Clinical and haemodynamic outcomes of balloon-expandable transcatheter mitral valve implantation: a 7-year experience

Clinical and haemodynamic outcomes of balloon-expandable transcatheter mitral valve implantation:... Abstract Aims We analysed the early and long-term clinical and haemodynamic outcomes of balloon-expandable transcatheter mitral valve implantation (TMVI) in an experienced centre. Methods and results All patients undergoing TMVI from July 2010 to July 2017 in our centre were prospectively included. Indication for TMVI relied on the judgement of the local heart team. Patients were followed at 1 month, 1 year, and yearly thereafter. A total of 91 patients underwent TMVI. The median age was 73 (57–81) years and 70% of patients were women. Patients were at high risk for surgery with a median EuroSCORE II of 9.6 (4.0–14.6) %. Indication for TMVI was bioprosthesis failure (valve-in-valve) in 37.3%, annuloplasty failure (valve-in-ring) in 33.0%, and severe mitral annulus calcification (MAC) in 29.7%. The transseptal approach was used in 92.3% of patients and balloon-expandable valves were used in all patients. Technical success was achieved in 84.6% of patients, one patient died during the procedure and haemodynamically significant left ventricular outflow tract obstruction occurred in three patients (3.3%). At 30 days, 7.7% of patients had died, without significant differences between groups, and a major stroke occurred in 2.2% of patients. The cumulative rates of all-cause mortality at 1-year and 2-year follow-up were 21.0% [95% confidence interval (CI) 9.9–38.8] and 35.7% (95% CI 19.2–56.5), respectively, with a higher late mortality in patients with MAC. The 2-year rates of re-intervention and valve thrombosis were 8.8% and 14.4%, respectively. At 6 months to 1 year, 68.9% of patients were in New York Heart Association Class I or II, and 90.7% of patients had mild or less mitral regurgitation. The mean transmitral gradient decreased from 9.3 ± 3.9 mmHg at baseline to 6.0 ± 2.3 mmHg at discharge (P < 0.001) without changes at 6-month to 1-year follow-up. Conclusion Transcatheter mitral valve implantation using balloon-expandable valves in selected patients with bioprosthesis or annuloplasty failure or severe MAC was associated with a low rate of peri-procedural complications and acceptable long-term outcomes. Transseptal, Transcatheter mitral valve implantation, Bioprosthesis failure, Annuloplasty failure, Mitral annulus calcification Introduction Transcatheter valve therapies initially emerged as an alternative to surgery for patients with heart valve disease and unmet treatment needs. Being rapidly adopted, its use has been greatly expanded and, nowadays, transcatheter aortic valve implantation (TAVI) and percutaneous mitral valve repair have become routine therapies.1,2 Although transcatheter mitral valve implantation (TMVI) is occasionally used in the setting of clinical research for the treatment of native valve disease, in clinical practice it is used to treat patients with bioprosthesis3,4 or annuloplasty ring failure5 or degenerative mitral valve disease with severe mitral annulus calcification (MAC).6 Nowadays, there are very limited data on commercial TMVI results and the existing evidence is mostly derived from multicentre case series compiling the very first experience of centres with limited follow-up.7–9 The lack of standardized recommendations for TMVI and clinical practices has resulted in a wide variability in the indications, techniques, and approaches used.3,5,7,8 This heterogeneity of data might have limited the reliability of the reported conclusions.7,8 We aimed to evaluate the safety and long-term clinical and haemodynamic results of valve-in-valve (ViV), valve-in-ring (ViR), and valve-in-MAC (ViMAC) TMVI performed by experienced operators in a single-centre study using the transseptal approach as the default. Methods Patient population All 91 patients undergoing TMVI in our centre from July 2010 to July 2017 were included. Indications for TMVI were severe symptomatic mitral valve disease due to bioprosthesis or ring failure or severe MAC in high-risk or inoperable patients in whom the heart team favoured percutaneous intervention over surgery. A small subset of the population consisted of young women with a desire for pregnancy or current pregnancy in whom TMVI was considered to avoid or delay a surgical reintervention, which should have been bioprosthesis implantation in these specific cases. Data were prospectively collected in local electronic case report forms. Mitral annulus calcification was defined as the presence of severe calcification of the mitral annulus covering at least 180° of the circumference. Outcomes were defined according to the Mitral Valve Academic Research Consortium (MVARC).10 Events occurring before the publication of the MVARC were retrospectively defined. Left ventricular outflow tract (LVOT) obstruction was defined as an increase in the LVOT gradient of >30 mmHg in basal conditions as evaluated by echocardiography. Haemodynamically significant LVOT obstruction was defined as a LVOT with a maximum gradient ≥50 mmHg in basal conditions. No provocative manoeuvers were systematically performed to detect subclinical LVOT obstruction, and exercise echocardiography was used only if discrepancy between symptoms and LVOT gradient was observed. Valve thrombosis was defined as the presence of at least one thickened leaflet with restricted motion or a mobile mass suggestive of thrombus confirmed by transoesophageal echocardiography (TOE) and contrast computed tomography (CT). Severe structural valve deterioration was defined as an irreversible failure of the transcatheter heart valve (THV) resulting in an increase of the transmitral gradients with a mean gradient >10 mmHg or >5 mmHg change from baseline, or severe, new or worsening (>2+/4+) intra-prosthetic mitral regurgitation.11 All patients signed consent forms before the procedures. The study complies with the Declaration of Helsinki and was carried out in accordance with the local legislation. Transcatheter mitral valve implantation work-up, approach selection, and procedures Transcatheter mitral valve implantation work-up description has been previously reported.12 Briefly, in addition to standard pre-operative examination, TOE and contrast CT were performed in order to identify concomitant diseases contraindicating the procedure (i.e. active endocarditis, severe paravalvular leaks, or partial disinsertion of mitral bioprosthesis or ring), confirm the feasibility of the procedure, evaluate the risk of LVOT obstruction, high residual transmitral gradients and paravalvular leaks, and to determine the size of the THV. The risk of LVOT obstruction was assessed after careful evaluation of all contributing factors [LVOT and left ventricular cavity dimensions, mitral-aorta angle (23) and the morphology of the anterior leaflet and subvalvular apparatus] by TOE and CT and the analysis of the dimensions of the neo-LVOT after simulation of the THV on CT images.12 In patients with an end-systole neo-LVOT <100 mm2, the risk of LVOT obstruction was considered prohibitive. All procedures were performed by a team of interventional cardiologists and cardiac surgeons, under general anaesthesia, with TOE and fluoroscopy guidance, using the SAPIEN XT or SAPIEN 3 THV (Edwards Lifesciences, Irvine, CA, USA). The default approach was transseptal except for the first two cases, which were performed via the transapical approach. Transseptal and transapical procedures were performed as previously described.12,13 Cases with severe MAC judged at high risk for LVOT obstruction underwent a preventive treatment: (i) alcohol septal ablation (ASA) in patients with a high risk or a contraindication for surgery and a risk of LVOT mainly due to the presence of a septal bulge and favourable coronary anatomy for ASA (presence of approachable septal perforator branches)13; (ii) hybrid TMVI using the transatrial approach in patients at high risk but operable and unfavourable anatomy for ASA, in order to resect the anterior leaflet and subvalvular apparatus before the implantation of the THV, and in those with concomitant valvular heart disease requiring surgery. The transatrial hybrid procedures were performed on-pump in the operating room.14 After sternotomy, the mitral valve was reached through the left atrium. After excision of the anterior leaflet and subvalvular apparatus, a stiff wire (Safari wire, Boston Scientific, Natick, MA, USA) was placed at the apex of the left ventricle. The THV was then advanced very carefully on the wire and deployed on direct visual guidance with a very slow inflation in order to adjust the position if necessary before the final implantation. The Certitude Delivery system was used. Once the THV was implanted and the patient weaned from cardiopulmonary bypass, a TOE evaluation was performed. No contrast injection was used during the procedures. The decision of post-dilation or implantation of a second prosthesis relied on the mechanism of the paravalvular leak deducted by careful evaluation (incomplete expansion or malposition). Antithrombotic therapy Anticoagulation with intravenous heparin was administered during the procedures (70 UI/Kg for transseptal and transapical TMVI and 300 UI/Kg for transatrial hybrid TMVI). Anticoagulation at therapeutic levels with heparin was restarted 2 h after transseptal and 6 h after transapical and hybrid procedures in the absence of complication. In addition, patients received 75 mg/day of aspirin which was initiated before the procedure. In the absence of contraindication, patients were discharged with vitamin K antagonists (VKA) with a target international normalized ratio of 2–3 and aspirin 75 mg/day for the first 3 months at least. VKA were discontinued thereafter if TOE confirmed the absence of valve thrombosis in patients who had no other indication for long-term anticoagulation therapy. In patients in whom valve thrombosis was detected, VKA were restarted lifelong. Follow-up All patients were followed up after the procedure at 1 month, 6 months, 1 year, and yearly thereafter through inpatient or outpatient clinic visits. No patient was lost to follow-up. Transthoracic- and TOE examinations were performed by expert echocardiographers at each visit. At 6 to 12-month follow-up, echocardiographic data were available in 54 patients, 90% of patients alive at that point. In addition, contrast CT was planned at each visit if no contraindication, in order to detect THV thrombosis or displacement. A total of 83.5% patients underwent at least one contrast CT examination after hospital discharge. More than one contrast CT examination was performed in 60% of patients alive at 6 months follow-up. Patients with severe kidney disease did not undergo contrast CT during the follow-up period. Statistical analysis Categorical variables are presented as frequencies and continuous variables as mean (standard deviation) or median (interquartile range) according to variable distribution. The Fisher exact test was used to compare qualitative variables. Comparisons of continuous variables were performed using the Analysis of Variance (ANOVA) or Kruskal–Wallis tests as appropriate. Tukey test for multiple comparisons was used if statistical significance was achieved. Cumulative outcomes at 1- and 2-year follow-up were assessed by the Kaplan–Meier estimates. The log-rank tests were used to compare survival curves. Univariate and multivariate Cox regression models were used to assess the association between the type of procedure and cumulative outcomes. Hazard proportional assumptions were confirmed by means of log-minus-log survival plots. A repeated measures model with interactions was used to compare the changes in mean transmitral gradient and area and mitral regurgitation. Pairwise multiple comparisons were performed using the Bonferroni adjustment for multiple testing. A P-value <0.05 was considered statistically significant and all tests were two-sided. All statistical analyses were conducted using the Statistical Package for Social Sciences, version 20 (SPSS Inc., IBM, New York, NY, USA) and JMP version 10.0 (SAS Institute Inc., Cary, NC, USA). Results Patients Baseline clinical and echocardiographic characteristics of the study population are displayed in Table 1. The median age was 73 (57–81) years and 64 patients (70.3%) were women. Five patients (5.5%) with cardiogenic shock underwent a rescue TMVI in an emergent setting. Patients were judged at high risk for surgery with a median EuroSCORE II of 9.6% (4.0–14.6) and median Logistic EuroSCORE of 16.7% (9.1–31.7). Overall, indications for TMVI were bioprosthesis failure in 34 (37. 3%) patients, ring annuloplasty failure in 30 (33.0%) patients and mitral disease with severe MAC in 27 (29.7%). The median time from last surgery to TMVI was 8 (4–11) years. The initial mitral disease is shown in Supplementary material online, Table S1. A mean transmitral gradient >5 mmHg was observed in 82.4% of patients and a mitral regurgitation ≥2/4 in 52.7%. Seven (25.9%) patients with MAC were considered at high risk for LVOT obstruction, requiring either preventive ASA [2 patients (7.4%), 21 and 97 days before TMVI] or resection of the anterior mitral leaflet using a hybrid approach (five patients, 18.5%). Main clinical and echocardiographic characteristics according to the indication of TMVI (ViV, ViR, and ViMAC) are shown in Table 1. Table 1 Baseline characteristics of the study population Entire cohort (n = 91) Valve-in-valve (n = 34) Valve-in-ring (n = 30) Valve-in-MAC (n = 27) P-value Clinical characteristics  Age (years) 73 (57–81) 73 (52–84) 70 (48–84) 73 (68–81) 0.305  Female 64 (70.3) 24 (70.6) 21 (70.0) 19 (70.4) 0.999  Body mass index (kg/m2) 26 ± 5 24 ± 5 26 ± 6 27 ± 5 0.070  NYHA class ≥III 79 (86.8) 31 (91.2) 24 (80.0) 24 (88.9) 0.461  Diabetes mellitus 22 (24.2) 6 (17.6) 4 (13.3) 12 (44.4)a,b 0.018  COPD 23 (25.3) 7 (20.6) 9 (30.0) 7 (25.9) 0.656  eGFR <60 mL/min 57 (62.6) 23 (67.6) 17 (56.7) 17 (62.9) 0.550  Paroxysmal/chronic AF 48 (52.7) 18 (52.9) 20 (66.7) 10 (37.0) 0.088  Coronary artery disease 32 (35.2) 12 (35.3) 8 (26.7) 12 (44.4) 0.373  Porcelain aorta 3 (3.3) 0 1 (3.3) 2 (7.4) 0.196  Hostile thorax/chest radiation 15 (16.5) 3 (8.8) 6 (20.0) 6 (22.2) 0.312  Previous cardiac surgery 78 (85.7) 34 (100) 30 (100) 14 (51.9) <0.001  Urgency of the procedure 0.155   Elective or urgent 86 (94.5) 30 (88.2) 29 (96.7) 27 (100)   Emergent or salvage 5 (5.5) 4 (11.8) 1 (3.3) 0  EuroSCORE II (%) 9.6 (4.0–14.6) 10.9 (5.5–18.5) 9.6 (3.7–12.8) 7.3 (3.0–14.0) 0.186  Logistic EuroSCORE 16.7 (9.1–31.7) 20.6 (12.5–39.6) 13.7 (7.2–30.2) 14.7 (9.2–20.6) 0.101 Medication  Diuretics 74 (81.3) 25 (73.5) 24 (80.0) 25 (92.6) 0.056  Anticoagulation 50 (54.9) 16 (47.1) 20 (66.7) 14 (44.4) 0.317  Statins 36 (39.6) 13 (38.2) 11 (36.7) 12 (46.2) 0.740 Echocardiographic findings  LVEF (%) 58 ± 10 58 ± 10 57 ± 10 57 ± 11 0.906  Left ventricular end-diastolic diameter (mm) 49 ± 8 49 ± 8 52 ± 9 47 ± 7b 0.033  Left ventricular end-systolic diameter (mm) 32 ± 9 31 ± 9 35 ± 8 28 ± 9b 0.034  Septal thickness (mm) 15 ± 4 17 ± 5 15 ± 4 15 ± 3 0.577  Peak mitral gradient >20 mmHg 45 (49.5) 20 (58.8) 10 (33.3) 15 (55.6) 0.052  Mean mitral gradient >5 mmHg 75 (82.4) 30 (88.2) 21 (70) 24 (88.9) 0.065  Mitral regurgitation ≥2/4 48 (52.7) 16 (47.1) 18 (60) 14 (51.8) 0.544  Left atrium area (cm2) 32 (28–38) 30 (27–37) 39 (29–45) 31 (28–38) 0.441  PASP (mmHg) 56 ± 14 59 ± 18 52 ± 11 55 ± 12 0.163  Tricuspid regurgitation >2/4 30 (33.0) 11 (34.4) 12 (40.0) 7 (25.9) 0.543 Entire cohort (n = 91) Valve-in-valve (n = 34) Valve-in-ring (n = 30) Valve-in-MAC (n = 27) P-value Clinical characteristics  Age (years) 73 (57–81) 73 (52–84) 70 (48–84) 73 (68–81) 0.305  Female 64 (70.3) 24 (70.6) 21 (70.0) 19 (70.4) 0.999  Body mass index (kg/m2) 26 ± 5 24 ± 5 26 ± 6 27 ± 5 0.070  NYHA class ≥III 79 (86.8) 31 (91.2) 24 (80.0) 24 (88.9) 0.461  Diabetes mellitus 22 (24.2) 6 (17.6) 4 (13.3) 12 (44.4)a,b 0.018  COPD 23 (25.3) 7 (20.6) 9 (30.0) 7 (25.9) 0.656  eGFR <60 mL/min 57 (62.6) 23 (67.6) 17 (56.7) 17 (62.9) 0.550  Paroxysmal/chronic AF 48 (52.7) 18 (52.9) 20 (66.7) 10 (37.0) 0.088  Coronary artery disease 32 (35.2) 12 (35.3) 8 (26.7) 12 (44.4) 0.373  Porcelain aorta 3 (3.3) 0 1 (3.3) 2 (7.4) 0.196  Hostile thorax/chest radiation 15 (16.5) 3 (8.8) 6 (20.0) 6 (22.2) 0.312  Previous cardiac surgery 78 (85.7) 34 (100) 30 (100) 14 (51.9) <0.001  Urgency of the procedure 0.155   Elective or urgent 86 (94.5) 30 (88.2) 29 (96.7) 27 (100)   Emergent or salvage 5 (5.5) 4 (11.8) 1 (3.3) 0  EuroSCORE II (%) 9.6 (4.0–14.6) 10.9 (5.5–18.5) 9.6 (3.7–12.8) 7.3 (3.0–14.0) 0.186  Logistic EuroSCORE 16.7 (9.1–31.7) 20.6 (12.5–39.6) 13.7 (7.2–30.2) 14.7 (9.2–20.6) 0.101 Medication  Diuretics 74 (81.3) 25 (73.5) 24 (80.0) 25 (92.6) 0.056  Anticoagulation 50 (54.9) 16 (47.1) 20 (66.7) 14 (44.4) 0.317  Statins 36 (39.6) 13 (38.2) 11 (36.7) 12 (46.2) 0.740 Echocardiographic findings  LVEF (%) 58 ± 10 58 ± 10 57 ± 10 57 ± 11 0.906  Left ventricular end-diastolic diameter (mm) 49 ± 8 49 ± 8 52 ± 9 47 ± 7b 0.033  Left ventricular end-systolic diameter (mm) 32 ± 9 31 ± 9 35 ± 8 28 ± 9b 0.034  Septal thickness (mm) 15 ± 4 17 ± 5 15 ± 4 15 ± 3 0.577  Peak mitral gradient >20 mmHg 45 (49.5) 20 (58.8) 10 (33.3) 15 (55.6) 0.052  Mean mitral gradient >5 mmHg 75 (82.4) 30 (88.2) 21 (70) 24 (88.9) 0.065  Mitral regurgitation ≥2/4 48 (52.7) 16 (47.1) 18 (60) 14 (51.8) 0.544  Left atrium area (cm2) 32 (28–38) 30 (27–37) 39 (29–45) 31 (28–38) 0.441  PASP (mmHg) 56 ± 14 59 ± 18 52 ± 11 55 ± 12 0.163  Tricuspid regurgitation >2/4 30 (33.0) 11 (34.4) 12 (40.0) 7 (25.9) 0.543 AF, atrial fibrillation; COPD, chronic obstructive pulmonary disease; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; PASP, pulmonary artery systolic pressure. a P < 0.05 vs. valve-in-valve. b P < 0.05 vs. valve-in-ring. Table 1 Baseline characteristics of the study population Entire cohort (n = 91) Valve-in-valve (n = 34) Valve-in-ring (n = 30) Valve-in-MAC (n = 27) P-value Clinical characteristics  Age (years) 73 (57–81) 73 (52–84) 70 (48–84) 73 (68–81) 0.305  Female 64 (70.3) 24 (70.6) 21 (70.0) 19 (70.4) 0.999  Body mass index (kg/m2) 26 ± 5 24 ± 5 26 ± 6 27 ± 5 0.070  NYHA class ≥III 79 (86.8) 31 (91.2) 24 (80.0) 24 (88.9) 0.461  Diabetes mellitus 22 (24.2) 6 (17.6) 4 (13.3) 12 (44.4)a,b 0.018  COPD 23 (25.3) 7 (20.6) 9 (30.0) 7 (25.9) 0.656  eGFR <60 mL/min 57 (62.6) 23 (67.6) 17 (56.7) 17 (62.9) 0.550  Paroxysmal/chronic AF 48 (52.7) 18 (52.9) 20 (66.7) 10 (37.0) 0.088  Coronary artery disease 32 (35.2) 12 (35.3) 8 (26.7) 12 (44.4) 0.373  Porcelain aorta 3 (3.3) 0 1 (3.3) 2 (7.4) 0.196  Hostile thorax/chest radiation 15 (16.5) 3 (8.8) 6 (20.0) 6 (22.2) 0.312  Previous cardiac surgery 78 (85.7) 34 (100) 30 (100) 14 (51.9) <0.001  Urgency of the procedure 0.155   Elective or urgent 86 (94.5) 30 (88.2) 29 (96.7) 27 (100)   Emergent or salvage 5 (5.5) 4 (11.8) 1 (3.3) 0  EuroSCORE II (%) 9.6 (4.0–14.6) 10.9 (5.5–18.5) 9.6 (3.7–12.8) 7.3 (3.0–14.0) 0.186  Logistic EuroSCORE 16.7 (9.1–31.7) 20.6 (12.5–39.6) 13.7 (7.2–30.2) 14.7 (9.2–20.6) 0.101 Medication  Diuretics 74 (81.3) 25 (73.5) 24 (80.0) 25 (92.6) 0.056  Anticoagulation 50 (54.9) 16 (47.1) 20 (66.7) 14 (44.4) 0.317  Statins 36 (39.6) 13 (38.2) 11 (36.7) 12 (46.2) 0.740 Echocardiographic findings  LVEF (%) 58 ± 10 58 ± 10 57 ± 10 57 ± 11 0.906  Left ventricular end-diastolic diameter (mm) 49 ± 8 49 ± 8 52 ± 9 47 ± 7b 0.033  Left ventricular end-systolic diameter (mm) 32 ± 9 31 ± 9 35 ± 8 28 ± 9b 0.034  Septal thickness (mm) 15 ± 4 17 ± 5 15 ± 4 15 ± 3 0.577  Peak mitral gradient >20 mmHg 45 (49.5) 20 (58.8) 10 (33.3) 15 (55.6) 0.052  Mean mitral gradient >5 mmHg 75 (82.4) 30 (88.2) 21 (70) 24 (88.9) 0.065  Mitral regurgitation ≥2/4 48 (52.7) 16 (47.1) 18 (60) 14 (51.8) 0.544  Left atrium area (cm2) 32 (28–38) 30 (27–37) 39 (29–45) 31 (28–38) 0.441  PASP (mmHg) 56 ± 14 59 ± 18 52 ± 11 55 ± 12 0.163  Tricuspid regurgitation >2/4 30 (33.0) 11 (34.4) 12 (40.0) 7 (25.9) 0.543 Entire cohort (n = 91) Valve-in-valve (n = 34) Valve-in-ring (n = 30) Valve-in-MAC (n = 27) P-value Clinical characteristics  Age (years) 73 (57–81) 73 (52–84) 70 (48–84) 73 (68–81) 0.305  Female 64 (70.3) 24 (70.6) 21 (70.0) 19 (70.4) 0.999  Body mass index (kg/m2) 26 ± 5 24 ± 5 26 ± 6 27 ± 5 0.070  NYHA class ≥III 79 (86.8) 31 (91.2) 24 (80.0) 24 (88.9) 0.461  Diabetes mellitus 22 (24.2) 6 (17.6) 4 (13.3) 12 (44.4)a,b 0.018  COPD 23 (25.3) 7 (20.6) 9 (30.0) 7 (25.9) 0.656  eGFR <60 mL/min 57 (62.6) 23 (67.6) 17 (56.7) 17 (62.9) 0.550  Paroxysmal/chronic AF 48 (52.7) 18 (52.9) 20 (66.7) 10 (37.0) 0.088  Coronary artery disease 32 (35.2) 12 (35.3) 8 (26.7) 12 (44.4) 0.373  Porcelain aorta 3 (3.3) 0 1 (3.3) 2 (7.4) 0.196  Hostile thorax/chest radiation 15 (16.5) 3 (8.8) 6 (20.0) 6 (22.2) 0.312  Previous cardiac surgery 78 (85.7) 34 (100) 30 (100) 14 (51.9) <0.001  Urgency of the procedure 0.155   Elective or urgent 86 (94.5) 30 (88.2) 29 (96.7) 27 (100)   Emergent or salvage 5 (5.5) 4 (11.8) 1 (3.3) 0  EuroSCORE II (%) 9.6 (4.0–14.6) 10.9 (5.5–18.5) 9.6 (3.7–12.8) 7.3 (3.0–14.0) 0.186  Logistic EuroSCORE 16.7 (9.1–31.7) 20.6 (12.5–39.6) 13.7 (7.2–30.2) 14.7 (9.2–20.6) 0.101 Medication  Diuretics 74 (81.3) 25 (73.5) 24 (80.0) 25 (92.6) 0.056  Anticoagulation 50 (54.9) 16 (47.1) 20 (66.7) 14 (44.4) 0.317  Statins 36 (39.6) 13 (38.2) 11 (36.7) 12 (46.2) 0.740 Echocardiographic findings  LVEF (%) 58 ± 10 58 ± 10 57 ± 10 57 ± 11 0.906  Left ventricular end-diastolic diameter (mm) 49 ± 8 49 ± 8 52 ± 9 47 ± 7b 0.033  Left ventricular end-systolic diameter (mm) 32 ± 9 31 ± 9 35 ± 8 28 ± 9b 0.034  Septal thickness (mm) 15 ± 4 17 ± 5 15 ± 4 15 ± 3 0.577  Peak mitral gradient >20 mmHg 45 (49.5) 20 (58.8) 10 (33.3) 15 (55.6) 0.052  Mean mitral gradient >5 mmHg 75 (82.4) 30 (88.2) 21 (70) 24 (88.9) 0.065  Mitral regurgitation ≥2/4 48 (52.7) 16 (47.1) 18 (60) 14 (51.8) 0.544  Left atrium area (cm2) 32 (28–38) 30 (27–37) 39 (29–45) 31 (28–38) 0.441  PASP (mmHg) 56 ± 14 59 ± 18 52 ± 11 55 ± 12 0.163  Tricuspid regurgitation >2/4 30 (33.0) 11 (34.4) 12 (40.0) 7 (25.9) 0.543 AF, atrial fibrillation; COPD, chronic obstructive pulmonary disease; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; PASP, pulmonary artery systolic pressure. a P < 0.05 vs. valve-in-valve. b P < 0.05 vs. valve-in-ring. Procedural findings and outcomes The transseptal approach was used in 92.3% of all patients and the SAPIEN 3 THV in the 58.2% of cases. Main procedural findings and outcomes in the study population and according to study groups are shown in Table 2. Post-dilation was more frequently used in ViR patients (35.7%, P = 0.009 for comparisons between groups) and a second prosthesis was more frequently implanted in ViMAC patients (25.9%, P = 0.025 for comparisons between groups). Table 2 Procedural findings and outcomes Entire cohort (n = 91) Valve-in-valve (n = 34) Valve-in-ring (n = 30) Valve-in-MAC (n = 27) P-value Procedural findings  Approach   Transeptal 84 (92.3) 32 (94.1) 30 (100) 22 (81.5) 0.027   Transapical/Hybrid surgery 7 (7.7) 2 (5.9) 0 5 (18.5)  Prosthesis type   SAPIEN XT 37 (40.7) 15 (44.1) 17 (58.6) 5 (18.5) 0.008   SAPIEN 3 53 (58.2) 19 (55.9) 12 (41.4) 22 (81.5)a,b  Prosthesis size (mm)   23 6 (6.6) 2 (5.9) 4 (13.8) 0 <0.001   26 49 (53.8) 16 (47.1) 22 (75.9)c 11 (40.7)b   29 35 (38.5) 16 (47.1) 3 (10.3)c 16 (59.3)  Post-dilatation 17 (18.7) 2 (5.9) 10 (35.7)c 5 (18.5) 0.009  Need for a second valve 13 (14.3) 1 (2.9) 5 (16.7) 6 (22.2)a 0.043 Procedural outcomes  Technical success 77 (84.6) 32 (94.1) 24 (80.0) 21 (77.7) 0.196  Death 1 (1.1) 1 (2.9) 0 0 0.999  Conversion to surgery 2 (2.2) 0 2 (6.7) 0 0.192  Tamponade 0 — — — —  Haemodynamically significant LVOT obstruction (gradient ≥50 mmHg) 3 (3.3) 1 (2.9) 0 2 (7.4) 0.388  Prosthesis embolization 2 (2.2) 1 (2.9) 1 (3.4) 0 0.999 Entire cohort (n = 91) Valve-in-valve (n = 34) Valve-in-ring (n = 30) Valve-in-MAC (n = 27) P-value Procedural findings  Approach   Transeptal 84 (92.3) 32 (94.1) 30 (100) 22 (81.5) 0.027   Transapical/Hybrid surgery 7 (7.7) 2 (5.9) 0 5 (18.5)  Prosthesis type   SAPIEN XT 37 (40.7) 15 (44.1) 17 (58.6) 5 (18.5) 0.008   SAPIEN 3 53 (58.2) 19 (55.9) 12 (41.4) 22 (81.5)a,b  Prosthesis size (mm)   23 6 (6.6) 2 (5.9) 4 (13.8) 0 <0.001   26 49 (53.8) 16 (47.1) 22 (75.9)c 11 (40.7)b   29 35 (38.5) 16 (47.1) 3 (10.3)c 16 (59.3)  Post-dilatation 17 (18.7) 2 (5.9) 10 (35.7)c 5 (18.5) 0.009  Need for a second valve 13 (14.3) 1 (2.9) 5 (16.7) 6 (22.2)a 0.043 Procedural outcomes  Technical success 77 (84.6) 32 (94.1) 24 (80.0) 21 (77.7) 0.196  Death 1 (1.1) 1 (2.9) 0 0 0.999  Conversion to surgery 2 (2.2) 0 2 (6.7) 0 0.192  Tamponade 0 — — — —  Haemodynamically significant LVOT obstruction (gradient ≥50 mmHg) 3 (3.3) 1 (2.9) 0 2 (7.4) 0.388  Prosthesis embolization 2 (2.2) 1 (2.9) 1 (3.4) 0 0.999 LVOT, left ventricular outflow tract. a P < 0.05 vs. valve-in-valve. b P < 0.05 vs. valve-in-ring. c P < 0.05 vs. valve-in-valve. Table 2 Procedural findings and outcomes Entire cohort (n = 91) Valve-in-valve (n = 34) Valve-in-ring (n = 30) Valve-in-MAC (n = 27) P-value Procedural findings  Approach   Transeptal 84 (92.3) 32 (94.1) 30 (100) 22 (81.5) 0.027   Transapical/Hybrid surgery 7 (7.7) 2 (5.9) 0 5 (18.5)  Prosthesis type   SAPIEN XT 37 (40.7) 15 (44.1) 17 (58.6) 5 (18.5) 0.008   SAPIEN 3 53 (58.2) 19 (55.9) 12 (41.4) 22 (81.5)a,b  Prosthesis size (mm)   23 6 (6.6) 2 (5.9) 4 (13.8) 0 <0.001   26 49 (53.8) 16 (47.1) 22 (75.9)c 11 (40.7)b   29 35 (38.5) 16 (47.1) 3 (10.3)c 16 (59.3)  Post-dilatation 17 (18.7) 2 (5.9) 10 (35.7)c 5 (18.5) 0.009  Need for a second valve 13 (14.3) 1 (2.9) 5 (16.7) 6 (22.2)a 0.043 Procedural outcomes  Technical success 77 (84.6) 32 (94.1) 24 (80.0) 21 (77.7) 0.196  Death 1 (1.1) 1 (2.9) 0 0 0.999  Conversion to surgery 2 (2.2) 0 2 (6.7) 0 0.192  Tamponade 0 — — — —  Haemodynamically significant LVOT obstruction (gradient ≥50 mmHg) 3 (3.3) 1 (2.9) 0 2 (7.4) 0.388  Prosthesis embolization 2 (2.2) 1 (2.9) 1 (3.4) 0 0.999 Entire cohort (n = 91) Valve-in-valve (n = 34) Valve-in-ring (n = 30) Valve-in-MAC (n = 27) P-value Procedural findings  Approach   Transeptal 84 (92.3) 32 (94.1) 30 (100) 22 (81.5) 0.027   Transapical/Hybrid surgery 7 (7.7) 2 (5.9) 0 5 (18.5)  Prosthesis type   SAPIEN XT 37 (40.7) 15 (44.1) 17 (58.6) 5 (18.5) 0.008   SAPIEN 3 53 (58.2) 19 (55.9) 12 (41.4) 22 (81.5)a,b  Prosthesis size (mm)   23 6 (6.6) 2 (5.9) 4 (13.8) 0 <0.001   26 49 (53.8) 16 (47.1) 22 (75.9)c 11 (40.7)b   29 35 (38.5) 16 (47.1) 3 (10.3)c 16 (59.3)  Post-dilatation 17 (18.7) 2 (5.9) 10 (35.7)c 5 (18.5) 0.009  Need for a second valve 13 (14.3) 1 (2.9) 5 (16.7) 6 (22.2)a 0.043 Procedural outcomes  Technical success 77 (84.6) 32 (94.1) 24 (80.0) 21 (77.7) 0.196  Death 1 (1.1) 1 (2.9) 0 0 0.999  Conversion to surgery 2 (2.2) 0 2 (6.7) 0 0.192  Tamponade 0 — — — —  Haemodynamically significant LVOT obstruction (gradient ≥50 mmHg) 3 (3.3) 1 (2.9) 0 2 (7.4) 0.388  Prosthesis embolization 2 (2.2) 1 (2.9) 1 (3.4) 0 0.999 LVOT, left ventricular outflow tract. a P < 0.05 vs. valve-in-valve. b P < 0.05 vs. valve-in-ring. c P < 0.05 vs. valve-in-valve. One patient with emergent rescue TMVI after surgical mitral valve replacement failure died during the procedure due to a hypovolemic shock occurring after multiple manoeuvers to place the THV within the surgical bioprosthesis, which had an intra-atrial, oblique position. These manoeuvers induced a plication of the catheter in the inferior vena cava, which probably ruptured. Overall, technical success was achieved in 84.6% of patients (94.1% of ViV, 80% of ViR, and 77.7% of ViMAC patients, P = 0.196). Two patients (2.2%) required emergent conversion to cardiac surgery: the first patient, with a left atrium of 1.5 L, had a perforation of the ascending aorta during the transseptal catheterization; the second one, with a totally radiolucent annuloplasty ring, had an embolization of the prosthesis in the left atrium despite TOE guidance. A post-TMVI haemodynamically significant LVOT obstruction with a maximum gradient ≥50 mmHg was observed in three patients (one ViV and two ViMAC). Two of them were without clinical consequences and the third one underwent successful bailout ASA due to initial haemodynamic compromise. None of the patients with preventive ASA (two patients) or resection of the anterior mitral leaflet had any significant LVOT obstruction. Prosthesis embolization occurred in two patients (2.2%), the aforementioned ViR patient and one ViV patient, due to undersizing of the THV. Thirty-day outcomes Thirty-day outcomes according to study groups are displayed in Table 3. Seven patients [7.7%; 95% confidence interval (CI) 3.7–15.5] had died, 5.8 (95% CI 2.5–13.4) % of patients with a non-emergent or salvage procedure. Thirty-day mortality among the 5 patients requiring an emergent procedure was 40 (95% CI 11.8–87.4) %. Two patients, both in the ViR group, required delayed surgical mitral valve replacement: one patient, with anterior leaflet repair with patch augmentation who had significant LVOT obstruction and high residual transmitral gradients after TMVI, and the second one, due to a partial disinsertion of the mitral ring with mitral regurgitation. A major stroke occurred in two patients (2.2, 95% CI 0.6–8.6%). An LVOT obstruction with a gradient >30 mmHg was observed in eight (8.9%; 95% CI 4.5–16.9) patients (5.9% in the ViV, 13.3% in the ViR and 7.4% in the ViMAC group, P = 0.649). In one patient this was confirmed after exercise echocardiography. No 30-day valve embolization occurred, although a slight late backwards displacement was observed in three (3.4%) patients with a ViMAC. Asymptomatic partial thrombosis of the prosthesis was detected in eight patients (9.1, 95 CI 4.7–17.4%), one of them being on extracorporeal membrane oxygenation due to advanced cardiac disease. Among them, a mild increase in transmitral gradients was detected in four (50%) patients: two ViR, one ViMAC and one VinV (delta mean gradient: 2.5 ± 1.6 mmHg). No increase in central regurgitation was observed and no embolic event occurred. Three patients (3.3%) required a percutaneous closure of the residual septal defect. In one patient the procedure was performed immediately after TMVI because of a severe right-to-left interatrial shunt resulting in oxygen desaturation after the retrieval of the delivery system. In the other two patients, the procedure was performed 5 and 7 days after TMVI due to the occurrence of heart failure and oxygen desaturation attributable to severe right-to-left interatrial shunt. Table 3 Thirty-day outcomes following transcatheter mitral valve implantation Entire cohort (n = 91) Valve-in-valve (n = 34) Valve-in-ring (n = 30) Valve-in-MAC (n = 27) P-value Death 7 (7.7) 2 (5.9) 2 (6.7) 3 (11.1) 0.788 Surgical mitral valve replacement 4 (4.4) 0 4 (13.3) 0 0.017 Stroke 4 (4.4) 2 (5.9) 0 2 (7.4) 0.455  Major 2 (2.2) 0 0 2 (7.4) 0.086  Minor 2 (2.2) 2 (5.9) 0 0 0.329 Life-threatening or fatal bleeding 4 (4.4) 2 (5.9) 1 (3.3) 1 (3.7) 0.999 Major vascular complications 6 (6.7) 2 (5.9) 2 (6.7) 2 (7.4) 0.999 LVOT obstruction (ΔP increase >30 mmHg) 8 (8.8) 2 (5.9) 4 (13.3) 2 (7.4) 0.648 Late valve embolization 0 — — — — Slight late displacement of the THV 3 (3.3) 0 0 3 (11.1) 0.023 THV thrombosis 8 (8.8) 3 (8.8) 2 (6.7) 3 (11.1) 0.900 Entire cohort (n = 91) Valve-in-valve (n = 34) Valve-in-ring (n = 30) Valve-in-MAC (n = 27) P-value Death 7 (7.7) 2 (5.9) 2 (6.7) 3 (11.1) 0.788 Surgical mitral valve replacement 4 (4.4) 0 4 (13.3) 0 0.017 Stroke 4 (4.4) 2 (5.9) 0 2 (7.4) 0.455  Major 2 (2.2) 0 0 2 (7.4) 0.086  Minor 2 (2.2) 2 (5.9) 0 0 0.329 Life-threatening or fatal bleeding 4 (4.4) 2 (5.9) 1 (3.3) 1 (3.7) 0.999 Major vascular complications 6 (6.7) 2 (5.9) 2 (6.7) 2 (7.4) 0.999 LVOT obstruction (ΔP increase >30 mmHg) 8 (8.8) 2 (5.9) 4 (13.3) 2 (7.4) 0.648 Late valve embolization 0 — — — — Slight late displacement of the THV 3 (3.3) 0 0 3 (11.1) 0.023 THV thrombosis 8 (8.8) 3 (8.8) 2 (6.7) 3 (11.1) 0.900 LVOT, left ventricular outflow tract; MR, mitral regurgitation; THV, transcatheter heart valve; TMVI, transcatheter mitral valve implantation; ΔP, basal maximal gradient. Table 3 Thirty-day outcomes following transcatheter mitral valve implantation Entire cohort (n = 91) Valve-in-valve (n = 34) Valve-in-ring (n = 30) Valve-in-MAC (n = 27) P-value Death 7 (7.7) 2 (5.9) 2 (6.7) 3 (11.1) 0.788 Surgical mitral valve replacement 4 (4.4) 0 4 (13.3) 0 0.017 Stroke 4 (4.4) 2 (5.9) 0 2 (7.4) 0.455  Major 2 (2.2) 0 0 2 (7.4) 0.086  Minor 2 (2.2) 2 (5.9) 0 0 0.329 Life-threatening or fatal bleeding 4 (4.4) 2 (5.9) 1 (3.3) 1 (3.7) 0.999 Major vascular complications 6 (6.7) 2 (5.9) 2 (6.7) 2 (7.4) 0.999 LVOT obstruction (ΔP increase >30 mmHg) 8 (8.8) 2 (5.9) 4 (13.3) 2 (7.4) 0.648 Late valve embolization 0 — — — — Slight late displacement of the THV 3 (3.3) 0 0 3 (11.1) 0.023 THV thrombosis 8 (8.8) 3 (8.8) 2 (6.7) 3 (11.1) 0.900 Entire cohort (n = 91) Valve-in-valve (n = 34) Valve-in-ring (n = 30) Valve-in-MAC (n = 27) P-value Death 7 (7.7) 2 (5.9) 2 (6.7) 3 (11.1) 0.788 Surgical mitral valve replacement 4 (4.4) 0 4 (13.3) 0 0.017 Stroke 4 (4.4) 2 (5.9) 0 2 (7.4) 0.455  Major 2 (2.2) 0 0 2 (7.4) 0.086  Minor 2 (2.2) 2 (5.9) 0 0 0.329 Life-threatening or fatal bleeding 4 (4.4) 2 (5.9) 1 (3.3) 1 (3.7) 0.999 Major vascular complications 6 (6.7) 2 (5.9) 2 (6.7) 2 (7.4) 0.999 LVOT obstruction (ΔP increase >30 mmHg) 8 (8.8) 2 (5.9) 4 (13.3) 2 (7.4) 0.648 Late valve embolization 0 — — — — Slight late displacement of the THV 3 (3.3) 0 0 3 (11.1) 0.023 THV thrombosis 8 (8.8) 3 (8.8) 2 (6.7) 3 (11.1) 0.900 LVOT, left ventricular outflow tract; MR, mitral regurgitation; THV, transcatheter heart valve; TMVI, transcatheter mitral valve implantation; ΔP, basal maximal gradient. Long-term cumulative outcomes At a median (interquartile range) follow-up of 13 (4–26) months, 30 (33.0%) patients had died, 26.4% from cardiovascular causes. Cumulative rates of all-cause mortality at 1-year and 2-year follow-up were 21.0% (95% CI 9.9–38.8) and 35.7% (95% CI 19.2–56.5), respectively. One-year cardiovascular mortality was 17.3% (95% CI 7.3–34.7) and 2-year, 26.4% (95% CI 12.5–47.1). Table 4 shows cumulative outcomes according to the indication of the procedure. Patients with ViMAC had higher mortality [hazard ration (HR) 2.39, 95% CI 1.01–5.86; P = 0.046] and a trend towards higher cardiovascular mortality (HR 2.80, 95% CI 0.94–8.46; P = 0.162) (Figure 1A and B). Univariate predictors of all-cause mortality are shown in Supplementary material online, Table S2. A ViMAC procedure (HR 3.49, 95% CI 1.44–8.48; P = 0.006), the presence of tricuspid regurgitation >2 (HR 2.73, 95% CI 1.23–1.07; P = 0.014) at baseline and the EuroSCORE-2 (HR 1.04, 95% CI 1.01–1.07; P = 0.009) were independent predictors of all-cause cumulative mortality after TMVI. Table 4 Cumulative clinical outcomes of transcatheter mitral valve implantation Entire cohort (n = 91) Valve-in-valve (n = 34) Valve-in-ring (n = 30) Valve-in-MAC (n = 27) P-value Death  n (%) 30 (33.0) 8 (23.5) 10 (33.3) 12 (44.4)  HR (95% CI) 1.0 0.82 (0.29–2.31) 2.39 (1.01–5.86)a 0.046 Cardiovascular death  n (%) 24 (26.4) 5 (14.7) 10 (33.3) 9 (33.3)  HR (95% CI) 1.0 1.30 (0.40–4.16) 2.80 (0.94–8.46) 0.125 Death or surgical valve replacement  n (%) 36 (39.6) 8 (23.5) 16 (53.3) 12 (44.4)  HR (95% CI) 1.0 1.58 (0.65–3.85) 2.34 (0.96–5.75) 0.175 Surgical mitral valve replacement  n (%) 7 (7.7) 0 7 (23.3) 0  HR (95% CI) 1.0 — — — Entire cohort (n = 91) Valve-in-valve (n = 34) Valve-in-ring (n = 30) Valve-in-MAC (n = 27) P-value Death  n (%) 30 (33.0) 8 (23.5) 10 (33.3) 12 (44.4)  HR (95% CI) 1.0 0.82 (0.29–2.31) 2.39 (1.01–5.86)a 0.046 Cardiovascular death  n (%) 24 (26.4) 5 (14.7) 10 (33.3) 9 (33.3)  HR (95% CI) 1.0 1.30 (0.40–4.16) 2.80 (0.94–8.46) 0.125 Death or surgical valve replacement  n (%) 36 (39.6) 8 (23.5) 16 (53.3) 12 (44.4)  HR (95% CI) 1.0 1.58 (0.65–3.85) 2.34 (0.96–5.75) 0.175 Surgical mitral valve replacement  n (%) 7 (7.7) 0 7 (23.3) 0  HR (95% CI) 1.0 — — — CI, confidence interval, HR, hazard ratio. a P < 0.05 vs. valve-in-ring. Table 4 Cumulative clinical outcomes of transcatheter mitral valve implantation Entire cohort (n = 91) Valve-in-valve (n = 34) Valve-in-ring (n = 30) Valve-in-MAC (n = 27) P-value Death  n (%) 30 (33.0) 8 (23.5) 10 (33.3) 12 (44.4)  HR (95% CI) 1.0 0.82 (0.29–2.31) 2.39 (1.01–5.86)a 0.046 Cardiovascular death  n (%) 24 (26.4) 5 (14.7) 10 (33.3) 9 (33.3)  HR (95% CI) 1.0 1.30 (0.40–4.16) 2.80 (0.94–8.46) 0.125 Death or surgical valve replacement  n (%) 36 (39.6) 8 (23.5) 16 (53.3) 12 (44.4)  HR (95% CI) 1.0 1.58 (0.65–3.85) 2.34 (0.96–5.75) 0.175 Surgical mitral valve replacement  n (%) 7 (7.7) 0 7 (23.3) 0  HR (95% CI) 1.0 — — — Entire cohort (n = 91) Valve-in-valve (n = 34) Valve-in-ring (n = 30) Valve-in-MAC (n = 27) P-value Death  n (%) 30 (33.0) 8 (23.5) 10 (33.3) 12 (44.4)  HR (95% CI) 1.0 0.82 (0.29–2.31) 2.39 (1.01–5.86)a 0.046 Cardiovascular death  n (%) 24 (26.4) 5 (14.7) 10 (33.3) 9 (33.3)  HR (95% CI) 1.0 1.30 (0.40–4.16) 2.80 (0.94–8.46) 0.125 Death or surgical valve replacement  n (%) 36 (39.6) 8 (23.5) 16 (53.3) 12 (44.4)  HR (95% CI) 1.0 1.58 (0.65–3.85) 2.34 (0.96–5.75) 0.175 Surgical mitral valve replacement  n (%) 7 (7.7) 0 7 (23.3) 0  HR (95% CI) 1.0 — — — CI, confidence interval, HR, hazard ratio. a P < 0.05 vs. valve-in-ring. Figure 1 View largeDownload slide Rates of overall and cardiovascular mortality. The Kaplan–Meier curves at 2-year follow-up for all-cause death (A) and cardiovascular death (B) according to the indication of transcatheter mitral valve implantation. Figure 1 View largeDownload slide Rates of overall and cardiovascular mortality. The Kaplan–Meier curves at 2-year follow-up for all-cause death (A) and cardiovascular death (B) according to the indication of transcatheter mitral valve implantation. Among ViMAC patients, 12 have died at last follow-up: eight (66.7%) from cardiovascular causes (three procedural related death, two due to heart failure, one sudden death, and two endocarditis) and four (33.3%) from non-cardiac causes. After hospital discharge, three more ViR patients required surgical mitral valve replacement (P = 0.002, Figure 2A). Kaplan–Meier curves for surgical mitral valve replacement or death at 2-year follow-up, according to the indication of the procedure, are shown in Figure 2B. The cumulative rates of 2-year re-intervention, stroke, and endocarditis were 8.8%, (95% CI 2.3–27.6), 4.5%, (95% CI 1.2–15.3), and 5.2% (95% CI 0.13–18.2), respectively. Transcatheter heart valve thrombosis occurred in three patients during the follow-up period: at 1 year (two patients) and 2.5 years (one patient). One of them had a significant increase in transmitral gradients which resolved with anticoagulation therapy. The cumulative 2 years rate of valve thrombosis was 14.4%, (95% CI 5.1–34.3). All patients were asymptomatic and thrombosis resolved in all cases with VKA. No case of late embolization was observed. Figure 2 View largeDownload slide Rates of surgical mitral valve replacement and death or surgical mitral valve replacement. The Kaplan–Meier curves at 2 years follow-up for surgical mitral valve replacement (A) and all-cause death or surgical mitral valve replacement (B) according to the study groups. Figure 2 View largeDownload slide Rates of surgical mitral valve replacement and death or surgical mitral valve replacement. The Kaplan–Meier curves at 2 years follow-up for surgical mitral valve replacement (A) and all-cause death or surgical mitral valve replacement (B) according to the study groups. Figure 3 shows the changes in New York Heart Association (NYHA) class over time. At 6-month to 1-year follow-up, 72.4% of patients were in NYHA Class I or II (vs. 17.9% at baseline, P < 0.001) and 69.2% of patients alive had at least 1 degree improvement in NYHA class at 6-month to 1-year follow-up. Figure 3 View largeDownload slide Functional status. Changes in New York Heart Association class over time. Figure 3 View largeDownload slide Functional status. Changes in New York Heart Association class over time. Subgroup of young women Twelve young women (mean age: 28 ± 6 years) underwent TMVI: a ViV TMVI was performed in five (41.7%) patients and a ViR TMVI in seven (58.3%). The desire for pregnancy in the near future (11 patients, 91.7%) or current pregnancy (one patient, 8.3%) was taken into consideration for the indication of TMVI. Three of them (25%) had previously undergone two or more cardiac surgeries. All these patients had severe mitral stenosis with a mean transmitral gradient of 13 ± 6 mmHg and three (25%) patients had in addition severe mitral regurgitation. The mean pulmonary artery systolic pressure (PASP) was of 49 ± 17 mmHg, 25% of patients had a PASP >60 mmHg and five (41.7%) patients had right ventricular dysfunction. No death, stroke, major vascular complication, or life-threatening bleeding occurred among the 12 young women undergoing TMVI (Table 5). Two out of the 12 young women had an uneventful pregnancy and delivery after successful TMVI. Table 5 Thirty-day outcomes following transcatheter mitral valve implantation in the subgroup of young women (n = 12) Young women n 95% CI event rate Death 0 0 (0–22.1) Surgical mitral valve replacement 2 16.7 (4.5–51.8) Stroke 0 0 (0–22.1)  Major — —  Minor — — Life-threatening or fatal bleeding 0 0 (0–22.1) Major vascular complications 0 0 (0–22.1) LVOT obstruction (ΔP increase >30 mmHg) 1 8.3 (1.2–46.1) Late valve embolization 0 0 (0–22.1) Slight late displacement of the THV 0 0 (0–22.1) THV thrombosis 1 8.3 (1.2–46.1) Young women n 95% CI event rate Death 0 0 (0–22.1) Surgical mitral valve replacement 2 16.7 (4.5–51.8) Stroke 0 0 (0–22.1)  Major — —  Minor — — Life-threatening or fatal bleeding 0 0 (0–22.1) Major vascular complications 0 0 (0–22.1) LVOT obstruction (ΔP increase >30 mmHg) 1 8.3 (1.2–46.1) Late valve embolization 0 0 (0–22.1) Slight late displacement of the THV 0 0 (0–22.1) THV thrombosis 1 8.3 (1.2–46.1) LVOT, left ventricular outflow tract; MR, mitral regurgitation; THV, transcatheter heart valve; TMVI, transcatheter mitral valve implantation; ΔP, basal maximal gradient. Table 5 Thirty-day outcomes following transcatheter mitral valve implantation in the subgroup of young women (n = 12) Young women n 95% CI event rate Death 0 0 (0–22.1) Surgical mitral valve replacement 2 16.7 (4.5–51.8) Stroke 0 0 (0–22.1)  Major — —  Minor — — Life-threatening or fatal bleeding 0 0 (0–22.1) Major vascular complications 0 0 (0–22.1) LVOT obstruction (ΔP increase >30 mmHg) 1 8.3 (1.2–46.1) Late valve embolization 0 0 (0–22.1) Slight late displacement of the THV 0 0 (0–22.1) THV thrombosis 1 8.3 (1.2–46.1) Young women n 95% CI event rate Death 0 0 (0–22.1) Surgical mitral valve replacement 2 16.7 (4.5–51.8) Stroke 0 0 (0–22.1)  Major — —  Minor — — Life-threatening or fatal bleeding 0 0 (0–22.1) Major vascular complications 0 0 (0–22.1) LVOT obstruction (ΔP increase >30 mmHg) 1 8.3 (1.2–46.1) Late valve embolization 0 0 (0–22.1) Slight late displacement of the THV 0 0 (0–22.1) THV thrombosis 1 8.3 (1.2–46.1) LVOT, left ventricular outflow tract; MR, mitral regurgitation; THV, transcatheter heart valve; TMVI, transcatheter mitral valve implantation; ΔP, basal maximal gradient. Changes in haemodynamics The mean transmitral gradient decreased from 9.3 ± 3.9 mmHg at baseline to 6.0 ± 2.3 mmHg at discharge (P < 0.001) without changes at 6-month to 1-year follow-up (6.3 ± 2.2 mmHg, P = 0.999). Changes in mean transmitral gradients according to study groups are shown in Figure 4A. The mean mitral valve area increased from 1.07 ± 0.32 cm2 at baseline to 1.68 ± 0.40 cm2 (P = 0.013) at discharge and 1.90 ± 0.49 cm2 at 6-month to 1-year follow-up (P = 0.001 for baseline to 1-year follow-up and P = 0.718 for discharge vs. 6-month to 1-year follow-up) (Figure 4B). Figure 4 View largeDownload slide Valve haemodynamics and the indication of transcatheter mitral valve implantation. Changes in mean transmitral gradients and mitral valve area over time according to study groups. Paired data are shown (n = 51). Figure 4 View largeDownload slide Valve haemodynamics and the indication of transcatheter mitral valve implantation. Changes in mean transmitral gradients and mitral valve area over time according to study groups. Paired data are shown (n = 51). Changes in the severity of mitral regurgitation over time are shown in Figure 5A. The mitral regurgitation grade was mild or less in 96.4% of patients at discharge and 90.7% of patients at the 6-month to 1-year follow-up. Moderate or severe mitral regurgitation at discharge was more frequent in patients with ViR procedures (10.7 vs. 0% in the other groups, P = 0.055). At 6-month to 1-year follow-up, 20% of ViR and 8.3% of ViMAC patients had moderate or severe mitral regurgitation, while no case was observed in the ViV group (P = 0.068) (Figure 5B). Figure 5 View largeDownload slide Mitral regurgitation and the indication of transcatheter mitral valve implantation. Changes in the severity of mitral regurgitation in the entire cohort (A) and rates of moderate to severe mitral regurgitation according to study groups (B) at different time points. Paired data are represented (n = 54). Figure 5 View largeDownload slide Mitral regurgitation and the indication of transcatheter mitral valve implantation. Changes in the severity of mitral regurgitation in the entire cohort (A) and rates of moderate to severe mitral regurgitation according to study groups (B) at different time points. Paired data are represented (n = 54). The severity of tricuspid regurgitation decreased at 6-month to 1-year follow-up (P = 0.009) (Figure 6). Tricuspid regurgitation >2 was observed in 34.2% at discharge and 22.2% at 6-month to 1-year follow-up (vs. 33% at baseline) (P = 0.380). A significant reduction was observed in PASP at 6-month to 1-year follow-up compared with baseline (54 ± 12 to 46 ± 11 mmHg, P = 0.002). Figure 6 View largeDownload slide Tricuspide regurgitation and transcatheter mitral valve implantation. Changes in tricuspid regurgitation over time. Paired data are represented (n = 41). Figure 6 View largeDownload slide Tricuspide regurgitation and transcatheter mitral valve implantation. Changes in tricuspid regurgitation over time. Paired data are represented (n = 41). A significant reduction was observed in left ventricular (LV) end-diastolic diameter (51 ± 9 vs. 47 ± 8 mm, P= 0.001) at the 6 to 12 months follow-up. However, no significant changes were observed in LV end-systolic diameter (32 ± 9 vs. 32 ± 9 P = 0.612) and left ventricular ejection fraction over time (58 ± 10 vs. 57± 11, P = 0.561). Twelve patients had more than 3 years of follow-up and two patients had more than 4 years follow-up. No case of structural valve deterioration was observed. Discussion This study shows that TMVI is feasible, appears to be safe when performed by experienced operators and to result in acceptable long-term clinical and haemodynamic outcomes. The anticipated safety concerns and technical challenges have slowed down the expansion of TMVI compared with TAVI. Two major issues have challenged the development of TMVI therapies: the anchoring of prostheses, hindered by the huge differences in systolic pressures between the left ventricle and the left atrium, and the risk of LVOT obstruction, which results from the anatomical proximity between the anterior leaflet and subvalvular apparatus of the mitral valve and the interventricular septum.15 Surgical bioprostheses or rings and severe MAC provide support for the anchoring of THV with sufficient radial force to counterbalance migration forces. Therefore, this study shows the results of TMVI in the three patient subsets in whom commercial balloon-expandable THVs are currently used. Although the transapical approach has been associated with an increased risk of mortality in patients undergoing TAVI, its use has been initially favoured over the transvenous, transseptal approach, due to the technical challenges of the transseptal catheterization and navigation in the left atrium using stiff catheters.3,7,8 This study shows that the transseptal approach may be safely used in most patients. Transcatheter mitral valve implantation was associated with a high rate of technical success and resulted in a reduction in transmitral gradients and mitral regurgitation, which were stable over time, and was associated with a low rate of paravalvular leaks. This translated into a significant improvement in functional class. Nonetheless, patients undergoing ViR TMVI had more frequently suboptimal haemodynamic results requiring surgery (compared with ViV and ViMAC),16 in accordance with previous reports.8,17,18 The type of surgical ring, the technique used for the repair of the anterior leaflet and subvalvular apparatus in addition to other anatomical characteristics may have an impact on the results of TMVI.12 Of note, a preceding TMVI did not preclude reoperation when necessary. The mortality associated with TMVI in this study was acceptable. Indeed, 30-day mortality is comparable to that of TAVI in real-world patients at high surgical risk19–21 including patients with failing aortic bioprostheses,22 and it is lower than that of reoperation after mitral surgery in current surgical series (∼12%),3–25 confirming the safety of TMVI when performed by experienced teams in accurately selected patients. Previous studies have shown the safety of TMVI when performed in patients with failing bioprostheses (ViV).3,8,26 However, higher mortality rates have been reported for ViR procedures (>8–11 vs. 6.7% in this study)8,26 and even more for ViMAC (∼30 vs. 11%),7 suggesting a gradient in complexity across these patient subsets and increased experience requirements. In fact, the volume per operator has been identified as a predictor of outcomes in TAVI.27 Although the initial primary mitral valve disease may have an impact on long-term outcomes after TMVI, no major impact is expected on 30-day outcomes given that parameters assessing the severity of the heart disease before TMVI were similar in all groups. Left ventricular outflow tract obstruction is one of the most feared complications and one of the main limitations of TMVI. However, its risk may be greatly reduced by an accurate screening, selection of patients and planning of the procedure.12 Only three patients had haemodynamically significant LVOT obstruction in this study, and all of them underwent TMVI at the beginning of our experience. The main mechanism of LVOT obstruction is the displacement of the anterior leaflet and subvalvular apparatus towards the septum,28 which happens in ViR and ViMAC TMVI. Thus, ASA at a distance from TMVI, as the first option, or hybrid procedures allowing for the resection of the anterior leaflet in patients with a severe MAC in whom ASA is not possible or may not be sufficient to reduce the risk of LVOT obstruction, if there is no contraindication to surgery in addition to the presence of MAC, seem promising strategies. Importantly, no patient having undergone a hybrid procedure or ASA had any significant LVOT obstruction. If it occurs during the procedure, rescue ASA may be lifesaving when haemodynamics is severely compromised. However, when the LVOT obstruction is initially well tolerated, the evolution seems favourable. Indeed, one of the patients with severe LVOT obstruction did not require any intervention early after the procedure and remained asymptomatic during the follow-up period. Repositionable and retrievable THVs may have an interest in this setting. Finally, a recent paper suggested that intentional percutaneous laceration of the anterior leaflet could prevent the occurrence of severe LVOT obstruction in five patients considered at high risk.29 However, the anterior leaflet, although lacerated, is not removed and a risk of LVOT obstruction persists. In fact, a gradient was observed in most patients. The efficacy of this technique needs to be confirmed in larger studies. Although overall cumulative long-term mortality in this study was comparable to that of TAVI or percutaneous mitral valve repair in high-risk patients, those with severe MAC had higher late mortality, mainly from cardiovascular causes, despite similar procedural mortality. Reasons for this excess mortality are largely unknown and probably related to patient intrinsic risk profile. Indeed, the presence of MAC is considered as an indicator of atherosclerosis burden,16 and has been associated with an increased risk of late cardiovascular and overall mortality.16,30,31 An accurate identification of the predictors of late mortality is necessary to improve patient selection and avoid futility and should be of utmost priority for future investigations. Concerns remain, in particular the risk of valve thrombosis, which occurred more frequently early after the procedure, although cases of late thrombosis were detected during the follow-up period. Of note, no symptom was associated with the occurrence of valve thrombosis. Extended anticoagulation therapy seems reasonable in these patients. As for surgical bioprostheses, at least 6 months of VKA therapy may be necessary after TMVI.1 Although no late THV migration occurred, late slight backward displacements were observed in three ViMAC patients. Even though the risk is reduced by an optimal sizing, this complication may occur even in patients with apparently accurate selection of the THV diameter. Thus, the potential occurrence of THV thrombosis and late backward displacement justifies a close follow-up, with clinical and echocardiographic evaluations, also required to detect valve endocarditis and degeneration. The role of CT in the long-term follow-up of these patients remains to be determined. This study provides new insights to the current evidence on TMVI results.7–9 Firstly, this is the study with the longest follow-up period (mean follow-up of 1 year). Secondly, this study provides data on late outcomes including rates of cardiovascular mortality, surgical mitral valve replacement, re-intervention, and endocarditis, for the first time. In particular, late outcomes in patients with ViMAC are unknown. Thirdly, changes in valve haemodynamics (including mitral regurgitation, mean transmitral gradient, and area) and main echocardiographic parameters (PASP, tricuspid regurgitation) are reported for the three subgroups over time, from baseline to the 6-month to 1-year follow-up. Also, this study provides data on changes in functional outcomes over time. Finally, it shows the results of TMVI in two subgroups of patients for whom it may be of particular interest: young women desiring pregnancy, given the risks associated with anticoagulation therapy and mechanical prostheses during pregnancy, and patients in cardiogenic shock, who were not evaluated in previous studies. Limitations Albeit this is the largest case series from an experienced centre, this is a single-centre study. This however provides optimal homogeneity in patient care and in data collection and analysis, but the results may not be generalizable. The evaluation of functional outcomes was limited to the assessment of the NYHA class. A lack of power to detect differences between groups cannot be ruled out. Although this study included the largest number of patients undergoing TMVI using the transseptal approach, no accurate conclusions can be drawn regarding the impact of the learning curve due to a low event rate, a limited number of patients per group and a different distribution of the study groups (ViMAC procedures were more frequently performed in the second half of the learning curve). There was no central adjudication committee. No provocative manoeuvers were used for the detection of subclinical LVOT obstruction. Conclusion In conclusion, when performed by experienced teams in adequately selected high-risk patients, TMVI is feasible, effective and safe and is associated with satisfactory long-term results. Future studies including larger populations and longer follow-up are needed to establish the precise role of TMVI in clinical practice. Supplementary material Supplementary material is available at European Heart Journal online. Conflict of interest: B.I. and A.V. received speaker’s fees from Edwards Lifesciences. D.H. is consultant and proctor for Edwards Lifesciences. The other authors do not declare any conflict of interest. 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Google Scholar CrossRef Search ADS PubMed 19 Gilard M , Eltchaninoff H , Iung B , Donzeau-Gouge P , Chevreul K , Fajadet J , Leprince P , Leguerrier A , Lievre M , Prat A , Teiger E , Lefevre T , Himbert D , Tchetche D , Carrie D , Albat B , Cribier A , Rioufol G , Sudre A , Blanchard D , Collet F , Dos Santos P , Meneveau N , Tirouvanziam A , Caussin C , Guyon P , Boschat J , Le Breton H , Collart F , Houel R , Delpine S , Souteyrand G , Favereau X , Ohlmann P , Doisy V , Grollier G , Gommeaux A , Claudel JP , Bourlon F , Bertrand B , Van Belle E , Laskar M. Registry of transcatheter aortic-valve implantation in high-risk patients . N Engl J Med 2012 ; 366 : 1705 – 1715 . Google Scholar CrossRef Search ADS PubMed 20 Eggebrecht H , Mehta RH. Transcatheter aortic valve implantation (TAVI) in Germany 2008-2014: on its way to standard therapy for aortic valve stenosis in the elderly? EuroIntervention 2016 ; 11 : 1029 – 1033 . Google Scholar CrossRef Search ADS PubMed 21 Ludman PF , Moat N , de Belder MA , Blackman DJ , Duncan A , Banya W , MacCarthy PA , Cunningham D , Wendler O , Marlee D , Hildick-Smith D , Young CP , Kovac J , Uren NG , Spyt T , Trivedi U , Howell J , Gray H. Transcatheter aortic valve implantation in the UK: temporal trends, predictors of outcome and 6 year follow up: a report from the UK TAVI registry 2007 to 2012 . Circulation 2015 ; 131 : 1181 – 1190 . Google Scholar CrossRef Search ADS PubMed 22 Webb JG , Mack MJ , White JM , Dvir D , Blanke P , Herrmann HC , Leipsic J , Kodali SK , Makkar R , Miller DC , Pibarot P , Pichard A , Satler LF , Svensson L , Alu MC , Suri RM , Leon MB. Transcatheter aortic valve implantation within degenerated aortic surgical bioprostheses partner 2 valve-in-valve registry . J Am Coll Cardiol 2017 ; 69 : 2253 – 2262 . 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Concomitant mitral annular calcification and severe aortic stenosis: prevalence, characteristics and outcome following transcatheter aortic valve replacement . Eur Heart J 2017 ; 38 : 1194 – 1203 . Google Scholar PubMed Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Heart Journal Oxford University Press

Clinical and haemodynamic outcomes of balloon-expandable transcatheter mitral valve implantation: a 7-year experience

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Oxford University Press
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.
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0195-668X
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1522-9645
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10.1093/eurheartj/ehy271
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Abstract

Abstract Aims We analysed the early and long-term clinical and haemodynamic outcomes of balloon-expandable transcatheter mitral valve implantation (TMVI) in an experienced centre. Methods and results All patients undergoing TMVI from July 2010 to July 2017 in our centre were prospectively included. Indication for TMVI relied on the judgement of the local heart team. Patients were followed at 1 month, 1 year, and yearly thereafter. A total of 91 patients underwent TMVI. The median age was 73 (57–81) years and 70% of patients were women. Patients were at high risk for surgery with a median EuroSCORE II of 9.6 (4.0–14.6) %. Indication for TMVI was bioprosthesis failure (valve-in-valve) in 37.3%, annuloplasty failure (valve-in-ring) in 33.0%, and severe mitral annulus calcification (MAC) in 29.7%. The transseptal approach was used in 92.3% of patients and balloon-expandable valves were used in all patients. Technical success was achieved in 84.6% of patients, one patient died during the procedure and haemodynamically significant left ventricular outflow tract obstruction occurred in three patients (3.3%). At 30 days, 7.7% of patients had died, without significant differences between groups, and a major stroke occurred in 2.2% of patients. The cumulative rates of all-cause mortality at 1-year and 2-year follow-up were 21.0% [95% confidence interval (CI) 9.9–38.8] and 35.7% (95% CI 19.2–56.5), respectively, with a higher late mortality in patients with MAC. The 2-year rates of re-intervention and valve thrombosis were 8.8% and 14.4%, respectively. At 6 months to 1 year, 68.9% of patients were in New York Heart Association Class I or II, and 90.7% of patients had mild or less mitral regurgitation. The mean transmitral gradient decreased from 9.3 ± 3.9 mmHg at baseline to 6.0 ± 2.3 mmHg at discharge (P < 0.001) without changes at 6-month to 1-year follow-up. Conclusion Transcatheter mitral valve implantation using balloon-expandable valves in selected patients with bioprosthesis or annuloplasty failure or severe MAC was associated with a low rate of peri-procedural complications and acceptable long-term outcomes. Transseptal, Transcatheter mitral valve implantation, Bioprosthesis failure, Annuloplasty failure, Mitral annulus calcification Introduction Transcatheter valve therapies initially emerged as an alternative to surgery for patients with heart valve disease and unmet treatment needs. Being rapidly adopted, its use has been greatly expanded and, nowadays, transcatheter aortic valve implantation (TAVI) and percutaneous mitral valve repair have become routine therapies.1,2 Although transcatheter mitral valve implantation (TMVI) is occasionally used in the setting of clinical research for the treatment of native valve disease, in clinical practice it is used to treat patients with bioprosthesis3,4 or annuloplasty ring failure5 or degenerative mitral valve disease with severe mitral annulus calcification (MAC).6 Nowadays, there are very limited data on commercial TMVI results and the existing evidence is mostly derived from multicentre case series compiling the very first experience of centres with limited follow-up.7–9 The lack of standardized recommendations for TMVI and clinical practices has resulted in a wide variability in the indications, techniques, and approaches used.3,5,7,8 This heterogeneity of data might have limited the reliability of the reported conclusions.7,8 We aimed to evaluate the safety and long-term clinical and haemodynamic results of valve-in-valve (ViV), valve-in-ring (ViR), and valve-in-MAC (ViMAC) TMVI performed by experienced operators in a single-centre study using the transseptal approach as the default. Methods Patient population All 91 patients undergoing TMVI in our centre from July 2010 to July 2017 were included. Indications for TMVI were severe symptomatic mitral valve disease due to bioprosthesis or ring failure or severe MAC in high-risk or inoperable patients in whom the heart team favoured percutaneous intervention over surgery. A small subset of the population consisted of young women with a desire for pregnancy or current pregnancy in whom TMVI was considered to avoid or delay a surgical reintervention, which should have been bioprosthesis implantation in these specific cases. Data were prospectively collected in local electronic case report forms. Mitral annulus calcification was defined as the presence of severe calcification of the mitral annulus covering at least 180° of the circumference. Outcomes were defined according to the Mitral Valve Academic Research Consortium (MVARC).10 Events occurring before the publication of the MVARC were retrospectively defined. Left ventricular outflow tract (LVOT) obstruction was defined as an increase in the LVOT gradient of >30 mmHg in basal conditions as evaluated by echocardiography. Haemodynamically significant LVOT obstruction was defined as a LVOT with a maximum gradient ≥50 mmHg in basal conditions. No provocative manoeuvers were systematically performed to detect subclinical LVOT obstruction, and exercise echocardiography was used only if discrepancy between symptoms and LVOT gradient was observed. Valve thrombosis was defined as the presence of at least one thickened leaflet with restricted motion or a mobile mass suggestive of thrombus confirmed by transoesophageal echocardiography (TOE) and contrast computed tomography (CT). Severe structural valve deterioration was defined as an irreversible failure of the transcatheter heart valve (THV) resulting in an increase of the transmitral gradients with a mean gradient >10 mmHg or >5 mmHg change from baseline, or severe, new or worsening (>2+/4+) intra-prosthetic mitral regurgitation.11 All patients signed consent forms before the procedures. The study complies with the Declaration of Helsinki and was carried out in accordance with the local legislation. Transcatheter mitral valve implantation work-up, approach selection, and procedures Transcatheter mitral valve implantation work-up description has been previously reported.12 Briefly, in addition to standard pre-operative examination, TOE and contrast CT were performed in order to identify concomitant diseases contraindicating the procedure (i.e. active endocarditis, severe paravalvular leaks, or partial disinsertion of mitral bioprosthesis or ring), confirm the feasibility of the procedure, evaluate the risk of LVOT obstruction, high residual transmitral gradients and paravalvular leaks, and to determine the size of the THV. The risk of LVOT obstruction was assessed after careful evaluation of all contributing factors [LVOT and left ventricular cavity dimensions, mitral-aorta angle (23) and the morphology of the anterior leaflet and subvalvular apparatus] by TOE and CT and the analysis of the dimensions of the neo-LVOT after simulation of the THV on CT images.12 In patients with an end-systole neo-LVOT <100 mm2, the risk of LVOT obstruction was considered prohibitive. All procedures were performed by a team of interventional cardiologists and cardiac surgeons, under general anaesthesia, with TOE and fluoroscopy guidance, using the SAPIEN XT or SAPIEN 3 THV (Edwards Lifesciences, Irvine, CA, USA). The default approach was transseptal except for the first two cases, which were performed via the transapical approach. Transseptal and transapical procedures were performed as previously described.12,13 Cases with severe MAC judged at high risk for LVOT obstruction underwent a preventive treatment: (i) alcohol septal ablation (ASA) in patients with a high risk or a contraindication for surgery and a risk of LVOT mainly due to the presence of a septal bulge and favourable coronary anatomy for ASA (presence of approachable septal perforator branches)13; (ii) hybrid TMVI using the transatrial approach in patients at high risk but operable and unfavourable anatomy for ASA, in order to resect the anterior leaflet and subvalvular apparatus before the implantation of the THV, and in those with concomitant valvular heart disease requiring surgery. The transatrial hybrid procedures were performed on-pump in the operating room.14 After sternotomy, the mitral valve was reached through the left atrium. After excision of the anterior leaflet and subvalvular apparatus, a stiff wire (Safari wire, Boston Scientific, Natick, MA, USA) was placed at the apex of the left ventricle. The THV was then advanced very carefully on the wire and deployed on direct visual guidance with a very slow inflation in order to adjust the position if necessary before the final implantation. The Certitude Delivery system was used. Once the THV was implanted and the patient weaned from cardiopulmonary bypass, a TOE evaluation was performed. No contrast injection was used during the procedures. The decision of post-dilation or implantation of a second prosthesis relied on the mechanism of the paravalvular leak deducted by careful evaluation (incomplete expansion or malposition). Antithrombotic therapy Anticoagulation with intravenous heparin was administered during the procedures (70 UI/Kg for transseptal and transapical TMVI and 300 UI/Kg for transatrial hybrid TMVI). Anticoagulation at therapeutic levels with heparin was restarted 2 h after transseptal and 6 h after transapical and hybrid procedures in the absence of complication. In addition, patients received 75 mg/day of aspirin which was initiated before the procedure. In the absence of contraindication, patients were discharged with vitamin K antagonists (VKA) with a target international normalized ratio of 2–3 and aspirin 75 mg/day for the first 3 months at least. VKA were discontinued thereafter if TOE confirmed the absence of valve thrombosis in patients who had no other indication for long-term anticoagulation therapy. In patients in whom valve thrombosis was detected, VKA were restarted lifelong. Follow-up All patients were followed up after the procedure at 1 month, 6 months, 1 year, and yearly thereafter through inpatient or outpatient clinic visits. No patient was lost to follow-up. Transthoracic- and TOE examinations were performed by expert echocardiographers at each visit. At 6 to 12-month follow-up, echocardiographic data were available in 54 patients, 90% of patients alive at that point. In addition, contrast CT was planned at each visit if no contraindication, in order to detect THV thrombosis or displacement. A total of 83.5% patients underwent at least one contrast CT examination after hospital discharge. More than one contrast CT examination was performed in 60% of patients alive at 6 months follow-up. Patients with severe kidney disease did not undergo contrast CT during the follow-up period. Statistical analysis Categorical variables are presented as frequencies and continuous variables as mean (standard deviation) or median (interquartile range) according to variable distribution. The Fisher exact test was used to compare qualitative variables. Comparisons of continuous variables were performed using the Analysis of Variance (ANOVA) or Kruskal–Wallis tests as appropriate. Tukey test for multiple comparisons was used if statistical significance was achieved. Cumulative outcomes at 1- and 2-year follow-up were assessed by the Kaplan–Meier estimates. The log-rank tests were used to compare survival curves. Univariate and multivariate Cox regression models were used to assess the association between the type of procedure and cumulative outcomes. Hazard proportional assumptions were confirmed by means of log-minus-log survival plots. A repeated measures model with interactions was used to compare the changes in mean transmitral gradient and area and mitral regurgitation. Pairwise multiple comparisons were performed using the Bonferroni adjustment for multiple testing. A P-value <0.05 was considered statistically significant and all tests were two-sided. All statistical analyses were conducted using the Statistical Package for Social Sciences, version 20 (SPSS Inc., IBM, New York, NY, USA) and JMP version 10.0 (SAS Institute Inc., Cary, NC, USA). Results Patients Baseline clinical and echocardiographic characteristics of the study population are displayed in Table 1. The median age was 73 (57–81) years and 64 patients (70.3%) were women. Five patients (5.5%) with cardiogenic shock underwent a rescue TMVI in an emergent setting. Patients were judged at high risk for surgery with a median EuroSCORE II of 9.6% (4.0–14.6) and median Logistic EuroSCORE of 16.7% (9.1–31.7). Overall, indications for TMVI were bioprosthesis failure in 34 (37. 3%) patients, ring annuloplasty failure in 30 (33.0%) patients and mitral disease with severe MAC in 27 (29.7%). The median time from last surgery to TMVI was 8 (4–11) years. The initial mitral disease is shown in Supplementary material online, Table S1. A mean transmitral gradient >5 mmHg was observed in 82.4% of patients and a mitral regurgitation ≥2/4 in 52.7%. Seven (25.9%) patients with MAC were considered at high risk for LVOT obstruction, requiring either preventive ASA [2 patients (7.4%), 21 and 97 days before TMVI] or resection of the anterior mitral leaflet using a hybrid approach (five patients, 18.5%). Main clinical and echocardiographic characteristics according to the indication of TMVI (ViV, ViR, and ViMAC) are shown in Table 1. Table 1 Baseline characteristics of the study population Entire cohort (n = 91) Valve-in-valve (n = 34) Valve-in-ring (n = 30) Valve-in-MAC (n = 27) P-value Clinical characteristics  Age (years) 73 (57–81) 73 (52–84) 70 (48–84) 73 (68–81) 0.305  Female 64 (70.3) 24 (70.6) 21 (70.0) 19 (70.4) 0.999  Body mass index (kg/m2) 26 ± 5 24 ± 5 26 ± 6 27 ± 5 0.070  NYHA class ≥III 79 (86.8) 31 (91.2) 24 (80.0) 24 (88.9) 0.461  Diabetes mellitus 22 (24.2) 6 (17.6) 4 (13.3) 12 (44.4)a,b 0.018  COPD 23 (25.3) 7 (20.6) 9 (30.0) 7 (25.9) 0.656  eGFR <60 mL/min 57 (62.6) 23 (67.6) 17 (56.7) 17 (62.9) 0.550  Paroxysmal/chronic AF 48 (52.7) 18 (52.9) 20 (66.7) 10 (37.0) 0.088  Coronary artery disease 32 (35.2) 12 (35.3) 8 (26.7) 12 (44.4) 0.373  Porcelain aorta 3 (3.3) 0 1 (3.3) 2 (7.4) 0.196  Hostile thorax/chest radiation 15 (16.5) 3 (8.8) 6 (20.0) 6 (22.2) 0.312  Previous cardiac surgery 78 (85.7) 34 (100) 30 (100) 14 (51.9) <0.001  Urgency of the procedure 0.155   Elective or urgent 86 (94.5) 30 (88.2) 29 (96.7) 27 (100)   Emergent or salvage 5 (5.5) 4 (11.8) 1 (3.3) 0  EuroSCORE II (%) 9.6 (4.0–14.6) 10.9 (5.5–18.5) 9.6 (3.7–12.8) 7.3 (3.0–14.0) 0.186  Logistic EuroSCORE 16.7 (9.1–31.7) 20.6 (12.5–39.6) 13.7 (7.2–30.2) 14.7 (9.2–20.6) 0.101 Medication  Diuretics 74 (81.3) 25 (73.5) 24 (80.0) 25 (92.6) 0.056  Anticoagulation 50 (54.9) 16 (47.1) 20 (66.7) 14 (44.4) 0.317  Statins 36 (39.6) 13 (38.2) 11 (36.7) 12 (46.2) 0.740 Echocardiographic findings  LVEF (%) 58 ± 10 58 ± 10 57 ± 10 57 ± 11 0.906  Left ventricular end-diastolic diameter (mm) 49 ± 8 49 ± 8 52 ± 9 47 ± 7b 0.033  Left ventricular end-systolic diameter (mm) 32 ± 9 31 ± 9 35 ± 8 28 ± 9b 0.034  Septal thickness (mm) 15 ± 4 17 ± 5 15 ± 4 15 ± 3 0.577  Peak mitral gradient >20 mmHg 45 (49.5) 20 (58.8) 10 (33.3) 15 (55.6) 0.052  Mean mitral gradient >5 mmHg 75 (82.4) 30 (88.2) 21 (70) 24 (88.9) 0.065  Mitral regurgitation ≥2/4 48 (52.7) 16 (47.1) 18 (60) 14 (51.8) 0.544  Left atrium area (cm2) 32 (28–38) 30 (27–37) 39 (29–45) 31 (28–38) 0.441  PASP (mmHg) 56 ± 14 59 ± 18 52 ± 11 55 ± 12 0.163  Tricuspid regurgitation >2/4 30 (33.0) 11 (34.4) 12 (40.0) 7 (25.9) 0.543 Entire cohort (n = 91) Valve-in-valve (n = 34) Valve-in-ring (n = 30) Valve-in-MAC (n = 27) P-value Clinical characteristics  Age (years) 73 (57–81) 73 (52–84) 70 (48–84) 73 (68–81) 0.305  Female 64 (70.3) 24 (70.6) 21 (70.0) 19 (70.4) 0.999  Body mass index (kg/m2) 26 ± 5 24 ± 5 26 ± 6 27 ± 5 0.070  NYHA class ≥III 79 (86.8) 31 (91.2) 24 (80.0) 24 (88.9) 0.461  Diabetes mellitus 22 (24.2) 6 (17.6) 4 (13.3) 12 (44.4)a,b 0.018  COPD 23 (25.3) 7 (20.6) 9 (30.0) 7 (25.9) 0.656  eGFR <60 mL/min 57 (62.6) 23 (67.6) 17 (56.7) 17 (62.9) 0.550  Paroxysmal/chronic AF 48 (52.7) 18 (52.9) 20 (66.7) 10 (37.0) 0.088  Coronary artery disease 32 (35.2) 12 (35.3) 8 (26.7) 12 (44.4) 0.373  Porcelain aorta 3 (3.3) 0 1 (3.3) 2 (7.4) 0.196  Hostile thorax/chest radiation 15 (16.5) 3 (8.8) 6 (20.0) 6 (22.2) 0.312  Previous cardiac surgery 78 (85.7) 34 (100) 30 (100) 14 (51.9) <0.001  Urgency of the procedure 0.155   Elective or urgent 86 (94.5) 30 (88.2) 29 (96.7) 27 (100)   Emergent or salvage 5 (5.5) 4 (11.8) 1 (3.3) 0  EuroSCORE II (%) 9.6 (4.0–14.6) 10.9 (5.5–18.5) 9.6 (3.7–12.8) 7.3 (3.0–14.0) 0.186  Logistic EuroSCORE 16.7 (9.1–31.7) 20.6 (12.5–39.6) 13.7 (7.2–30.2) 14.7 (9.2–20.6) 0.101 Medication  Diuretics 74 (81.3) 25 (73.5) 24 (80.0) 25 (92.6) 0.056  Anticoagulation 50 (54.9) 16 (47.1) 20 (66.7) 14 (44.4) 0.317  Statins 36 (39.6) 13 (38.2) 11 (36.7) 12 (46.2) 0.740 Echocardiographic findings  LVEF (%) 58 ± 10 58 ± 10 57 ± 10 57 ± 11 0.906  Left ventricular end-diastolic diameter (mm) 49 ± 8 49 ± 8 52 ± 9 47 ± 7b 0.033  Left ventricular end-systolic diameter (mm) 32 ± 9 31 ± 9 35 ± 8 28 ± 9b 0.034  Septal thickness (mm) 15 ± 4 17 ± 5 15 ± 4 15 ± 3 0.577  Peak mitral gradient >20 mmHg 45 (49.5) 20 (58.8) 10 (33.3) 15 (55.6) 0.052  Mean mitral gradient >5 mmHg 75 (82.4) 30 (88.2) 21 (70) 24 (88.9) 0.065  Mitral regurgitation ≥2/4 48 (52.7) 16 (47.1) 18 (60) 14 (51.8) 0.544  Left atrium area (cm2) 32 (28–38) 30 (27–37) 39 (29–45) 31 (28–38) 0.441  PASP (mmHg) 56 ± 14 59 ± 18 52 ± 11 55 ± 12 0.163  Tricuspid regurgitation >2/4 30 (33.0) 11 (34.4) 12 (40.0) 7 (25.9) 0.543 AF, atrial fibrillation; COPD, chronic obstructive pulmonary disease; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; PASP, pulmonary artery systolic pressure. a P < 0.05 vs. valve-in-valve. b P < 0.05 vs. valve-in-ring. Table 1 Baseline characteristics of the study population Entire cohort (n = 91) Valve-in-valve (n = 34) Valve-in-ring (n = 30) Valve-in-MAC (n = 27) P-value Clinical characteristics  Age (years) 73 (57–81) 73 (52–84) 70 (48–84) 73 (68–81) 0.305  Female 64 (70.3) 24 (70.6) 21 (70.0) 19 (70.4) 0.999  Body mass index (kg/m2) 26 ± 5 24 ± 5 26 ± 6 27 ± 5 0.070  NYHA class ≥III 79 (86.8) 31 (91.2) 24 (80.0) 24 (88.9) 0.461  Diabetes mellitus 22 (24.2) 6 (17.6) 4 (13.3) 12 (44.4)a,b 0.018  COPD 23 (25.3) 7 (20.6) 9 (30.0) 7 (25.9) 0.656  eGFR <60 mL/min 57 (62.6) 23 (67.6) 17 (56.7) 17 (62.9) 0.550  Paroxysmal/chronic AF 48 (52.7) 18 (52.9) 20 (66.7) 10 (37.0) 0.088  Coronary artery disease 32 (35.2) 12 (35.3) 8 (26.7) 12 (44.4) 0.373  Porcelain aorta 3 (3.3) 0 1 (3.3) 2 (7.4) 0.196  Hostile thorax/chest radiation 15 (16.5) 3 (8.8) 6 (20.0) 6 (22.2) 0.312  Previous cardiac surgery 78 (85.7) 34 (100) 30 (100) 14 (51.9) <0.001  Urgency of the procedure 0.155   Elective or urgent 86 (94.5) 30 (88.2) 29 (96.7) 27 (100)   Emergent or salvage 5 (5.5) 4 (11.8) 1 (3.3) 0  EuroSCORE II (%) 9.6 (4.0–14.6) 10.9 (5.5–18.5) 9.6 (3.7–12.8) 7.3 (3.0–14.0) 0.186  Logistic EuroSCORE 16.7 (9.1–31.7) 20.6 (12.5–39.6) 13.7 (7.2–30.2) 14.7 (9.2–20.6) 0.101 Medication  Diuretics 74 (81.3) 25 (73.5) 24 (80.0) 25 (92.6) 0.056  Anticoagulation 50 (54.9) 16 (47.1) 20 (66.7) 14 (44.4) 0.317  Statins 36 (39.6) 13 (38.2) 11 (36.7) 12 (46.2) 0.740 Echocardiographic findings  LVEF (%) 58 ± 10 58 ± 10 57 ± 10 57 ± 11 0.906  Left ventricular end-diastolic diameter (mm) 49 ± 8 49 ± 8 52 ± 9 47 ± 7b 0.033  Left ventricular end-systolic diameter (mm) 32 ± 9 31 ± 9 35 ± 8 28 ± 9b 0.034  Septal thickness (mm) 15 ± 4 17 ± 5 15 ± 4 15 ± 3 0.577  Peak mitral gradient >20 mmHg 45 (49.5) 20 (58.8) 10 (33.3) 15 (55.6) 0.052  Mean mitral gradient >5 mmHg 75 (82.4) 30 (88.2) 21 (70) 24 (88.9) 0.065  Mitral regurgitation ≥2/4 48 (52.7) 16 (47.1) 18 (60) 14 (51.8) 0.544  Left atrium area (cm2) 32 (28–38) 30 (27–37) 39 (29–45) 31 (28–38) 0.441  PASP (mmHg) 56 ± 14 59 ± 18 52 ± 11 55 ± 12 0.163  Tricuspid regurgitation >2/4 30 (33.0) 11 (34.4) 12 (40.0) 7 (25.9) 0.543 Entire cohort (n = 91) Valve-in-valve (n = 34) Valve-in-ring (n = 30) Valve-in-MAC (n = 27) P-value Clinical characteristics  Age (years) 73 (57–81) 73 (52–84) 70 (48–84) 73 (68–81) 0.305  Female 64 (70.3) 24 (70.6) 21 (70.0) 19 (70.4) 0.999  Body mass index (kg/m2) 26 ± 5 24 ± 5 26 ± 6 27 ± 5 0.070  NYHA class ≥III 79 (86.8) 31 (91.2) 24 (80.0) 24 (88.9) 0.461  Diabetes mellitus 22 (24.2) 6 (17.6) 4 (13.3) 12 (44.4)a,b 0.018  COPD 23 (25.3) 7 (20.6) 9 (30.0) 7 (25.9) 0.656  eGFR <60 mL/min 57 (62.6) 23 (67.6) 17 (56.7) 17 (62.9) 0.550  Paroxysmal/chronic AF 48 (52.7) 18 (52.9) 20 (66.7) 10 (37.0) 0.088  Coronary artery disease 32 (35.2) 12 (35.3) 8 (26.7) 12 (44.4) 0.373  Porcelain aorta 3 (3.3) 0 1 (3.3) 2 (7.4) 0.196  Hostile thorax/chest radiation 15 (16.5) 3 (8.8) 6 (20.0) 6 (22.2) 0.312  Previous cardiac surgery 78 (85.7) 34 (100) 30 (100) 14 (51.9) <0.001  Urgency of the procedure 0.155   Elective or urgent 86 (94.5) 30 (88.2) 29 (96.7) 27 (100)   Emergent or salvage 5 (5.5) 4 (11.8) 1 (3.3) 0  EuroSCORE II (%) 9.6 (4.0–14.6) 10.9 (5.5–18.5) 9.6 (3.7–12.8) 7.3 (3.0–14.0) 0.186  Logistic EuroSCORE 16.7 (9.1–31.7) 20.6 (12.5–39.6) 13.7 (7.2–30.2) 14.7 (9.2–20.6) 0.101 Medication  Diuretics 74 (81.3) 25 (73.5) 24 (80.0) 25 (92.6) 0.056  Anticoagulation 50 (54.9) 16 (47.1) 20 (66.7) 14 (44.4) 0.317  Statins 36 (39.6) 13 (38.2) 11 (36.7) 12 (46.2) 0.740 Echocardiographic findings  LVEF (%) 58 ± 10 58 ± 10 57 ± 10 57 ± 11 0.906  Left ventricular end-diastolic diameter (mm) 49 ± 8 49 ± 8 52 ± 9 47 ± 7b 0.033  Left ventricular end-systolic diameter (mm) 32 ± 9 31 ± 9 35 ± 8 28 ± 9b 0.034  Septal thickness (mm) 15 ± 4 17 ± 5 15 ± 4 15 ± 3 0.577  Peak mitral gradient >20 mmHg 45 (49.5) 20 (58.8) 10 (33.3) 15 (55.6) 0.052  Mean mitral gradient >5 mmHg 75 (82.4) 30 (88.2) 21 (70) 24 (88.9) 0.065  Mitral regurgitation ≥2/4 48 (52.7) 16 (47.1) 18 (60) 14 (51.8) 0.544  Left atrium area (cm2) 32 (28–38) 30 (27–37) 39 (29–45) 31 (28–38) 0.441  PASP (mmHg) 56 ± 14 59 ± 18 52 ± 11 55 ± 12 0.163  Tricuspid regurgitation >2/4 30 (33.0) 11 (34.4) 12 (40.0) 7 (25.9) 0.543 AF, atrial fibrillation; COPD, chronic obstructive pulmonary disease; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; PASP, pulmonary artery systolic pressure. a P < 0.05 vs. valve-in-valve. b P < 0.05 vs. valve-in-ring. Procedural findings and outcomes The transseptal approach was used in 92.3% of all patients and the SAPIEN 3 THV in the 58.2% of cases. Main procedural findings and outcomes in the study population and according to study groups are shown in Table 2. Post-dilation was more frequently used in ViR patients (35.7%, P = 0.009 for comparisons between groups) and a second prosthesis was more frequently implanted in ViMAC patients (25.9%, P = 0.025 for comparisons between groups). Table 2 Procedural findings and outcomes Entire cohort (n = 91) Valve-in-valve (n = 34) Valve-in-ring (n = 30) Valve-in-MAC (n = 27) P-value Procedural findings  Approach   Transeptal 84 (92.3) 32 (94.1) 30 (100) 22 (81.5) 0.027   Transapical/Hybrid surgery 7 (7.7) 2 (5.9) 0 5 (18.5)  Prosthesis type   SAPIEN XT 37 (40.7) 15 (44.1) 17 (58.6) 5 (18.5) 0.008   SAPIEN 3 53 (58.2) 19 (55.9) 12 (41.4) 22 (81.5)a,b  Prosthesis size (mm)   23 6 (6.6) 2 (5.9) 4 (13.8) 0 <0.001   26 49 (53.8) 16 (47.1) 22 (75.9)c 11 (40.7)b   29 35 (38.5) 16 (47.1) 3 (10.3)c 16 (59.3)  Post-dilatation 17 (18.7) 2 (5.9) 10 (35.7)c 5 (18.5) 0.009  Need for a second valve 13 (14.3) 1 (2.9) 5 (16.7) 6 (22.2)a 0.043 Procedural outcomes  Technical success 77 (84.6) 32 (94.1) 24 (80.0) 21 (77.7) 0.196  Death 1 (1.1) 1 (2.9) 0 0 0.999  Conversion to surgery 2 (2.2) 0 2 (6.7) 0 0.192  Tamponade 0 — — — —  Haemodynamically significant LVOT obstruction (gradient ≥50 mmHg) 3 (3.3) 1 (2.9) 0 2 (7.4) 0.388  Prosthesis embolization 2 (2.2) 1 (2.9) 1 (3.4) 0 0.999 Entire cohort (n = 91) Valve-in-valve (n = 34) Valve-in-ring (n = 30) Valve-in-MAC (n = 27) P-value Procedural findings  Approach   Transeptal 84 (92.3) 32 (94.1) 30 (100) 22 (81.5) 0.027   Transapical/Hybrid surgery 7 (7.7) 2 (5.9) 0 5 (18.5)  Prosthesis type   SAPIEN XT 37 (40.7) 15 (44.1) 17 (58.6) 5 (18.5) 0.008   SAPIEN 3 53 (58.2) 19 (55.9) 12 (41.4) 22 (81.5)a,b  Prosthesis size (mm)   23 6 (6.6) 2 (5.9) 4 (13.8) 0 <0.001   26 49 (53.8) 16 (47.1) 22 (75.9)c 11 (40.7)b   29 35 (38.5) 16 (47.1) 3 (10.3)c 16 (59.3)  Post-dilatation 17 (18.7) 2 (5.9) 10 (35.7)c 5 (18.5) 0.009  Need for a second valve 13 (14.3) 1 (2.9) 5 (16.7) 6 (22.2)a 0.043 Procedural outcomes  Technical success 77 (84.6) 32 (94.1) 24 (80.0) 21 (77.7) 0.196  Death 1 (1.1) 1 (2.9) 0 0 0.999  Conversion to surgery 2 (2.2) 0 2 (6.7) 0 0.192  Tamponade 0 — — — —  Haemodynamically significant LVOT obstruction (gradient ≥50 mmHg) 3 (3.3) 1 (2.9) 0 2 (7.4) 0.388  Prosthesis embolization 2 (2.2) 1 (2.9) 1 (3.4) 0 0.999 LVOT, left ventricular outflow tract. a P < 0.05 vs. valve-in-valve. b P < 0.05 vs. valve-in-ring. c P < 0.05 vs. valve-in-valve. Table 2 Procedural findings and outcomes Entire cohort (n = 91) Valve-in-valve (n = 34) Valve-in-ring (n = 30) Valve-in-MAC (n = 27) P-value Procedural findings  Approach   Transeptal 84 (92.3) 32 (94.1) 30 (100) 22 (81.5) 0.027   Transapical/Hybrid surgery 7 (7.7) 2 (5.9) 0 5 (18.5)  Prosthesis type   SAPIEN XT 37 (40.7) 15 (44.1) 17 (58.6) 5 (18.5) 0.008   SAPIEN 3 53 (58.2) 19 (55.9) 12 (41.4) 22 (81.5)a,b  Prosthesis size (mm)   23 6 (6.6) 2 (5.9) 4 (13.8) 0 <0.001   26 49 (53.8) 16 (47.1) 22 (75.9)c 11 (40.7)b   29 35 (38.5) 16 (47.1) 3 (10.3)c 16 (59.3)  Post-dilatation 17 (18.7) 2 (5.9) 10 (35.7)c 5 (18.5) 0.009  Need for a second valve 13 (14.3) 1 (2.9) 5 (16.7) 6 (22.2)a 0.043 Procedural outcomes  Technical success 77 (84.6) 32 (94.1) 24 (80.0) 21 (77.7) 0.196  Death 1 (1.1) 1 (2.9) 0 0 0.999  Conversion to surgery 2 (2.2) 0 2 (6.7) 0 0.192  Tamponade 0 — — — —  Haemodynamically significant LVOT obstruction (gradient ≥50 mmHg) 3 (3.3) 1 (2.9) 0 2 (7.4) 0.388  Prosthesis embolization 2 (2.2) 1 (2.9) 1 (3.4) 0 0.999 Entire cohort (n = 91) Valve-in-valve (n = 34) Valve-in-ring (n = 30) Valve-in-MAC (n = 27) P-value Procedural findings  Approach   Transeptal 84 (92.3) 32 (94.1) 30 (100) 22 (81.5) 0.027   Transapical/Hybrid surgery 7 (7.7) 2 (5.9) 0 5 (18.5)  Prosthesis type   SAPIEN XT 37 (40.7) 15 (44.1) 17 (58.6) 5 (18.5) 0.008   SAPIEN 3 53 (58.2) 19 (55.9) 12 (41.4) 22 (81.5)a,b  Prosthesis size (mm)   23 6 (6.6) 2 (5.9) 4 (13.8) 0 <0.001   26 49 (53.8) 16 (47.1) 22 (75.9)c 11 (40.7)b   29 35 (38.5) 16 (47.1) 3 (10.3)c 16 (59.3)  Post-dilatation 17 (18.7) 2 (5.9) 10 (35.7)c 5 (18.5) 0.009  Need for a second valve 13 (14.3) 1 (2.9) 5 (16.7) 6 (22.2)a 0.043 Procedural outcomes  Technical success 77 (84.6) 32 (94.1) 24 (80.0) 21 (77.7) 0.196  Death 1 (1.1) 1 (2.9) 0 0 0.999  Conversion to surgery 2 (2.2) 0 2 (6.7) 0 0.192  Tamponade 0 — — — —  Haemodynamically significant LVOT obstruction (gradient ≥50 mmHg) 3 (3.3) 1 (2.9) 0 2 (7.4) 0.388  Prosthesis embolization 2 (2.2) 1 (2.9) 1 (3.4) 0 0.999 LVOT, left ventricular outflow tract. a P < 0.05 vs. valve-in-valve. b P < 0.05 vs. valve-in-ring. c P < 0.05 vs. valve-in-valve. One patient with emergent rescue TMVI after surgical mitral valve replacement failure died during the procedure due to a hypovolemic shock occurring after multiple manoeuvers to place the THV within the surgical bioprosthesis, which had an intra-atrial, oblique position. These manoeuvers induced a plication of the catheter in the inferior vena cava, which probably ruptured. Overall, technical success was achieved in 84.6% of patients (94.1% of ViV, 80% of ViR, and 77.7% of ViMAC patients, P = 0.196). Two patients (2.2%) required emergent conversion to cardiac surgery: the first patient, with a left atrium of 1.5 L, had a perforation of the ascending aorta during the transseptal catheterization; the second one, with a totally radiolucent annuloplasty ring, had an embolization of the prosthesis in the left atrium despite TOE guidance. A post-TMVI haemodynamically significant LVOT obstruction with a maximum gradient ≥50 mmHg was observed in three patients (one ViV and two ViMAC). Two of them were without clinical consequences and the third one underwent successful bailout ASA due to initial haemodynamic compromise. None of the patients with preventive ASA (two patients) or resection of the anterior mitral leaflet had any significant LVOT obstruction. Prosthesis embolization occurred in two patients (2.2%), the aforementioned ViR patient and one ViV patient, due to undersizing of the THV. Thirty-day outcomes Thirty-day outcomes according to study groups are displayed in Table 3. Seven patients [7.7%; 95% confidence interval (CI) 3.7–15.5] had died, 5.8 (95% CI 2.5–13.4) % of patients with a non-emergent or salvage procedure. Thirty-day mortality among the 5 patients requiring an emergent procedure was 40 (95% CI 11.8–87.4) %. Two patients, both in the ViR group, required delayed surgical mitral valve replacement: one patient, with anterior leaflet repair with patch augmentation who had significant LVOT obstruction and high residual transmitral gradients after TMVI, and the second one, due to a partial disinsertion of the mitral ring with mitral regurgitation. A major stroke occurred in two patients (2.2, 95% CI 0.6–8.6%). An LVOT obstruction with a gradient >30 mmHg was observed in eight (8.9%; 95% CI 4.5–16.9) patients (5.9% in the ViV, 13.3% in the ViR and 7.4% in the ViMAC group, P = 0.649). In one patient this was confirmed after exercise echocardiography. No 30-day valve embolization occurred, although a slight late backwards displacement was observed in three (3.4%) patients with a ViMAC. Asymptomatic partial thrombosis of the prosthesis was detected in eight patients (9.1, 95 CI 4.7–17.4%), one of them being on extracorporeal membrane oxygenation due to advanced cardiac disease. Among them, a mild increase in transmitral gradients was detected in four (50%) patients: two ViR, one ViMAC and one VinV (delta mean gradient: 2.5 ± 1.6 mmHg). No increase in central regurgitation was observed and no embolic event occurred. Three patients (3.3%) required a percutaneous closure of the residual septal defect. In one patient the procedure was performed immediately after TMVI because of a severe right-to-left interatrial shunt resulting in oxygen desaturation after the retrieval of the delivery system. In the other two patients, the procedure was performed 5 and 7 days after TMVI due to the occurrence of heart failure and oxygen desaturation attributable to severe right-to-left interatrial shunt. Table 3 Thirty-day outcomes following transcatheter mitral valve implantation Entire cohort (n = 91) Valve-in-valve (n = 34) Valve-in-ring (n = 30) Valve-in-MAC (n = 27) P-value Death 7 (7.7) 2 (5.9) 2 (6.7) 3 (11.1) 0.788 Surgical mitral valve replacement 4 (4.4) 0 4 (13.3) 0 0.017 Stroke 4 (4.4) 2 (5.9) 0 2 (7.4) 0.455  Major 2 (2.2) 0 0 2 (7.4) 0.086  Minor 2 (2.2) 2 (5.9) 0 0 0.329 Life-threatening or fatal bleeding 4 (4.4) 2 (5.9) 1 (3.3) 1 (3.7) 0.999 Major vascular complications 6 (6.7) 2 (5.9) 2 (6.7) 2 (7.4) 0.999 LVOT obstruction (ΔP increase >30 mmHg) 8 (8.8) 2 (5.9) 4 (13.3) 2 (7.4) 0.648 Late valve embolization 0 — — — — Slight late displacement of the THV 3 (3.3) 0 0 3 (11.1) 0.023 THV thrombosis 8 (8.8) 3 (8.8) 2 (6.7) 3 (11.1) 0.900 Entire cohort (n = 91) Valve-in-valve (n = 34) Valve-in-ring (n = 30) Valve-in-MAC (n = 27) P-value Death 7 (7.7) 2 (5.9) 2 (6.7) 3 (11.1) 0.788 Surgical mitral valve replacement 4 (4.4) 0 4 (13.3) 0 0.017 Stroke 4 (4.4) 2 (5.9) 0 2 (7.4) 0.455  Major 2 (2.2) 0 0 2 (7.4) 0.086  Minor 2 (2.2) 2 (5.9) 0 0 0.329 Life-threatening or fatal bleeding 4 (4.4) 2 (5.9) 1 (3.3) 1 (3.7) 0.999 Major vascular complications 6 (6.7) 2 (5.9) 2 (6.7) 2 (7.4) 0.999 LVOT obstruction (ΔP increase >30 mmHg) 8 (8.8) 2 (5.9) 4 (13.3) 2 (7.4) 0.648 Late valve embolization 0 — — — — Slight late displacement of the THV 3 (3.3) 0 0 3 (11.1) 0.023 THV thrombosis 8 (8.8) 3 (8.8) 2 (6.7) 3 (11.1) 0.900 LVOT, left ventricular outflow tract; MR, mitral regurgitation; THV, transcatheter heart valve; TMVI, transcatheter mitral valve implantation; ΔP, basal maximal gradient. Table 3 Thirty-day outcomes following transcatheter mitral valve implantation Entire cohort (n = 91) Valve-in-valve (n = 34) Valve-in-ring (n = 30) Valve-in-MAC (n = 27) P-value Death 7 (7.7) 2 (5.9) 2 (6.7) 3 (11.1) 0.788 Surgical mitral valve replacement 4 (4.4) 0 4 (13.3) 0 0.017 Stroke 4 (4.4) 2 (5.9) 0 2 (7.4) 0.455  Major 2 (2.2) 0 0 2 (7.4) 0.086  Minor 2 (2.2) 2 (5.9) 0 0 0.329 Life-threatening or fatal bleeding 4 (4.4) 2 (5.9) 1 (3.3) 1 (3.7) 0.999 Major vascular complications 6 (6.7) 2 (5.9) 2 (6.7) 2 (7.4) 0.999 LVOT obstruction (ΔP increase >30 mmHg) 8 (8.8) 2 (5.9) 4 (13.3) 2 (7.4) 0.648 Late valve embolization 0 — — — — Slight late displacement of the THV 3 (3.3) 0 0 3 (11.1) 0.023 THV thrombosis 8 (8.8) 3 (8.8) 2 (6.7) 3 (11.1) 0.900 Entire cohort (n = 91) Valve-in-valve (n = 34) Valve-in-ring (n = 30) Valve-in-MAC (n = 27) P-value Death 7 (7.7) 2 (5.9) 2 (6.7) 3 (11.1) 0.788 Surgical mitral valve replacement 4 (4.4) 0 4 (13.3) 0 0.017 Stroke 4 (4.4) 2 (5.9) 0 2 (7.4) 0.455  Major 2 (2.2) 0 0 2 (7.4) 0.086  Minor 2 (2.2) 2 (5.9) 0 0 0.329 Life-threatening or fatal bleeding 4 (4.4) 2 (5.9) 1 (3.3) 1 (3.7) 0.999 Major vascular complications 6 (6.7) 2 (5.9) 2 (6.7) 2 (7.4) 0.999 LVOT obstruction (ΔP increase >30 mmHg) 8 (8.8) 2 (5.9) 4 (13.3) 2 (7.4) 0.648 Late valve embolization 0 — — — — Slight late displacement of the THV 3 (3.3) 0 0 3 (11.1) 0.023 THV thrombosis 8 (8.8) 3 (8.8) 2 (6.7) 3 (11.1) 0.900 LVOT, left ventricular outflow tract; MR, mitral regurgitation; THV, transcatheter heart valve; TMVI, transcatheter mitral valve implantation; ΔP, basal maximal gradient. Long-term cumulative outcomes At a median (interquartile range) follow-up of 13 (4–26) months, 30 (33.0%) patients had died, 26.4% from cardiovascular causes. Cumulative rates of all-cause mortality at 1-year and 2-year follow-up were 21.0% (95% CI 9.9–38.8) and 35.7% (95% CI 19.2–56.5), respectively. One-year cardiovascular mortality was 17.3% (95% CI 7.3–34.7) and 2-year, 26.4% (95% CI 12.5–47.1). Table 4 shows cumulative outcomes according to the indication of the procedure. Patients with ViMAC had higher mortality [hazard ration (HR) 2.39, 95% CI 1.01–5.86; P = 0.046] and a trend towards higher cardiovascular mortality (HR 2.80, 95% CI 0.94–8.46; P = 0.162) (Figure 1A and B). Univariate predictors of all-cause mortality are shown in Supplementary material online, Table S2. A ViMAC procedure (HR 3.49, 95% CI 1.44–8.48; P = 0.006), the presence of tricuspid regurgitation >2 (HR 2.73, 95% CI 1.23–1.07; P = 0.014) at baseline and the EuroSCORE-2 (HR 1.04, 95% CI 1.01–1.07; P = 0.009) were independent predictors of all-cause cumulative mortality after TMVI. Table 4 Cumulative clinical outcomes of transcatheter mitral valve implantation Entire cohort (n = 91) Valve-in-valve (n = 34) Valve-in-ring (n = 30) Valve-in-MAC (n = 27) P-value Death  n (%) 30 (33.0) 8 (23.5) 10 (33.3) 12 (44.4)  HR (95% CI) 1.0 0.82 (0.29–2.31) 2.39 (1.01–5.86)a 0.046 Cardiovascular death  n (%) 24 (26.4) 5 (14.7) 10 (33.3) 9 (33.3)  HR (95% CI) 1.0 1.30 (0.40–4.16) 2.80 (0.94–8.46) 0.125 Death or surgical valve replacement  n (%) 36 (39.6) 8 (23.5) 16 (53.3) 12 (44.4)  HR (95% CI) 1.0 1.58 (0.65–3.85) 2.34 (0.96–5.75) 0.175 Surgical mitral valve replacement  n (%) 7 (7.7) 0 7 (23.3) 0  HR (95% CI) 1.0 — — — Entire cohort (n = 91) Valve-in-valve (n = 34) Valve-in-ring (n = 30) Valve-in-MAC (n = 27) P-value Death  n (%) 30 (33.0) 8 (23.5) 10 (33.3) 12 (44.4)  HR (95% CI) 1.0 0.82 (0.29–2.31) 2.39 (1.01–5.86)a 0.046 Cardiovascular death  n (%) 24 (26.4) 5 (14.7) 10 (33.3) 9 (33.3)  HR (95% CI) 1.0 1.30 (0.40–4.16) 2.80 (0.94–8.46) 0.125 Death or surgical valve replacement  n (%) 36 (39.6) 8 (23.5) 16 (53.3) 12 (44.4)  HR (95% CI) 1.0 1.58 (0.65–3.85) 2.34 (0.96–5.75) 0.175 Surgical mitral valve replacement  n (%) 7 (7.7) 0 7 (23.3) 0  HR (95% CI) 1.0 — — — CI, confidence interval, HR, hazard ratio. a P < 0.05 vs. valve-in-ring. Table 4 Cumulative clinical outcomes of transcatheter mitral valve implantation Entire cohort (n = 91) Valve-in-valve (n = 34) Valve-in-ring (n = 30) Valve-in-MAC (n = 27) P-value Death  n (%) 30 (33.0) 8 (23.5) 10 (33.3) 12 (44.4)  HR (95% CI) 1.0 0.82 (0.29–2.31) 2.39 (1.01–5.86)a 0.046 Cardiovascular death  n (%) 24 (26.4) 5 (14.7) 10 (33.3) 9 (33.3)  HR (95% CI) 1.0 1.30 (0.40–4.16) 2.80 (0.94–8.46) 0.125 Death or surgical valve replacement  n (%) 36 (39.6) 8 (23.5) 16 (53.3) 12 (44.4)  HR (95% CI) 1.0 1.58 (0.65–3.85) 2.34 (0.96–5.75) 0.175 Surgical mitral valve replacement  n (%) 7 (7.7) 0 7 (23.3) 0  HR (95% CI) 1.0 — — — Entire cohort (n = 91) Valve-in-valve (n = 34) Valve-in-ring (n = 30) Valve-in-MAC (n = 27) P-value Death  n (%) 30 (33.0) 8 (23.5) 10 (33.3) 12 (44.4)  HR (95% CI) 1.0 0.82 (0.29–2.31) 2.39 (1.01–5.86)a 0.046 Cardiovascular death  n (%) 24 (26.4) 5 (14.7) 10 (33.3) 9 (33.3)  HR (95% CI) 1.0 1.30 (0.40–4.16) 2.80 (0.94–8.46) 0.125 Death or surgical valve replacement  n (%) 36 (39.6) 8 (23.5) 16 (53.3) 12 (44.4)  HR (95% CI) 1.0 1.58 (0.65–3.85) 2.34 (0.96–5.75) 0.175 Surgical mitral valve replacement  n (%) 7 (7.7) 0 7 (23.3) 0  HR (95% CI) 1.0 — — — CI, confidence interval, HR, hazard ratio. a P < 0.05 vs. valve-in-ring. Figure 1 View largeDownload slide Rates of overall and cardiovascular mortality. The Kaplan–Meier curves at 2-year follow-up for all-cause death (A) and cardiovascular death (B) according to the indication of transcatheter mitral valve implantation. Figure 1 View largeDownload slide Rates of overall and cardiovascular mortality. The Kaplan–Meier curves at 2-year follow-up for all-cause death (A) and cardiovascular death (B) according to the indication of transcatheter mitral valve implantation. Among ViMAC patients, 12 have died at last follow-up: eight (66.7%) from cardiovascular causes (three procedural related death, two due to heart failure, one sudden death, and two endocarditis) and four (33.3%) from non-cardiac causes. After hospital discharge, three more ViR patients required surgical mitral valve replacement (P = 0.002, Figure 2A). Kaplan–Meier curves for surgical mitral valve replacement or death at 2-year follow-up, according to the indication of the procedure, are shown in Figure 2B. The cumulative rates of 2-year re-intervention, stroke, and endocarditis were 8.8%, (95% CI 2.3–27.6), 4.5%, (95% CI 1.2–15.3), and 5.2% (95% CI 0.13–18.2), respectively. Transcatheter heart valve thrombosis occurred in three patients during the follow-up period: at 1 year (two patients) and 2.5 years (one patient). One of them had a significant increase in transmitral gradients which resolved with anticoagulation therapy. The cumulative 2 years rate of valve thrombosis was 14.4%, (95% CI 5.1–34.3). All patients were asymptomatic and thrombosis resolved in all cases with VKA. No case of late embolization was observed. Figure 2 View largeDownload slide Rates of surgical mitral valve replacement and death or surgical mitral valve replacement. The Kaplan–Meier curves at 2 years follow-up for surgical mitral valve replacement (A) and all-cause death or surgical mitral valve replacement (B) according to the study groups. Figure 2 View largeDownload slide Rates of surgical mitral valve replacement and death or surgical mitral valve replacement. The Kaplan–Meier curves at 2 years follow-up for surgical mitral valve replacement (A) and all-cause death or surgical mitral valve replacement (B) according to the study groups. Figure 3 shows the changes in New York Heart Association (NYHA) class over time. At 6-month to 1-year follow-up, 72.4% of patients were in NYHA Class I or II (vs. 17.9% at baseline, P < 0.001) and 69.2% of patients alive had at least 1 degree improvement in NYHA class at 6-month to 1-year follow-up. Figure 3 View largeDownload slide Functional status. Changes in New York Heart Association class over time. Figure 3 View largeDownload slide Functional status. Changes in New York Heart Association class over time. Subgroup of young women Twelve young women (mean age: 28 ± 6 years) underwent TMVI: a ViV TMVI was performed in five (41.7%) patients and a ViR TMVI in seven (58.3%). The desire for pregnancy in the near future (11 patients, 91.7%) or current pregnancy (one patient, 8.3%) was taken into consideration for the indication of TMVI. Three of them (25%) had previously undergone two or more cardiac surgeries. All these patients had severe mitral stenosis with a mean transmitral gradient of 13 ± 6 mmHg and three (25%) patients had in addition severe mitral regurgitation. The mean pulmonary artery systolic pressure (PASP) was of 49 ± 17 mmHg, 25% of patients had a PASP >60 mmHg and five (41.7%) patients had right ventricular dysfunction. No death, stroke, major vascular complication, or life-threatening bleeding occurred among the 12 young women undergoing TMVI (Table 5). Two out of the 12 young women had an uneventful pregnancy and delivery after successful TMVI. Table 5 Thirty-day outcomes following transcatheter mitral valve implantation in the subgroup of young women (n = 12) Young women n 95% CI event rate Death 0 0 (0–22.1) Surgical mitral valve replacement 2 16.7 (4.5–51.8) Stroke 0 0 (0–22.1)  Major — —  Minor — — Life-threatening or fatal bleeding 0 0 (0–22.1) Major vascular complications 0 0 (0–22.1) LVOT obstruction (ΔP increase >30 mmHg) 1 8.3 (1.2–46.1) Late valve embolization 0 0 (0–22.1) Slight late displacement of the THV 0 0 (0–22.1) THV thrombosis 1 8.3 (1.2–46.1) Young women n 95% CI event rate Death 0 0 (0–22.1) Surgical mitral valve replacement 2 16.7 (4.5–51.8) Stroke 0 0 (0–22.1)  Major — —  Minor — — Life-threatening or fatal bleeding 0 0 (0–22.1) Major vascular complications 0 0 (0–22.1) LVOT obstruction (ΔP increase >30 mmHg) 1 8.3 (1.2–46.1) Late valve embolization 0 0 (0–22.1) Slight late displacement of the THV 0 0 (0–22.1) THV thrombosis 1 8.3 (1.2–46.1) LVOT, left ventricular outflow tract; MR, mitral regurgitation; THV, transcatheter heart valve; TMVI, transcatheter mitral valve implantation; ΔP, basal maximal gradient. Table 5 Thirty-day outcomes following transcatheter mitral valve implantation in the subgroup of young women (n = 12) Young women n 95% CI event rate Death 0 0 (0–22.1) Surgical mitral valve replacement 2 16.7 (4.5–51.8) Stroke 0 0 (0–22.1)  Major — —  Minor — — Life-threatening or fatal bleeding 0 0 (0–22.1) Major vascular complications 0 0 (0–22.1) LVOT obstruction (ΔP increase >30 mmHg) 1 8.3 (1.2–46.1) Late valve embolization 0 0 (0–22.1) Slight late displacement of the THV 0 0 (0–22.1) THV thrombosis 1 8.3 (1.2–46.1) Young women n 95% CI event rate Death 0 0 (0–22.1) Surgical mitral valve replacement 2 16.7 (4.5–51.8) Stroke 0 0 (0–22.1)  Major — —  Minor — — Life-threatening or fatal bleeding 0 0 (0–22.1) Major vascular complications 0 0 (0–22.1) LVOT obstruction (ΔP increase >30 mmHg) 1 8.3 (1.2–46.1) Late valve embolization 0 0 (0–22.1) Slight late displacement of the THV 0 0 (0–22.1) THV thrombosis 1 8.3 (1.2–46.1) LVOT, left ventricular outflow tract; MR, mitral regurgitation; THV, transcatheter heart valve; TMVI, transcatheter mitral valve implantation; ΔP, basal maximal gradient. Changes in haemodynamics The mean transmitral gradient decreased from 9.3 ± 3.9 mmHg at baseline to 6.0 ± 2.3 mmHg at discharge (P < 0.001) without changes at 6-month to 1-year follow-up (6.3 ± 2.2 mmHg, P = 0.999). Changes in mean transmitral gradients according to study groups are shown in Figure 4A. The mean mitral valve area increased from 1.07 ± 0.32 cm2 at baseline to 1.68 ± 0.40 cm2 (P = 0.013) at discharge and 1.90 ± 0.49 cm2 at 6-month to 1-year follow-up (P = 0.001 for baseline to 1-year follow-up and P = 0.718 for discharge vs. 6-month to 1-year follow-up) (Figure 4B). Figure 4 View largeDownload slide Valve haemodynamics and the indication of transcatheter mitral valve implantation. Changes in mean transmitral gradients and mitral valve area over time according to study groups. Paired data are shown (n = 51). Figure 4 View largeDownload slide Valve haemodynamics and the indication of transcatheter mitral valve implantation. Changes in mean transmitral gradients and mitral valve area over time according to study groups. Paired data are shown (n = 51). Changes in the severity of mitral regurgitation over time are shown in Figure 5A. The mitral regurgitation grade was mild or less in 96.4% of patients at discharge and 90.7% of patients at the 6-month to 1-year follow-up. Moderate or severe mitral regurgitation at discharge was more frequent in patients with ViR procedures (10.7 vs. 0% in the other groups, P = 0.055). At 6-month to 1-year follow-up, 20% of ViR and 8.3% of ViMAC patients had moderate or severe mitral regurgitation, while no case was observed in the ViV group (P = 0.068) (Figure 5B). Figure 5 View largeDownload slide Mitral regurgitation and the indication of transcatheter mitral valve implantation. Changes in the severity of mitral regurgitation in the entire cohort (A) and rates of moderate to severe mitral regurgitation according to study groups (B) at different time points. Paired data are represented (n = 54). Figure 5 View largeDownload slide Mitral regurgitation and the indication of transcatheter mitral valve implantation. Changes in the severity of mitral regurgitation in the entire cohort (A) and rates of moderate to severe mitral regurgitation according to study groups (B) at different time points. Paired data are represented (n = 54). The severity of tricuspid regurgitation decreased at 6-month to 1-year follow-up (P = 0.009) (Figure 6). Tricuspid regurgitation >2 was observed in 34.2% at discharge and 22.2% at 6-month to 1-year follow-up (vs. 33% at baseline) (P = 0.380). A significant reduction was observed in PASP at 6-month to 1-year follow-up compared with baseline (54 ± 12 to 46 ± 11 mmHg, P = 0.002). Figure 6 View largeDownload slide Tricuspide regurgitation and transcatheter mitral valve implantation. Changes in tricuspid regurgitation over time. Paired data are represented (n = 41). Figure 6 View largeDownload slide Tricuspide regurgitation and transcatheter mitral valve implantation. Changes in tricuspid regurgitation over time. Paired data are represented (n = 41). A significant reduction was observed in left ventricular (LV) end-diastolic diameter (51 ± 9 vs. 47 ± 8 mm, P= 0.001) at the 6 to 12 months follow-up. However, no significant changes were observed in LV end-systolic diameter (32 ± 9 vs. 32 ± 9 P = 0.612) and left ventricular ejection fraction over time (58 ± 10 vs. 57± 11, P = 0.561). Twelve patients had more than 3 years of follow-up and two patients had more than 4 years follow-up. No case of structural valve deterioration was observed. Discussion This study shows that TMVI is feasible, appears to be safe when performed by experienced operators and to result in acceptable long-term clinical and haemodynamic outcomes. The anticipated safety concerns and technical challenges have slowed down the expansion of TMVI compared with TAVI. Two major issues have challenged the development of TMVI therapies: the anchoring of prostheses, hindered by the huge differences in systolic pressures between the left ventricle and the left atrium, and the risk of LVOT obstruction, which results from the anatomical proximity between the anterior leaflet and subvalvular apparatus of the mitral valve and the interventricular septum.15 Surgical bioprostheses or rings and severe MAC provide support for the anchoring of THV with sufficient radial force to counterbalance migration forces. Therefore, this study shows the results of TMVI in the three patient subsets in whom commercial balloon-expandable THVs are currently used. Although the transapical approach has been associated with an increased risk of mortality in patients undergoing TAVI, its use has been initially favoured over the transvenous, transseptal approach, due to the technical challenges of the transseptal catheterization and navigation in the left atrium using stiff catheters.3,7,8 This study shows that the transseptal approach may be safely used in most patients. Transcatheter mitral valve implantation was associated with a high rate of technical success and resulted in a reduction in transmitral gradients and mitral regurgitation, which were stable over time, and was associated with a low rate of paravalvular leaks. This translated into a significant improvement in functional class. Nonetheless, patients undergoing ViR TMVI had more frequently suboptimal haemodynamic results requiring surgery (compared with ViV and ViMAC),16 in accordance with previous reports.8,17,18 The type of surgical ring, the technique used for the repair of the anterior leaflet and subvalvular apparatus in addition to other anatomical characteristics may have an impact on the results of TMVI.12 Of note, a preceding TMVI did not preclude reoperation when necessary. The mortality associated with TMVI in this study was acceptable. Indeed, 30-day mortality is comparable to that of TAVI in real-world patients at high surgical risk19–21 including patients with failing aortic bioprostheses,22 and it is lower than that of reoperation after mitral surgery in current surgical series (∼12%),3–25 confirming the safety of TMVI when performed by experienced teams in accurately selected patients. Previous studies have shown the safety of TMVI when performed in patients with failing bioprostheses (ViV).3,8,26 However, higher mortality rates have been reported for ViR procedures (>8–11 vs. 6.7% in this study)8,26 and even more for ViMAC (∼30 vs. 11%),7 suggesting a gradient in complexity across these patient subsets and increased experience requirements. In fact, the volume per operator has been identified as a predictor of outcomes in TAVI.27 Although the initial primary mitral valve disease may have an impact on long-term outcomes after TMVI, no major impact is expected on 30-day outcomes given that parameters assessing the severity of the heart disease before TMVI were similar in all groups. Left ventricular outflow tract obstruction is one of the most feared complications and one of the main limitations of TMVI. However, its risk may be greatly reduced by an accurate screening, selection of patients and planning of the procedure.12 Only three patients had haemodynamically significant LVOT obstruction in this study, and all of them underwent TMVI at the beginning of our experience. The main mechanism of LVOT obstruction is the displacement of the anterior leaflet and subvalvular apparatus towards the septum,28 which happens in ViR and ViMAC TMVI. Thus, ASA at a distance from TMVI, as the first option, or hybrid procedures allowing for the resection of the anterior leaflet in patients with a severe MAC in whom ASA is not possible or may not be sufficient to reduce the risk of LVOT obstruction, if there is no contraindication to surgery in addition to the presence of MAC, seem promising strategies. Importantly, no patient having undergone a hybrid procedure or ASA had any significant LVOT obstruction. If it occurs during the procedure, rescue ASA may be lifesaving when haemodynamics is severely compromised. However, when the LVOT obstruction is initially well tolerated, the evolution seems favourable. Indeed, one of the patients with severe LVOT obstruction did not require any intervention early after the procedure and remained asymptomatic during the follow-up period. Repositionable and retrievable THVs may have an interest in this setting. Finally, a recent paper suggested that intentional percutaneous laceration of the anterior leaflet could prevent the occurrence of severe LVOT obstruction in five patients considered at high risk.29 However, the anterior leaflet, although lacerated, is not removed and a risk of LVOT obstruction persists. In fact, a gradient was observed in most patients. The efficacy of this technique needs to be confirmed in larger studies. Although overall cumulative long-term mortality in this study was comparable to that of TAVI or percutaneous mitral valve repair in high-risk patients, those with severe MAC had higher late mortality, mainly from cardiovascular causes, despite similar procedural mortality. Reasons for this excess mortality are largely unknown and probably related to patient intrinsic risk profile. Indeed, the presence of MAC is considered as an indicator of atherosclerosis burden,16 and has been associated with an increased risk of late cardiovascular and overall mortality.16,30,31 An accurate identification of the predictors of late mortality is necessary to improve patient selection and avoid futility and should be of utmost priority for future investigations. Concerns remain, in particular the risk of valve thrombosis, which occurred more frequently early after the procedure, although cases of late thrombosis were detected during the follow-up period. Of note, no symptom was associated with the occurrence of valve thrombosis. Extended anticoagulation therapy seems reasonable in these patients. As for surgical bioprostheses, at least 6 months of VKA therapy may be necessary after TMVI.1 Although no late THV migration occurred, late slight backward displacements were observed in three ViMAC patients. Even though the risk is reduced by an optimal sizing, this complication may occur even in patients with apparently accurate selection of the THV diameter. Thus, the potential occurrence of THV thrombosis and late backward displacement justifies a close follow-up, with clinical and echocardiographic evaluations, also required to detect valve endocarditis and degeneration. The role of CT in the long-term follow-up of these patients remains to be determined. This study provides new insights to the current evidence on TMVI results.7–9 Firstly, this is the study with the longest follow-up period (mean follow-up of 1 year). Secondly, this study provides data on late outcomes including rates of cardiovascular mortality, surgical mitral valve replacement, re-intervention, and endocarditis, for the first time. In particular, late outcomes in patients with ViMAC are unknown. Thirdly, changes in valve haemodynamics (including mitral regurgitation, mean transmitral gradient, and area) and main echocardiographic parameters (PASP, tricuspid regurgitation) are reported for the three subgroups over time, from baseline to the 6-month to 1-year follow-up. Also, this study provides data on changes in functional outcomes over time. Finally, it shows the results of TMVI in two subgroups of patients for whom it may be of particular interest: young women desiring pregnancy, given the risks associated with anticoagulation therapy and mechanical prostheses during pregnancy, and patients in cardiogenic shock, who were not evaluated in previous studies. Limitations Albeit this is the largest case series from an experienced centre, this is a single-centre study. This however provides optimal homogeneity in patient care and in data collection and analysis, but the results may not be generalizable. The evaluation of functional outcomes was limited to the assessment of the NYHA class. A lack of power to detect differences between groups cannot be ruled out. Although this study included the largest number of patients undergoing TMVI using the transseptal approach, no accurate conclusions can be drawn regarding the impact of the learning curve due to a low event rate, a limited number of patients per group and a different distribution of the study groups (ViMAC procedures were more frequently performed in the second half of the learning curve). There was no central adjudication committee. No provocative manoeuvers were used for the detection of subclinical LVOT obstruction. Conclusion In conclusion, when performed by experienced teams in adequately selected high-risk patients, TMVI is feasible, effective and safe and is associated with satisfactory long-term results. Future studies including larger populations and longer follow-up are needed to establish the precise role of TMVI in clinical practice. Supplementary material Supplementary material is available at European Heart Journal online. Conflict of interest: B.I. and A.V. received speaker’s fees from Edwards Lifesciences. D.H. is consultant and proctor for Edwards Lifesciences. The other authors do not declare any conflict of interest. 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European Heart JournalOxford University Press

Published: May 19, 2018

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