NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE

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1 NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE INTERVENTIONAL PROCEDURES PROGRAMME Interventional procedure overview of transcatheter valvein-valve implantation for aortic bioprosthetic valve dysfunction A malfunctioning aortic valve is often treated by replacing it with an artificial valve through open heart surgery. Transcatheter aortic valve implantation (TAVI) avoids open heart surgery and involves inserting an artificial valve using a catheter (tube) inserted through a small cut in the skin and then through the arteries to the heart. The artificial valves are often bioprosthetic, which means that they are made of animal tissue or a combination of animal tissue and metal and other materials. If a bioprosthetic valve (inserted either through open heart surgery or by TAVI) fails, another bioprosthetic valve can be placed within it using a catheter to restore valve function. This is known as valve-in-valve TAVI. Introduction The National Institute for Health and Care Excellence (NICE) has prepared this interventional procedure overview to help members of the Interventional Procedures Advisory Committee (IPAC) make recommendations about the safety and efficacy of an interventional procedure. It is based on a rapid review of the medical literature and specialist opinion. It should not be regarded as a definitive assessment of the procedure. Date prepared This interventional procedure overview was prepared in March 2014 and updated in May Procedure name Transcatheter valve-in-valve implantation for the treatment of aortic bioprosthetic valve dysfunction Specialty societies Society for Cardiothoracic Surgery of Great Britain and Ireland British Cardiovascular Intervention Society. Page 1 of 56

2 Description Indications and current treatment The 2 main indications for aortic valve replacement are aortic stenosis and aortic regurgitation. Symptoms of aortic stenosis and regurgitation typically include shortness of breath and chest pain on exertion. The increased cardiac workload can lead to heart failure. Surgical aortic valve replacement (SAVR) with an artificial prosthesis (biological or mechanical) is the conventional treatment for patients with severe aortic valve dysfunction who are well enough for open heart surgery. Although bioprosthetic valves have some advantages over mechanical valves, they may degenerate and fail over time. The standard treatment for a failed bioprosthetic valve is repeat open heart surgery, with a further valve replacement. Re-operative surgery is associated with significant morbidity and a higher risk of mortality than primary surgery. Valvein-valve transcatheter aortic valve implantation (ViV-TAVI) has been developed as a less invasive alternative treatment that avoids the need for cardiopulmonary bypass. It can be used for the treatment of failed bioprosthetic aortic valves originally placed either by transcatheter aortic valve implantation (TAVI) or by open heart surgery. In particular, it has been used for rescue of suboptimal TAVI. What the procedure involves The procedure is done with the patient under general or local anaesthesia, with imaging guidance using fluoroscopy and usually transoesophageal echocardiography. Prophylactic antibiotics and anticoagulant medication are given before and during the procedure. Temporary peripheral extracorporeal circulatory support (usually through the femoral vessels) is sometimes used. A new prosthetic valve is mounted within a stent, which is either self-expanding or expanded using balloon inflation. It is delivered by catheter across the failed bioprosthetic aortic valve. Access to the aortic valve can be achieved transluminally, with entry to the circulation through the femoral or other large artery (sometimes known as a percutaneous or endovascular approach), or through apical puncture of the left ventricle (a transapical, or transventricular approach). In the transluminal approach, surgical exposure and closure of the artery may be needed. How access to the aortic valve is achieved depends on whether there are factors that make the passage of a catheter through the circulation difficult, such as peripheral arterial disease. The procedure is technically similar to TAVI for aortic stenosis into a native aortic valve (see NICE interventional procedure guidance 421), but some modifications to the technique have been reported. Instead of dilating the failed aortic bioprosthetic valve with a balloon, the new prosthetic valve is attached tightly into the orifice of the failed bioprosthetic valve, pushing the old valve leaflets aside. The important modification is slow and gradual valve deployment (without rapid inflation of the balloon) with angiography to enable accurate positioning of the valve. The old prosthesis is used as a guide for positioning the new valve. The size of the new Page 2 of 56

3 valve is usually selected so that its external diameter matches or exceeds the internal diameter of the old valve. Clinical assessment tools Clinical assessment of severity of aortic stenosis New York Heart Association (NYHA) heart failure classification: this is used to classify the severity of breathlessness from class I, in which the patient has no limitation in daily physical activity, to class IV, in which the patient is breathless at rest. Haemodynamic assessment (usually by echocardiography and doppler): Aortic valve area (cm 2 ) or aortic valve area index (relative to body surface area; cm 2 /m 2 ). An aortic valve area less than 0.6 cm 2 /m 2 indicates severe aortic stenosis. Transaortic gradient (mmhg). Peak transaortic valve gradient more than 64 mmhg and mean transaortic valve gradient more than 40 mmhg indicates severe aortic stenosis. The logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE) measures patient risk at the time of surgery using a logisticregression equation on a 0 100% scale (higher scores indicating greater risk; a score higher than 20% indicates very high surgical risk). Clinical assessment of severity of aortic regurgitation Quantification by cardiac catheterisation Mild (grade 1+): a small amount of contrast enters the left ventricle during diastole and clears with each systole. Moderate (grade 2+): more contrast enters with each diastole and faint opacification of the entire left ventricular chamber occurs. Moderately severe (grade 3+): left ventricular chamber is well opacified and equal in density when compared with the ascending aorta. Severe (grade 4+): complete, dense opacification of the ventricular chamber on the first beat, and the left ventricle is more densely opacified than the ascending aorta. Quantification by colour-flow doppler Jet height/left ventricular outflow tract (LVOT) height: Mild (1+): less than 25%. Moderate (2+): 25 46%. Moderately severe (3+): 47 64%. Severe (4+): 65% or more. Regurgitant jet area/lvot area: Mild (1+): less than 4%. Page 3 of 56

4 Moderate (2+): 4 24%. Moderately severe (3+): 25 59%. Severe (4+): 60% or more. Literature review Rapid review of literature The medical literature was searched to identify studies and reviews relevant to transcatheter valve-in-valve implantation for aortic bioprosthetic valve dysfunction. Searches were conducted of the following databases, covering the period from their commencement to 28 May 2014: MEDLINE, PREMEDLINE, EMBASE, Cochrane Library and other databases. Trial registries and the Internet were also searched. No language restriction was applied to the searches (see appendix C for details of search strategy). Relevant published studies identified during consultation or resolution that are published after this date may also be considered for inclusion. The following selection criteria (table 1) were applied to the abstracts identified by the literature search. Where selection criteria could not be determined from the abstracts the full paper was retrieved. Table 1 Inclusion criteria for identification of relevant studies Characteristic Publication type Patient Intervention/test Outcome Language Criteria Clinical studies were included. Emphasis was placed on identifying good quality studies. Abstracts were excluded where no clinical outcomes were reported, or where the paper was a review, editorial, or a laboratory or animal study. Conference abstracts were also excluded because of the difficulty of appraising study methodology, unless they reported specific adverse events that were not available in the published literature. Patients with aortic bioprosthetic valve dysfunction. Transcatheter valve-in-valve implantation. Articles were retrieved if the abstract contained information relevant to the safety and/or efficacy. Non-English-language articles were excluded unless they were thought to add substantively to the English-language evidence base. List of studies included in the overview This overview is based on approximately 859 patients from 9 case series 1,2,3,4,5,6,7,8,11, 2 comparative case series 9,10 and 1 case report 12. Other studies that were considered to be relevant to the procedure but were not included in the main extraction table (table 2) have been listed in appendix A. Page 4 of 56

5 Table 2 Summary of key efficacy and safety findings on transcatheter valve-in-valve implantation for the treatment of aortic bioprosthetic valve dysfunction Abbreviations used: ASE, American Society of Echocardiography; AR, aortic regurgitation; EuroSCORE, European System for CARDIAC Operative Risk Evaluation; IQR, interquartile range; LVEF, left ventricular ejection fraction; NR, not reported; NYHA, New York Heart Association; PPM, patient-prosthesis mismatch; STS, Society of Thoracic Surgeons; TEE, transoesophageal echocardiogram; TTE, transthoracic echocardiogram; VARC, Valve Academic Research Consortium; ViV-TAVI, valve-in-valve transcatheter aortic valve implantation. Study details Key efficacy findings Key safety findings Comments Studies of patients with degenerated aortic surgical bioprosthesis Dvir D (2014) 1 Valve-in-Valve International Data (VIVID) Register (independent register by experts). Case series (retrospective and prospective data) Europe, North America, Australia, New Zealand and the Middle East (55 centres) Recruitment period: 2007 to Study population: patients with degenerated aortic bioprosthetic valves. n=459 Bioprosthesis mode of failure (according to ASE): stenosis (39.4%, 181/459), regurgitation (30.3%, 139/459), or combined stenosis and regurgitation (30%, 139/459). Type of degenerated bioprosthesis: stented 79.7% (366/459), stentless 20.3% (93/459). Surgical valve size:<21mm: 29.5% (133/459), >21 and <25 mm: 38.3% (176/459), >25 mm:30.3% (139/459), unknown 4% (11/459) Number of patients analysed: 459 Procedural echocardiographic outcomes (mean±sd) All (n=45 9) Steno sis (n=18 1) Regur gitatio n (n=13 9) Peak aortic valve gradient (mmhg) Baseli ne 30 days 60.8± ± year 30± ± ± ± ± ± ± 15.4 Mean aortic valve gradient (mmhg) Baseli ne 30 days 36.2± ± year 16.9± ± ± ± 9.5 Aortic valve area (cm 2 ) Baseli ne 30 days 0.95± ± year 1.38±± 0.42 Mean LVEF % 0.69± ± ± ± ± ± ± ± ± 0.48 Comb ined (n=13 9) 64.6± ± ± ± ± ± ± ± ± 0.45 p value <.001 < <.001 < < Procedural adverse events % (n) Ostial coronary obstruction. Attempted device retrieval during self-expandable procedures due to device malposition (further details not reported) Implantation of a second TAVI valve (due to device malposition) Complications at 30 days and 1 year % (n) 2 (more frequent in stenosis group (3.9%; p=.02) 10.3 (21/213) 5.7 (26/459) All-cause mortality at 30 days 7.6 (35/459) Cardiovascular deaths 6.5 (30/459) all-cause mortality at 1 year 16.8 (62/459) Major stroke^ 1.7 (8/459) Major vascular complication (further details not reported)^ 9.2 (42/459) Major/life threatening bleeding 8.1 (37/459) Acute kidney injury type II/III 7.4 (34/459) Follow-up issues Complete follow up. Other issues Data were collected retrospectively for cases performed before register initiation and prospectively thereafter. There was no significant difference in STS scores when stratified according to mechanism of failure. Comparative data between the CoreValve and Edwards SAPIEN groups not reported here. Page 5 of 56

6 Abbreviations used: ASE, American Society of Echocardiography; AR, aortic regurgitation; EuroSCORE, European System for CARDIAC Operative Risk Evaluation; IQR, interquartile range; LVEF, left ventricular ejection fraction; NR, not reported; NYHA, New York Heart Association; PPM, patient-prosthesis mismatch; STS, Society of Thoracic Surgeons; TEE, transoesophageal echocardiogram; TTE, transthoracic echocardiogram; VARC, Valve Academic Research Consortium; ViV-TAVI, valve-in-valve transcatheter aortic valve implantation. Study details Key efficacy findings Key safety findings Comments Stenosis group had more stented valves (95% vs 60.4% vs 78.4%) and more small valves (37% vs 20.9% vs 26.6%, p=.005). >1 previous SAVR, % (n): 13.5% (62/459) Age: mean 77.6 years Sex: 44% (205/459) female Logistic EuroSCORE: 29% STS score: 10 % Mean time from last SAVR-VIV: 9 years Technique: ViV-TAVI Devices: balloon and self-expandable valves, CoreValve (n=213) [23, 26, 29, 31 mm] and Edwards SAPIEN (n=246) [20,23,26,29 mm]. Access: transfemoral 58.8% (n=270), transapical 37.3% (n=171), transaxillary 8% (n=13), direct aortic 1.1% (n=5). Follow-up: median 302 days Conflict of interest/source of funding: Authors report serving as proctors and consultants for different manufacturers. Some received honoraria and grants. Baseli ne 30 days 50.3± ± ± ± ± ± ± ± 19 Aortic regurgitation ( moderate)^, %(n) Baseli ne 30 days 64.5 (296/4 59) 5.4 (25) 12 (22) ^according to ASE criteria NYHA functional class Baseline All (n=45 9) I/II 7.8 (35/45 9) III/IV 96 (313/4 59) 30 days I/II 96 (313/4 59) III/IV 7.4 (25/45 9) 100(1 39) 8 (5) 9.4 (13) Steno sis (n=18 1) 7.7 (14/18 1) 98 (167/1 81) 91.3 (126/1 81) 8.7 (12/18 1) 1 year 96% (n=313/459) Regur gitatio n (n=13 9) 7.2 (10/13 9) 98 (129/1 39) 94.3 (100/1 39) 5.7 (6/139 ) 97.1 (135) < (7).04 combi ned (n=13 9) 7.9 (11/13 9) 91 (128/1 39) 96 (87/13 9) 7.4 (7/139 ) P value Permanent pacemaker implantation 8.3 (38/459) Severe patient prosthesis mismatch (incidence lower in regurgitation group compared to stenosis and combined group (19.3% vs 36.1 and 36.4%; p=.03). ^ According to VARC definition 31.8 Patients in the stenosis group had a higher 30 day mortality rate (10.5% vs 4.3% in the regurgitation group and 7.2% in the combined group; p=.04). 1 year mortality was higher among patients undergoing transapical procedures, those with STS scores higher than 20%, and with a baseline LVEF of less than 45%. Page 6 of 56

7 Abbreviations used: ASE, American Society of Echocardiography; AR, aortic regurgitation; EuroSCORE, European System for CARDIAC Operative Risk Evaluation; IQR, interquartile range; LVEF, left ventricular ejection fraction; NR, not reported; NYHA, New York Heart Association; PPM, patient-prosthesis mismatch; STS, Society of Thoracic Surgeons; TEE, transoesophageal echocardiogram; TTE, transthoracic echocardiogram; VARC, Valve Academic Research Consortium; ViV-TAVI, valve-in-valve transcatheter aortic valve implantation. Study details Key efficacy findings Key safety findings Comments I/II 86.2 (163) 84.9 (62) 85.2 (46) 88.7 (55).34 III/IV 13.8 (26) 15.1 (11/26 ) 14.8 (8/26) 11.3 (7/26).34 Survival (Kaplan Meier survival curve) The overall 1-year survival rate was 83.2 % (95% CI 80.8% 84.7%; 62 deaths; 228 survivors). Patients in the stenosis group had worse 1-year survival (76.6%; 95% CI, %; 34 deaths, 86 survivors) in comparison with the regurgitation group (91.2%; 95% CI, %; 10 deaths, 76 survivors) and the combined group 83.9%; 95% CI, %; 18 deaths, 66 survivors) (p=.01). Patients with small valves had worse 1-year survival after VIV procedure (74.8%; 95% CI %; 27 deaths; 57 survivors) vs with intermediate sized valves (81.8%; 95% CI, %; 26 deaths; 92 survivors) or with large valves (93.3%; 95% CI, %; 7 deaths; 73 survivors) (p=0.001). Factors associated with mortality within 1 year included having small surgical bioprosthesis ( 21mm; hazard ratio, 04; 95%CI, ; p=.02) and baseline stenosis (vs regurgitation, hazard ratio, 3.07; 95% CI, ; p=.008). Page 7 of 56

8 Abbreviations used: ASE, American Society of Echocardiography; AR, aortic regurgitation; EuroSCORE, European System for CARDIAC Operative Risk Evaluation; IQR, interquartile range; LVEF, left ventricular ejection fraction; NR, not reported; NYHA, New York Heart Association; PPM, patient-prosthesis mismatch; STS, Society of Thoracic Surgeons; TEE, transoesophageal echocardiogram; TTE, transthoracic echocardiogram; VARC, Valve Academic Research Consortium; ViV-TAVI, valve-in-valve transcatheter aortic valve implantation. Study details Key efficacy findings Key safety findings Comments Eggerbrecht H (2011) 2 Number of patients analysed: 47 Major procedural complications Procedural outcomes % (n=47) Study design issues: Case series (retrospective) ViV-TAVI Overall procedural complications 19 (9/47) 1 patient received Independent register on ViV-TAVI by % (n=47) Vascular access-related 13 (6/47) simultaneous mitral experts. Implantation success* 100 complications and aortic Ideal implantation^ 92 (43/47) Bail-out implantation of second 4 (2/47) bioprosthesis Germany and Switzerland (9 centres). Implantation too low ^ 8 (4/47) TAVI prosthesis during the replacement. Recruitment period: 2005 to Procedural success 98 (46/47) procedure * Defined as successful implantation into the failed (1 for severe central regurgitation Other issues: Study population: high-risk patients with surgical bioprosthesis. after transapical implant; 1 for low implantation of 29 mm CoreValve degenerated aortic surgical ^ Judged by the operator as ideal or too low. with severe paravalvular bioprosthesis. n=47 Degenerated bioprosthetic valves: stented 96% (45/47), stentless 4% (2/47) Mode of failure: xenograft stenosis 47% (22/47), severe regurgitation 32% (15/47), mixed stenosis and regurgitation 21% (10/47) Diameter of failed prosthesis: 23 mm Surgical implantation of prosthesis: 113 ± 65 months before ViV-TAVI. Age: mean 79.8 ± 7.1 years Sex: 40% female Logistic EuroSCORE: 35.0 ± 18.5% STS score: 11.6 ± 8.5% Mean LVEF(%): 52±12 Patient selection criteria: high-risk patients with multiple comorbidities from local TAVI database. Procedural echocardiographic outcomes Mean transvalvular gradient (mmhg) Mean aortic valve area (cm 2 ) Valve regurgitation % (n) Before ViV-TAVI (n=47) After ViV- TAVI (n=47) 38 ± ± 10 p value Not reported 0.90 ± ± 0.47 < Moderate or severe 48% (25/47) None or mild 98% (46/47) Not reported Smaller degenerated prostheses tend to show higher gradients after ViV than larger prostheses. NYHA functional class NYHA class Baseline ViV-TAVI % Discharge ViV-TAVI regurgitation) Refractory low cardiac output 2 (1/47) Need for mechanical resuscitation 4 (2/47) (no further details reported) Conversion to open aortic valve 0 replacement Major post-procedural complications % (n=47)^ 34 (16/47) Additional in-hospital complications Renal failure needing dialysis 9 (4/47) New pacemaker (for 11 (5/47) atrioventricular block)* Low output cardiac failure 6 (3/47) Infectious/septic complications 6 (3/47) (such as pneumonia) Bleeding at transapical site 2 (1/47) (needing surgical revision by thoracotomy) Arrhythmias 6 (3/47) * The rate of pacemaker implantation was not significantly different between the CoreRevalving system (33%) and the Edwards Sapien valve (6%), (values not reported). Page 8 of 56 Authors noted the likelihood that inexperienced operators, the different case mix and sites pioneering the ViV-TAVI procedure would have contributed to the mortality rates.

9 Abbreviations used: ASE, American Society of Echocardiography; AR, aortic regurgitation; EuroSCORE, European System for CARDIAC Operative Risk Evaluation; IQR, interquartile range; LVEF, left ventricular ejection fraction; NR, not reported; NYHA, New York Heart Association; PPM, patient-prosthesis mismatch; STS, Society of Thoracic Surgeons; TEE, transoesophageal echocardiogram; TTE, transthoracic echocardiogram; VARC, Valve Academic Research Consortium; ViV-TAVI, valve-in-valve transcatheter aortic valve implantation. Study details Key efficacy findings Key safety findings Comments Technique: ViV-TAVI. Transapical approach: 47% (22/47) Logistic EuroSCORE: 38.8 ± 19.2% Transfemoral approach: 53% (25/47) Logistic EuroSCORE: 31.6 ± 17.5% Devices: Edwards SAPIEN: 75% (35/47); size: 23 mm: 62% (29/47), 26 mm: 13% (6/47) CoreValve (Medtronic): 25% (12/47); size: 26 mm: 23% (11/47), 29 mm: 2% (1/47) General anaesthesia: 36% (17/47), all transfemoral Valvuloplasty before TAVI: 51% (24/47) Intraprocedural TEE: 66% (31/47) Balloon dilation after TAVI: 2% (1/47) (n=47) % (n=46) I 0 26 (12/46) II 4 (2/47) 53 (25/46) III 83 (39/47) 2 (1/46) IV 13 (6/47) 0 ^ 1 patient died during the procedure. Mortality in those with major complications All-cause 30-day mortality rate (5 were treated by transapical approach) Procedural death (caused by refractory low cardiac output) In-hospital deaths (3 caused by low output cardiac failure; 1 as a result of arrhythmia, 3 related to postoperative sepsis or infection) % (n=47) 17 (8/47) 2 (1/47) 15 (7/47) There were no stroke or valve embolisation events. 5/8 deaths occurred in the first half of the case series. Follow-up: 30 days Conflict of interest/source of funding:2 authors received honorarium for lectures or consulting fees from the manufacturers (Medtronic and Edwards).1 author is the cofounder of a device (Jena Valve). Page 9 of 56

10 Abbreviations used: ASE, American Society of Echocardiography; AR, aortic regurgitation; EuroSCORE, European System for CARDIAC Operative Risk Evaluation; IQR, interquartile range; LVEF, left ventricular ejection fraction; NR, not reported; NYHA, New York Heart Association; PPM, patient-prosthesis mismatch; STS, Society of Thoracic Surgeons; TEE, transoesophageal echocardiogram; TTE, transthoracic echocardiogram; VARC, Valve Academic Research Consortium; ViV-TAVI, valve-in-valve transcatheter aortic valve implantation. Study details Key efficacy findings Key safety findings Comments Ihlberg L (2013) 3 Number of patients analysed: 45 Complications in 30 days % (n) Follow-up issues: Case series (retrospective) Independent Nordic ViV register by physicians. Nordic countries (11 centres) Recruitment period: 2008 to 2012 Study population: patients who had ViV- TAVI in cardiac surgical centres for degenerated aortic surgical bioprosthesis n=45 Degenerated bioprosthesis: stented porcine (17/45), stented pericardial (21/45), stentless porcine (4/45), homograft (3/45). Mode of failure: valve stenosis 51% (23/45), regurgitation 29% (13/45), combined 18% (8/45), I unknown. Surgical implantation of prosthesis: 8.7 ± 3.5 years before ViV-TAVI. Age: mean 80.6 years Sex: 42% (19/45) female Logistic EuroSCORE: 35.4 ± 16.1% STS score: 14.6% Patient selection criteria: centres that performed at least 1 ViV-TAVI procedure included. Procedural outcomes % (n) Technical success* 95.6 Technical failure 1 patient had a second valve implantation due to malposition of the first implanted CoreValve. 1 severe intravalvular aortic regurgitation due to leaflet dysfunction of a SAPIEN device, converted to open surgery after 3 days. (43/45) 4.4 (2/45) * Definition according to Valve Academic Research Consortium consensus document criteria. Procedural echocardiographic outcomes Mean transvalvular gradient (mmhg) Peak transvalvular gradient (mmhg) Mean aortic valve area (cm 2 ) Mean LVEF % Before ViV-TAVI (n=45) 30 days after ViV- TAVI (n=45) 1 year after ViV TAVI (n=29) NR 16.4 ± ± 7. 8 NR 28.9 ± ± 11.2 NR 1.3 ± 0.4 < ± ± 11.7 NR Intra-procedural mortality 0 Procedural mortality 0 Bleeding (no further details reported) 13 (6/45) Occlusive external iliac artery dissection (managed by endovascular stent grafting) 2(1/45) Moderate paravalvular leak 2(1/45) Peri-procedural myocardial infarction 2/45 Mortality (in patients with a periprocedural MI) (1 died on second post-operative day, as the left coronary ostium was partially obstructed by the torn porcine leaflet of the bioprosthesis) 1 patient died of aspiration pneumonia and respiratory insufficiency. 4 (2/45) Major stroke 2(1/45) Permanent pacemaker (in1 with stented valve and 2 with stentless valve) Complications after 30 days: Deaths: 15.5% (7/45) 7 (3/45) 2 cardiac-related: 1 prosthetic valve endocarditis at 3 months and 1 congestive heart failure at 22 months. 3 non-cardiac-related (1 subdural haemorrhage at 8 months, chronic myeloid leukaemia at 8 months and traumatic head injury at 14 months) and 2 unknown. Only 29 patients completed 1-year follow-up. Study design issues: More patients in NYHA class IV in the SAPIEN group preoperatively (42% vs 18%, p=0.032). Page 10 of 56

11 Abbreviations used: ASE, American Society of Echocardiography; AR, aortic regurgitation; EuroSCORE, European System for CARDIAC Operative Risk Evaluation; IQR, interquartile range; LVEF, left ventricular ejection fraction; NR, not reported; NYHA, New York Heart Association; PPM, patient-prosthesis mismatch; STS, Society of Thoracic Surgeons; TEE, transoesophageal echocardiogram; TTE, transthoracic echocardiogram; VARC, Valve Academic Research Consortium; ViV-TAVI, valve-in-valve transcatheter aortic valve implantation. Study details Key efficacy findings Key safety findings Comments Technique: ViV-TAVI. Transapical approach: 56% (25/45) Transfemoral approach: 38% (17/45), transaortic in 2 and subclavian in 1 case. At 1 month, all but 1 patient had either no or mild paravalvular leakage. 17% of patients had high postprocedural mean gradients ( 20 mmhg) and remained unchanged at 12 months. Devices: Edwards SAPIEN: 73% (33/45); size: 23 mm. CoreValve (Medtronic): 27% (12/45); size: 26 mm. General anaesthesia and TEE monitoring were used for most SAPIEN procedures but less frequently for CoreValve (94% vs 42%, p=0.001; and 94% vs 33%, p=0.001). Pre-implantation valvuloplasty was performed in 33% of the procedures. Follow-up: mean 14.4 months NYHA functional class NYHA class Baseline ViV-TAVI % (n=45) Discharge ViV-TAVI % (n=45) I 0 37 (16/45) II 0 51 (22/45) III 67 (30/45) 2 (1/45) IV 33 (15/45) 0 At 1 year, 89.7% (26/29) remained in NYHA functional class I and II Survival The cumulative survival at 6, 12 and 24 months was 93.2%, 88.1% and 84.1% respectively. Conflict of interest/source of funding: 3 authors are proctors for Edward Lifesciences. 1 author is a proctor for Medtronic, 1 author received moderate honoraria from Medtronic and St Jude Medical. Page 11 of 56

12 Abbreviations used: ASE, American Society of Echocardiography; AR, aortic regurgitation; EuroSCORE, European System for CARDIAC Operative Risk Evaluation; IQR, interquartile range; LVEF, left ventricular ejection fraction; NR, not reported; NYHA, New York Heart Association; PPM, patient-prosthesis mismatch; STS, Society of Thoracic Surgeons; TEE, transoesophageal echocardiogram; TTE, transthoracic echocardiogram; VARC, Valve Academic Research Consortium; ViV-TAVI, valve-in-valve transcatheter aortic valve implantation. Study details Key efficacy findings Key safety findings Comments Bedogni F (2011) 4 Number of patients analysed: 25 Procedural complications Follow-up issues: Case series Italy (8 centres) Recruitment period: not reported Study population: high-risk patients with failed surgical aortic bioprosthesis. n=25 Degenerated prosthesis: (18 stented and 7 stentless) Mode of failure: group A (mainly stenotic 36% [9/25]) group B (mainly regurgitant 64% [16/25]) (10 stented and 6 stentless) NYHA class III: 21 patients; class IV: 4 patients Age: mean 84 ± 3.2 years Sex: 60% female Logistic EuroSCORE: 31.5 ± 14.8% STS score: 8.2 ± 4.2 Patient selection criteria: >75 years, coronary artery disease, malignancy, hepatic cirrhosis, COPD, severe pulmonary hypertension, porcelain aorta, low ejection fraction, renal failure, and peripheral obstructive artery disease. Logistic EuroSCORE and STS score were calculated. Patients with symptomatic heart failure (NYHA class III and NYHA class IV) Echocardiographic criteria for bioprosthesis dysfunction with aortic valve area <1 cm 2 and/or aortic Implantation success and survival ViV-TAVI % (n=25) Implantation success day survival 88 6-month survival 84 Definitions were according to Valve Academic Research Consortium consensus document criteria. Post procedural echocardiographic outcomes Mean transa ortic gradie nt (mmh g) Aortic valve area (cm 2 ) LVEF (%) Group A stenosis (n=9) Baseli ne 77.6 ± mon th follo w- up 34.6 ± ± ± ± ± 10 p val ue Not sign ifica nt Not sign ifica nt Group B regurgitation (n=16) Bas elin e 36.8 ± 24 Act ual figur es 6- month followup 20.2 ± 7.2 Actual figures not reporte p val ue 0.01 Not sign ifica nt % (n=25) Intraprocedural mortality 0 Acute left main occlusion 4 (1/25) (immediately after ViV-TAVI in a stentless xenograft, successfully treated with percutaneous coronary intervention) Intraprocedural and periprocedural cerebrovascular 0 events Adverse events at 30 days Mortality 1 patient died of cardiogenic shock caused by ostial left main occlusion 48 hours after ViV-TAVI in a stenotic prosthesis. Angiography showed a Mitraflow valve leaflet overriding the left main ostium and significantly impairing blood flow; this was treated by percutaneous coronary intervention but treatment was unsuccessful. 1 patient urgently admitted with cardiogenic shock caused by a severely stenotic primary valve (Mitraflow 21) and died of multiorgan failure 17 days after ViV- TAVI. A third patient died of acute heart failure 26 days after the procedure. % (n=25) 12 (3/25) Mortality data complete in 100% of patients. Echocardiographic outcomes at last follow-up were not available for 1 patient in the regurgitant group. Study design issues: No difference in procedure between the 2 groups. Other issues: Authors noted higher 30-day mortality (n=3) than expected for perioperative mortality predicted by STS score (8.2 ± 4.2). Page 12 of 56

13 Abbreviations used: ASE, American Society of Echocardiography; AR, aortic regurgitation; EuroSCORE, European System for CARDIAC Operative Risk Evaluation; IQR, interquartile range; LVEF, left ventricular ejection fraction; NR, not reported; NYHA, New York Heart Association; PPM, patient-prosthesis mismatch; STS, Society of Thoracic Surgeons; TEE, transoesophageal echocardiogram; TTE, transthoracic echocardiogram; VARC, Valve Academic Research Consortium; ViV-TAVI, valve-in-valve transcatheter aortic valve implantation. Study details Key efficacy findings Key safety findings Comments regurgitation grade 3 or higher. Technique: ViV-TAVI Route of implantation: Transfemoral: 88% (22/25) Transaxillary : 12% (3/25) General anaesthesia: 40% (10/25) Surgical access: 35% (9/25) Dual antiplatelet therapy for all patients. Aspirin indefinitely and clopidogrel (75 mg/day) for 6 months Balloon valvuloplasty: 30% (8/25) (6 in group A; 2 in group B) Post-dilation: 12% (3/25) 1 in stenotic group A and 2 in regurgitant group B, temporary pacemaker in all patients. Device used: 18-F Core ReValving System (CRS) (Medtronic); size: 26 mm: 76% (19/25); 29 mm: 24% (6/25) (chosen by internal size of the failed prosthesis) AR (Grad e) % (n) Grad e 1 or Gra de 2 (n= 2/9) not rep orte d Gra de 3 or d Grade 0 or 1 (87.5, n=14/1 6) Grade 2 (15, n=2/16) Functional outcome (NYHA class) at 6-month follow up NHYA functional class improved in 84% (21/25) of survivors to class I and II compared with 100% patients having a baseline functional class of III or IV. Myocardial infarction 8 (2/25) Stroke 0 New-onset renal failure 4 (1/25) Definitive pacemaker 12 (3/25) Cumulative event rate at 6 months Mortality (another patient died because of severe respiratory insufficiency) % (n=25) 16 (4/25) Stroke 0 Myocardial infarction 8 (2/25) New-onset renal failure 4 (1/25) Definitive pacemaker (2 patients with stented bioprosthesis, 2 stentless) (another patient needed pacemaker implantation for a complete atrioventricular block) Major bleeding 0 Repeat valve interventions 0 16 (4/25) Follow-up: 6 months (mean) Conflict of interest/source of funding: 6 of the authors are consultants for the manufacturer (Medtronic). Page 13 of 56

14 Abbreviations used: ASE, American Society of Echocardiography; AR, aortic regurgitation; EuroSCORE, European System for CARDIAC Operative Risk Evaluation; IQR, interquartile range; LVEF, left ventricular ejection fraction; NR, not reported; NYHA, New York Heart Association; PPM, patient-prosthesis mismatch; STS, Society of Thoracic Surgeons; TEE, transoesophageal echocardiogram; TTE, transthoracic echocardiogram; VARC, Valve Academic Research Consortium; ViV-TAVI, valve-in-valve transcatheter aortic valve implantation. Study details Key efficacy findings Key safety findings Comments Piazza N (2011) 5 Number of patients analysed: 20 Intraprocedural complications % (n=20) Follow-up issues: Case series (prospective) Germany Recruitment period: 2007 to 2011 Study population: high surgical risk patients with failed surgical aortic bioprosthesis n=20 Type of failed prostheses: stented 70% (14/20), stentless: 30% (6/20). Mode of failure: aortic stenosis: 50% (10/20), aortic regurgitation (by ECG or aortography): 45% (9/20), combination aortic stenosis and regurgitation: 1 Age: mean 75 ± 13 years Sex: 60% (12/20) female Logistic EuroSCORE: mean 27 ± 13% STS score: 7 ± 4% Primary surgical valve operation: mean 5 ± 2 years before TAVI. Patient selection criteria: high-surgical-risk patients with failing surgical aortic bioprosthesis, with stented or stentless aortic valve prostheses with internal diameters between 18 and 27 mm. Technique TAVI in surgical aortic valve (SAV) implantation. Procedural outcomes % (n=20) Procedural success* 90 (18/20) Unsuccessful procedure 10 (2/20) 1 patient, procedure aborted and converted to surgical aortic valve replacement (SAVR). 1 patient died. 30-day survival 85 (17/20) * Defined as successful implantation of a TAV in a SAV with the patient leaving the catheterisation laboratory alive. Post-procedural echocardiographic outcomes (inhospital) The mean post-procedural transaortic valve gradient was 20.0 ± 7.5 mmhg. Intraprocedural mortality (after pre-implant balloon aortic valvuloplasty, cardiac arrest occurred in 1 patient [ stone heart ]. No attempt was made to deploy valve and an immediate cardiopulmonary bypass was done but the patient died during the procedure). Stroke 0 Permanent pacemaker 0 Conversion to open surgery 1 (CoreValve prosthesis dislocated into ascending aorta twice while partially deployed. Prosthesis was retrieved, procedure aborted and converted to SAVR). In-hospital complications within 30 days % (n=19) In-hospital mortality caused by myocardial infarction 1. Moderate to severe paravalvular aortic regurgitation noted after 26 mm CoreValve prosthesis implantation, treated by implantation of a 23 mm Edwards Sapien within first prosthesis. Angiography demonstrated mild to moderate paravalvular aortic regurgitation. A myocardial infarction was diagnosed (based on rising cardiac biomarkers) on day 3 and patient died from cardiogenic shock.) (2/19) Very short follow-up period. Page 14 of 56

15 Abbreviations used: ASE, American Society of Echocardiography; AR, aortic regurgitation; EuroSCORE, European System for CARDIAC Operative Risk Evaluation; IQR, interquartile range; LVEF, left ventricular ejection fraction; NR, not reported; NYHA, New York Heart Association; PPM, patient-prosthesis mismatch; STS, Society of Thoracic Surgeons; TEE, transoesophageal echocardiogram; TTE, transthoracic echocardiogram; VARC, Valve Academic Research Consortium; ViV-TAVI, valve-in-valve transcatheter aortic valve implantation. Study details Key efficacy findings Key safety findings Comments Device: CoreValve (Medtronic) 15% (3/20), Edwards Sapien (Edwards Lifesciences) 85% (17/20) Route of implantation: transapical approach: 75% (15/20), transfemoral approach: 20% (4/20) Diameter size: 23 mm: 60% (12/20) transapical patients; 26 mm: 25% (5/20); 29 mm: 10% (2/20) General anaesthesia or local anaesthesia (with mild sedation) based on underlying comorbidities. Pre-implant balloon valvuloplasty performed only in stenosis patients. Balloon aortic valvuloplasty and rapid pacing during valve deployment used in some patients. Left main coronary occlusion following TAV in SAV, treated by successful left main coronary stenting, patient died in hospital on day 2 from multi-organ failure). Stroke 0 Permanent pacemaker 0 Paravalvular aortic regurgitation None to trivial 50 (10/19) Mild Mild to moderate 30 (6/19) 10 (2/19) Follow-up: within 30 days Conflict of interest/source of funding: 1 author is a consultant for a manufacturer (Medtronic) and 1 author is a proctor for another manufacturer (Edwards Lifesciences) Page 15 of 56

16 Abbreviations used: ASE, American Society of Echocardiography; AR, aortic regurgitation; EuroSCORE, European System for CARDIAC Operative Risk Evaluation; IQR, interquartile range; LVEF, left ventricular ejection fraction; NR, not reported; NYHA, New York Heart Association; PPM, patient-prosthesis mismatch; STS, Society of Thoracic Surgeons; TEE, transoesophageal echocardiogram; TTE, transthoracic echocardiogram; VARC, Valve Academic Research Consortium; ViV-TAVI, valve-in-valve transcatheter aortic valve implantation. Study details Key efficacy findings Key safety findings Comments Pasic M (2011) 6 Number of patients analysed: 14 Procedural complications Follow-up issues: Case series Germany (single centre) Recruitment period: 2008 Study population: high-risk patients with degenerated biological aortic valve prosthesis (11 xenograft prosthesis, 3 aortic homograft); (10 stented, 4 stentless) Degenerated biological valve external diameter: 21 mm: 29% (4/14); 23 mm: 50% (7/14); 25 to 28mm: 21% (3/14) n=14 Age: mean 73.3 ± 13.1 years Sex: 35.7% (5/14) female Mean STS score: 21.9% ± 10.9% (range 4.2% to 42%) Mean logistic EuroSCORE: 45.3% ± 22% NYHA functional class: III or IV Primary valve procedure: mean 8.9 ± 4.7 years Patient selection criteria: patients at very high risk for conventional repeat surgery because of comorbidities or technical or surgical considerations (porcelain aorta, polymorbidity, coronary artery disease, poor LVEF). Exclusion criteria: paravalvular leakage Procedural success: 100% 30-day survival: 86% (Simultaneously and on an elective basis 1 patient had a coronary stent for coronary artery disease, 1 had a renal stent and 1 had a cardiopulmonary bypass for LVEF of 10%). Procedural echocardiographic outcomes Mean transvalvular gradient (mmhg) Mean aortic valve area (cm 2 ) Before ViV-TAVI (n=14) 27.2 ± ± 0.36 LVEF (%) 45% ± 13% Valve regurgitation (grade) (n) Grade 3 (n=5) Grade 2 (n=3) Grade 1-0 (n=6) After ViV- TAVI (n=14) 10.3 ± ± % ± 16% Grade 0 (n=14) p value NR NR 0.59 Procedural echocardiographic outcomes for stented and stentless valves Mean transvalvular gradient (mmhg) Stented valves (n=10) Stentless valves (n=4) Complication ViV-TAVI (n=14) Intraprocedural mortality 0 Conversion to open surgery 0 Early postoperative complications Complication ViV-TAVI % (n=14) Mortality 0 Respiratory problems (further 7 (1/14) details not reported) Myocardial infarction 0 Pacemaker implant 0 Bleeding 0 Wound healing problems 0 Clinical neurological deficits 0 Temporary dialysis 0 Late postoperative complications Complication Mortality (1. pulmonary problems 3 months after the procedure ( complications of urological surgery 4.5 months after the procedure Endocarditis (3 months after the procedure, patient had another operation and a new valve was inserted by conventional surgical method; the postoperative course was uneventful) ViV-TAVI % (n=14) 14 (2/14) 7 (1/14) Follow-up varied and was limited. Study design issues: Modified technique used. 4 patients with a small prosthesis of 21 mm external diameter (internal diameter of 17 mm) were considered for the procedure on a palliative basis. Study population issues: 4 patients had severe mitral valve regurgitation. Page 16 of 56

17 Abbreviations used: ASE, American Society of Echocardiography; AR, aortic regurgitation; EuroSCORE, European System for CARDIAC Operative Risk Evaluation; IQR, interquartile range; LVEF, left ventricular ejection fraction; NR, not reported; NYHA, New York Heart Association; PPM, patient-prosthesis mismatch; STS, Society of Thoracic Surgeons; TEE, transoesophageal echocardiogram; TTE, transthoracic echocardiogram; VARC, Valve Academic Research Consortium; ViV-TAVI, valve-in-valve transcatheter aortic valve implantation. Study details Key efficacy findings Key safety findings Comments and acute or subacute endocarditis Technique: ViV-TAVI Transapical approach Device: Edwards SAPIEN; size: 26 mm: 29% (4/14), 23 mm: 71% (10/14) The Berlin addition : slight modification of the standard transapical TAVI technique included slow and gradual valve deployment supported by simultaneous angiographic visualisation to enable optimal positioning of the new valve (without balloon dilatation of the degenerated prosthesis). Procedure was monitored by fluoroscopy, angiography and intraoperative TEE. Temporary epicardial wires left in place after the procedure for a week. Postoperative aspirin and clopidogrel given. Follow-up: 2 20 months Conflict of interest/source of funding: first 4 authors have been proctors to the manufacturer (Edwards Lifesciences). Before ViV-TAVI After ViV-TAVI Mean aortic valve area (cm 2 ) Before ViV-TAVI After ViV-TAVI 29 ± ± ± ± ± ± ± ± 0.51 Follow-up echocardiographic outcomes at 2 20 months follow-up Before ViV- TAVI (n=14) Mean transvalvular 27.2 gradient (mmhg) ± 16.9 LVEF (%) 45 Mean left ventricular end diastolic diameter (mm) Valve regurgitation (Grade) Mitral insufficiency (Grade) NYHA functional class ViV-TAVI (n=12) 13.1 ± ± 11 ± 13 Not reported 53 ± 10 Grade 1-3 Grade 0 Regressed in all patients Grade 2 NHYA class was III or IV at baseline and improved to class I or II at follow-up period. Page 17 of 56

18 Abbreviations used: ASE, American Society of Echocardiography; AR, aortic regurgitation; EuroSCORE, European System for CARDIAC Operative Risk Evaluation; IQR, interquartile range; LVEF, left ventricular ejection fraction; NR, not reported; NYHA, New York Heart Association; PPM, patient-prosthesis mismatch; STS, Society of Thoracic Surgeons; TEE, transoesophageal echocardiogram; TTE, transthoracic echocardiogram; VARC, Valve Academic Research Consortium; ViV-TAVI, valve-in-valve transcatheter aortic valve implantation. Study details Key efficacy findings Key safety findings Comments Sieffert M (2012) 7 Number of patients analysed: 11 Follow-up issues Case series (retrospective) Germany Recruitment period: 2008 to 2011 Study population: patients with severe degeneration of implanted xenograft bioprostheses Type of prosthesis: stented (21 to 25 mm): 90% (10/11), stentless (27 mm): 10% (1/11) Mode of failure: stenosis: 36% (4/11) AR: 36% (4/11) mostly caused by prolapse of a single cusp, combination of AR and stenosis: 27% (3/11). n=11 Age: mean 79.3 ± 6.1 years Sex: 18% (2/11) female Logistic EuroSCORE: 31.8 ± 24.1% Surgical aortic valve implanted 16 ± 6.2 years before ViV Patient selection criteria: significant signs of valve dysfunction (stenosis, regurgitation, mixed disease) long time since bioprosthetic aortic valve replacement, with severe comorbidities and at high surgical risk. Technique: ViV-TAVI Approach: transapical 100% Device: balloon-expandable Edwards Sapien valve (Edwards Lifesciences). Echocardiographic valve function outcomes PPM after ViV-TAVI is defined as an indexed effective orifice area (ieoa) of 0.85 cm 2 /m 2 or less (moderate) or 0.65 cm 2 /m 2 or less (severe), determined by discharge echocardiography. ieoa (cm 2 / m 2 ) Mean aortic valve gradi ent (mmh g) AR (grad e) Severe PPM Group 1 (ieoa <0.65 cm 2 /m 2 ) (n=5) Baseli ne 0.5 ± ± ± 1.1 Disch arge 0.58 ± ± ± 0.5 p val ue Not sig nific ant Not sig nific ant Moderate/no PPM Group 2 (ieoa >0.65 cm 2 /m 2 ) (n=6) Basel ine 0.6 ± ± ± 1.3 Disc harg e 0.8 ± ± ± 0.5 p valu e Not signif icant At 6-month follow up no significant changes were found in mean aortic valve gradient, LVEF or AR in group 1 (n=3) or group 2 (n=4). AR was trace in all but 1 patient, who had a grade 2 paravalvular AR that was not considered to be clinically relevant. NYHA functional class Post-procedural complications Group 1 (ieoa <0.65 cm/m) % (n=5) Death 2 (1 due to low cardiac output on day 8. 1 due to metastatic prostate carcinoma 246 days after the Conversion to surgical aortic valve replacement (SAVR) procedure). 1 (symptoms of heart failure and severe PPM, treated by SAVR and root enlargement for symptomatic stenosis (ieoa, 0.4 cm 2 /m 2 ) 426 days after ViV- TAVI) Group 2 (ieoa <0.65 cm/m) % (n=6) 1 (caused by sudden cardiac failure at the rehabilitation clinic on day 33). 4 patients (2 in each group) were lost to follow up at 6 months. Study design issues Small number of patients in the analysis. Other issues Authors noted that larger prostheses seem to carry a lower risk of PPM. Page 18 of 56

19 Abbreviations used: ASE, American Society of Echocardiography; AR, aortic regurgitation; EuroSCORE, European System for CARDIAC Operative Risk Evaluation; IQR, interquartile range; LVEF, left ventricular ejection fraction; NR, not reported; NYHA, New York Heart Association; PPM, patient-prosthesis mismatch; STS, Society of Thoracic Surgeons; TEE, transoesophageal echocardiogram; TTE, transthoracic echocardiogram; VARC, Valve Academic Research Consortium; ViV-TAVI, valve-in-valve transcatheter aortic valve implantation. Study details Key efficacy findings Key safety findings Comments Size: 23 mm: 91% (10/11) 26mm: 9% (1/11) General anaesthesia: 100% (11/11) Pre-implant balloon aortic valvuloplasty was not done but rapid pacing and fluoroscopy were used. Follow-up: 6 months or 1 year Conflict of interest/source of funding: One author received lecture fees from a manufacturer (Edward Lifesciences). Group 1 (ieoa <0.65 cm 2 /m 2 ) % (n=5) Group 2 (ieoa <0.65 cm 2 /m 2 ) % (n=6) Baseline 3.2 ± ± days 1.7 ± ± months 5 ± ± 0.8 NS Survival p value Total Kaplan Meier survival and log rank testing did not detect any differences in survival between the 2 groups (p = 0.67). Page 19 of 56

20 Abbreviations used: ASE, American Society of Echocardiography; AR, aortic regurgitation; EuroSCORE, European System for CARDIAC Operative Risk Evaluation; IQR, interquartile range; LVEF, left ventricular ejection fraction; NR, not reported; NYHA, New York Heart Association; PPM, patient-prosthesis mismatch; STS, Society of Thoracic Surgeons; TEE, transoesophageal echocardiogram; TTE, transthoracic echocardiogram; VARC, Valve Academic Research Consortium; ViV-TAVI, valve-in-valve transcatheter aortic valve implantation. Study details Key efficacy findings Key safety findings Comments UK TAVI register (V3 data set)8 Case series (retrospective and prospective data) Recruitment period: 2007 to 201 Study population: patients with TAVI in valve in failing bioprosthesis. n=135 Age and sex: NR Logistic EuroSCORE: NR STS score: NR Mean time from last SAVR-NR Number of patients analysed: 135 Procedural adverse events % (n) Adverse events % (n) Major vascular injury 0.7 (1/135) Emergency ViV 3.7 (5/135) Device embolization 1.5 (2/135) CVA 1.5 (2/135) Pacing post procedure 4.4 (6/135) Myocardial infarction 0.7 (1/135) Other issues All data is self-reported by the participating centres Out of a total of149 ViVs, data for patients with Valve in TAVI prosthesis have been excluded as they represent a different cohort (n=14/149). Technique: ViV-TAVI Devices: NR Follow-up: NR Mortality ^ According to VARC definition Mortality at 30 days: 5.9% (8/135) Mortality at 1 year: 14.1% (19/135) Conflict of interest/source of funding: NR Page 20 of 56

21 Abbreviations used: ASE, American Society of Echocardiography; AR, aortic regurgitation; EuroSCORE, European System for CARDIAC Operative Risk Evaluation; IQR, interquartile range; LVEF, left ventricular ejection fraction; NR, not reported; NYHA, New York Heart Association; PPM, patient-prosthesis mismatch; STS, Society of Thoracic Surgeons; TEE, transoesophageal echocardiogram; TTE, transthoracic echocardiogram; VARC, Valve Academic Research Consortium; ViV-TAVI, valve-in-valve transcatheter aortic valve implantation. Study details Key efficacy findings Key safety findings Comments Studies of patients with rescue of suboptimal valve in valve implantations Ussia GP (2011) 9 Comparative case series (prospective study) Italian CoreValve Register Italy (14 centres) Recruitment period: not reported Study population: Patients undergoing TAVI and those with severe paraprosthetic leaks (PPL) due to malposition and having a second prosthesis implanted inside the first one. n=663 (24 ViV [3.6%] vs 639 TAVI ) Device malposition in patients undergoing ViV: too low deployment in left ventricle in 75% (n=18/24); high deployment above annulus in 25% (n=6/24). Age: ViV group: mean 80.3 years, TAVI group: mean 81.0 years Sex: ViV group: 54.1% (13/24) female, TAVI group: 56% (358/639) female Mean logistic EuroSCORE: 23.0 ± 13.7% Patient selection criteria: not reported. Technique: ViV vs TAVI technique Route of implantation: Number of patients analysed: 663 (24 ViV vs639 TAVI ) Procedural success ViV group % (n=24) TAVI group % (n=639) p valve Procedural success* 30-day survival not reported 1-year survival not reported * Defined as device deployment with fall of transaortic peak-to-peak gradient, without any peri-procedural major adverse cardiovascular and cerebrovascular event (MACCE) within 24 hours of prosthesis implantation. Functional outcome (NHYA class) NHYA class III/lV ViV % (n=24) TAVI % (n=639) 64.9 p value Baseline (19/24) (415/639) Discharge days year Actual numbers followed up not reported Echocardiographic outcomes Mean transaortic ViV (n=24) TAVI (n=639) p value Procedural complications Complication ViV % (n=24) TAVI % (n=639) p value Intraprocedural mortality (6/639) Intraprocedural major adverse cerebrovascular and cardiac events (MACCE)* (18/639) Major access site complications^ (1/24) (12/639) Cardiac tamponade (8/639) * Defined as the composite of death resulting from any cause, myocardial infarction, stroke, or conversion to open heart surgery. ^ Defined as vascular rupture with fatal bleeding or need for urgent vascular surgery or transcatheter repair. Mortality at 30 days and other major adverse events Complication Mortality (any cause) Major adverse cerebrovascular and cardiac ViV % (n=24) TAVI % (n=639) p value Follow-up issues: No loss to follow up reported. Study population issues: No statistically significant difference in baseline clinical characteristics between patients in the ViV group and those in the TAVI group. Other issues: The authors highlight that it is unclear if the presence of 2 valves could impact on the long-term durability of the prosthesis. Authors suggest that high success rate might be due to increasing operator familiarity and confidence in device. Page 21 of 56