032; p ¼ 0.715 for difference). Discussion This is the first study investigating the prognostic effect of the EVEREST inclusion criteria on acute and long-term
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Table 1 Baseline characteristics Variable
EVEREST (n¼59)
non-EVEREST (n¼75)
Age (years) 72.8 10.4 73.8 10.2 Women 18 (31%) 34 (45%) Systemic hypertension 47 (80%) 63 (84%) Diabetes mellitus 8 (14%) 13 (17%) Coronary artery disease 30 (51%) 40 (53%) Previous myocardial 12 (20%) 14 (19%) infarction Previous percutaneous 24 (41%) 35 (47%) coronary intervention Previous coronary11 (19%) 13 (17%) artery bypass grafting Atrial fibrillation 34 (58%) 46 (61%) Left ventricular ejection 47.5 15.8 43.4 19.3 fraction (%) Implanted electrical device 12 (20%) 29 (39%) (pacemaker/ implantable cardioverter defibrillator/ cardiac resynchronization therapy device) Impaired renal function 16 (27%) 19 (25%) Pulmonary disease 24 (41%) 24 (32%) Previous stroke 7 (12%) 9 (12%) New York Heart Association functional class II 8 (14%) 3 (4%) III 35 (59%) 50 (67%) IV 16 (27%) 22 (29%) Mitral regurgitation / etiology primary 36 (61%) 44 (59%) secondary 23 (39%) 31 (41%) Mitral regurgitation / severity III/IV 26 (44%) 28 (37%) IV/IV 33 (56%) 47 (63%) Logistic EuroSCORE I, %; 12.9 (4.0 e 28.2) 14 (6.6 e 25.5) median (25th e 75th percentile) STS mortality score, %; 10.7 (3.7 e 12.8) 10.1 (3.9 e 20.8) median (25th e 75th percentile)
p value
Table 2 All non-EVEREST patients according to EVEREST exclusion criteria (n¼75) EVEREST exclusion criteria
0.510 0.108 0.651 0.636 0.862 0.829 0.599 1.000 0.724 0.217 0.025
0.845 0.365 1.000 0.152
0.860
0.480
0.728
0.967
Data are given as mean SD, unless otherwise stated. EuroSCORE I ¼ European System for Cardiac Operative Risk Evaluation I; STS ¼ Society of Thoracic Surgery.
outcome and on repair durability up to 3.5 years after TMVR—both in primary and secondary MR. We could demonstrate a significant reduction of MR severity with a primary success rate of 95.5%—regardless of the EVEREST criteria and MR etiology. Although 56.9% of our patient population would have been excluded from the EVEREST II trial, we achieved comparable acute results in both groups. Nevertheless, non-EVEREST patients were significantly more likely to be treated by RI due to MR recurrence. This is probably because of complex MV pathologies. Taking those 17 patients into account who were non-EVEREST
Main pathology in P1- and/or A1-segment (prolapse þ/- flail) Main pathology in P3- and/or A3-segment (prolapse þ/- flail) Morbus Barlow with flail gap < 10 mm with flail gap 10 mm with bileaflet flail Flail gap 10 mm Flail width > 15 mm with MVOA < 4 cm2 MVOA < 4 cm2 with prolapse þ flail gap < 10 mm with LVEF 20% Prior mitral valve surgery with prolapse þ flail gap < 10 mm with prior Alfieri suture þ MVOA < 4 cm2 with prior annuloplasty Coaptation length < 2 mm Cleft LVEF < 25 % and/or LVESD > 55 mm
Number of patients 11 (15%) 9 (12%) 5 (7%) 2 1 1 6 (8%) 3 (4%) 1 3 (4%) 1 1 2 (3%) 1 1 14 (19%) 4 (5%) 18 (24%)
A1/A3 ¼ anterior mitral valve leaflet - lateral/medial segment; LVEF ¼ left ventricular ejection fraction; LVESD ¼ left ventricular endsystolic diameter; MVOA ¼ mitral valve orifice area; P1/P3 ¼ posterior mitral valve leaflet - lateral/medial segment.
and needed an RI, only 4 patients displayed a secondary MR—2 of those with a coaptation length <2 mm. The remaining 13 patients presented with complex primary MV pathologies. Of note, the presence of flail width >15 mm was predictive for need for RI, whereas flail gap 10 mm indicated a strong trend. Moreover, all the EVEREST patients who needed an RI displayed a primary MR. Thus, our results support the assumption of previous studies that selected patients especially with secondary MR can benefit more from TMVR.3e5,14,16 Furthermore, high-risk patients with advanced LV dysfunction not amenable to surgery may derive particular benefit from TMVR8,16,17 and should not be precluded from this treatment option even if the coaptation length is <2 mm. Similarly, Adamo et al8 suggested an extension of the use of TMVR to patients with secondary MR including patients with a coaptation length <2 mm. Moreover, Adamo et al did not observe a significant reverse remodeling in their study population which might be because of a more advanced stage of disease (i.e., more dilated left ventricle and lower LV ejection fraction).8 Therefore, an earlier intervention in secondary MR might be of prognostic relevance in clinical outcome and in terms of sufficient MR reduction. Attizzani et al7 demonstrated similar rates of safety and efficacy in their patient population according to EVEREST criteria through a 12-month follow-up. They reported only 2 second clip procedures with no MV surgery. This very low RI rate might be associated with the high amount of secondary MR included (>80% had secondary MR),7 whereas in our cohort 59.7% of the patients presented with primary MR. However, even primary MR with medial and lateral MV
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Figure 3. (A) End point with death of any cause. Kaplan-Meier estimates freedom from death of any cause. Blue line indicates EVEREST patients (n ¼ 59), red line indicates non-EVEREST patients (n ¼ 75). (B) End point with RI. Kaplan-Meier estimates freedom from RI composed of MV surgery and second TMVR. Blue line indicates EVEREST patients (n ¼ 59) and red line indicates non-EVEREST patients (n ¼ 75).
Table 3 Long-term clinical outcome
Table 4 Comparison of all non-EVEREST patients with and without reintervention
Variable
EVEREST non-EVEREST (n¼59) (n¼75)
Hazard Ratio [95 % CI]
p value
Death of any cause Reintervention second clip procedure mitral valve surgery
14 (28%)
18 (27%)
0.85 [0.42-1.72]
0.656
4 (11%) 1 (2%)
17 (37%) 7 (13%)
0.24 [0.08-0.71] 0.16 [0.02-1.29]
0.010 0.085
3 (9%)
11 (28%)
0.27 [0.08-0.98]
0.047
Events are presented as absolute numbers and Kaplan-Meier estimates in percentage. CI ¼ confidence interval.
pathologies can be successfully treated by TMVR with comparable long-term results to the “ideal” central pathology, but it is technically more challenging. Altogether, high-risk patients with suboptimal anatomic criteria should not be deprived of TMVR and there is a need for establishing new eligibility criteria—particularly in the hands of experienced TMVR users. Nonetheless, it is very important to carefully select the patients and to have an interdisciplinary approach by a “heart team” for developing the ideal treatment plan and for identifying the high-risk/inoperable patients in whom TMVR is feasible—especially if a patient’s anatomy is not in accordance with the EVEREST inclusion criteria. In particular, improvements in the interventional strategy are warranted for reducing the need for RI. In our study, there was no significant difference in the number of clips implanted comparing EVEREST to non-EVEREST patients (most often 1 clip per procedure was placed). Previous studies have shown that especially in primary MR often >1 clip per procedure is needed.18,19 There are actually some case reports presenting treatment strategies with
EVEREST II exclusion criteria
Main pathology in P1-/A1- and/or P3-/A3-segment Barlow’s disease Flail gap 10 mm Flail width > 15 mm MVOA < 4 cm2 Prior mitral valve surgery Coaptation length < 2 mm Cleft LVEF < 25 % and/or LVESD > 55 mm
Reintervention
p value
Yes (n¼17)
No (n¼58)
3 (18%)
16 (28%)
0.407
3 (5%) 4 (7%) 0 4 (7%) 2 (4%) 12 (21%) 3 (5%) 18 (31%)
0.338 0.051 0.001 0.883 0.438 0.406 0.909 0.114
2 4* 3 1
(12%) (24%) (18%) (6%) 0 2 (12%) 1 (6%) 2 (12%)
A1/A3 ¼ anterior mitral valve leaflet - lateral/medial segment; LVEF ¼ left ventricular ejection fraction; LVESD ¼ left ventricular endsystolic diameter; MVOA ¼ mitral valve orifice area; P1/P3 ¼ posterior mitral valve leaflet - lateral/medial segment. * One patient had a second clip procedure within 49 days due to partial clip detachment, within 849 days after index procedure there was again a partial clip detachment detected, consequently the patient was transferred to surgery for mitral valve replacement.
“multiple-clip-placements” or “zipping-by-clipping.”20,21 Therefore, one may consider >1 clip placement in primary MR to “stabilize” the initial/acute MR reduction in regard to the long-term success. Because most of the patients treated with TMVR are high-risk patients and not amenable to surgery, the “several clip strategy” may become a very important issue in secondary MR as well. Particularly, in patients with LV dilation, which might progress over years and, thus, cause further mitral annulus dilation, thus again emphasizing the ideal/earlier timing for TMVR to achieve LV remodeling. Alternative approaches may
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Figure 4. MR severity comparing baseline to longest available follow-up. MR compared from baseline to last available FUV (longest FUV) with a median of 381 days. Results are matched for baseline to longest FUV. The analysis was performed on patients alive and free from RI at each time point. Difference between EVEREST to non-EVEREST patients: p ¼ 0.221. FUV ¼ follow-up visit.
Figure 5. NYHA functional class comparing baseline to longest available follow-up. NYHA functional class compared from baseline to last available FUV (longest FUV) with a median of 652 days. Results are matched for baseline to longest FUV. The analysis was performed on patients alive and free from RI at each time point. Difference between EVEREST to non-EVEREST patients: p ¼ 0.253. FUV ¼ follow-up visit.
include the combination of percutaneous MV annuloplasty with TMVR and interventional MV replacements. One limitation of the study is the relatively small number of enrolled patients, although our study displays one of the largest, published single-center experiences yet. Moreover, our study population consisted of a very heterogeneous
group with patients not amenable to surgery and others denying surgery after detailed education considering the available and recommended therapy options. Finally, no imputation for the deceased patients’ data was performed. This might have led to an overestimation of the positive effects caused by TMVR.
Valvular Heart Disease/MitraClip Outcome According to EVEREST Criteria
Disclosures Prof. Mehilli and Prof. Hausleiter received speaker honoraria from Abbot Vascular. Dr. Sonne and Dr. Lesevic received speaker honoraria and travel grants from Abbott Vascular. Dr. Orban received speaker honoraria from Roche and travel grants from Abbott Vascular, Bayer, and Roche. Prof. Schunkert received lecture fees from AstraZeneca, Bayer Vital, Brahms GmbH, Medtronic, Mitsubishi Pharma, MSD SHARP and DOHME, Novartis, Servier, Takeda, Cordis, Genzyme, and Synlab, speaker honoraria from Sanofi-Aventis and Daiichi-Sankyo and grants from BristolMyers Squibb. Prof. Kastrati received lecture fees from Daiichi-Sankyo and lecture fees and fees for advisory board activities from Astra-Zeneca. All other authors have no conflicts of interest to declare.
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