Transcatheter Aortic Valve Implantation (TAVI) for Treatment of Aortic Valve Stenosis Part A

Transcription

1 Transcatheter Aortic Valve Implantation (TAVI) for Treatment of Aortic Valve Stenosis Part A S Sehatzadeh, K Kaulback 2009 Suggested Citation Sehatzadeh S, Kaulback K. Transcatheter aortic valve implantation (TAVI) for treatment of aortic valve stenosis part A [Internet]. Toronto: Queen s Printer for Ontario; 2009 [cited date]. 39 p. Available from: TAVI Preliminary Report Part A (2009)

2 Table of Contents Table of Contents... 2 List of Tables... 3 List of Figures... 4 List of Abbreviations... 5 Background... 6 Objective of Analysis... 6 Clinical Need and Target Population... 6 Aortic Valve Stenosis... 6 Prevalence... 7 Technology/Technique... 7 Evidence-Based Analysis... 8 Research Questions... 8 Research Methods... 8 Literature Search... 8 Inclusion Criteria... 8 Exclusion Criteria... 8 Outcomes of Interest... 8 Statistical Analysis... 9 Quality of Evidence... 9 Results of Evidence-Based Analysis Mortality Emergent Conversion to Surgery New Valve Function Ventricular Function Postprocedural Complications Quality of Life Conclusions Appendices Appendix 1: Search Strategies Appendix 2: Quality of Studies and GRADE Tables Appendix 3: Clinical Data References TAVI Preliminary Report Part A (2009) 2

3 List of Tables Table 1: Hemodynamic Parameters Used for Diagnosis of AVS... 7 Table 2: Body of Evidence Examined According to Design Table 3: Characteristics and Patient Clinical Data: TF Implantation of Edwards SAPIEN Valve.. 11 Table 4: Characteristics and Patient Clinical Data: TF Implantation of CoreValve Table 5: Characteristics and Patient Clinical Data: TA Implantation of Edwards SAPIEN Valve.. 13 Table 6: Mean AVA Before and After TA TAVI Table 7: Mean Transaortic Pressure Gradient Before and After TA TAVI Table 8: LVEF Before and After TF TAVI Table 9: LVEF Before and After TA TAVI Table 10: Ventricular and Atrial Measurements Before and After TF TAVI Table 11: Pooled Estimates for Postprocedural Complications Table 12: Quality of Life Scores Reported by TAVI Studies Table A1: GRADE Quality of Evidence for TAVI Table A2: Periprocedural Outcomes, Studies on TF Implantation of Edwards SAPIEN Valve Table A3: Hemodynamic Changes, Studies on TF Implantation of Edwards SAPIEN Valve Table A4: Hospital and Mortality Outcomes, Studies on TF Implantation of Edwards SAPIEN Valve Table A5: Postprocedural Complications, Studies on TF Implantation of Edwards SAPIEN Valve Table A6: Periprocedural Outcomes, Studies on TF Implantation of CoreValve Table A7: Hemodynamic Changes, Studies on TF Implantation of CoreValve Table A8: Hospital and Mortality Outcomes, Studies on TF Implantation of CoreValve Table A9: Postprocedural Complications, Studies on TF Implantation of CoreValve Table A10: Periprocedural Outcomes, Studies on TA Implantation of Edwards SAPIEN Valve Table A11: Hemodynamic Changes, Studies on TA Implantation of Edwards SAPIEN Valve Table A12: Hospital and Mortality Outcomes, Studies on TA Implantation of Edwards SAPIEN Valve. 35 Table A13: Postprocedural Complications, Studies on TA Implantation of Edwards SAPIEN Valve TAVI Preliminary Report Part A (2009) 3

4 List of Figures Figure 1: Pooled 30-Day and Follow-up Mortality Rates Figure 2: Mortality Rates Reported by One European Registry With 6 Months Follow-up Figure 3: Mortality Rates Reported by One United States Registry With 5.3 Months Follow-up Figure 4: Pooled Rate of Emergent Conversion to savr Figure 5: Mean AVA Before and After TF TAVI Figure 6: Mean Transaortic Pressure Gradient Before and After TF TAVI Figure 7: LVEF Before and After TF TAVI Figure 8: Mean NYHA Class Before and After TF TAVI TAVI Preliminary Report Part A (2009) 4

5 List of Abbreviations AVA AVS BV CI EuroSCORE IV LVEF LVMI MI MM NYHA RCT savr SD STS TA TAVI TF Aortic valve area Aortic valve stenosis Balloon valvuloplasty Confidence interval European System for Cardiac Operative Risk Evaluation Inverse variance Left ventricular ejection fraction Left ventricular mass index Myocardial infarction Medical management Not reported New York Heart Association Randomized controlled trial Surgical aortic valve replacement Standard deviation Society of Thoracic Surgeons Transapical Transcatheter aortic valve implantation Transfemoral TAVI Preliminary Report Part A (2009) 5

6 Background Note: This report (Part A) was written in 2009 but was not published at that time, pending approval of the transcatheter aortic valve implantation device by Health Canada. Part B (the 2012 update) is available here: Objective of Analysis The objective of this review is to evaluate the safety and effectiveness of transcatheter aortic valve implantation (TAVI) for the treatment of aortic valve stenosis (AVS) in symptomatic older adults. Clinical Need and Target Population Aortic Valve Stenosis AVS is the most common acquired heart valve disease (1) and a major cause of cardiovascular morbidity in older adults. (2) Mortality rises sharply when symptoms develop, with an average survival of 2 to 3 years. (3) Accordingly, standard therapeutic guidelines recommend surgical replacement of the aortic valve in symptomatic patients with severe AVS. (4) Symptoms of AVS usually develop gradually after an asymptomatic latent period. Exertional dyspnea or fatigue is the most common initial complaint. The process of maintaining cardiac output against the resistance to ejection of blood from the left ventricle into the aorta leads to left ventricular hypertrophy, with an increase in left ventricular wall thickness and mass. As the pressure continues to rise, blood flows back into the lungs and causes dyspnea. Severe forms of AVS prevent blood from reaching the brain and the rest of the body, causing light-headedness and fainting. Heart failure ensues if the condition remains untreated. Causes of Aortic Valve Stenosis Senile degenerative AVS is believed to be caused by a mechanism similar to that of atherosclerosis. (5) In the senile form, a progressive build-up of calcium deposits within the valve cusps occurs between the sixth and eighth decades of life. Rheumatic fever is now a very rare cause of AVS in developed countries. When rheumatic fever affects the aortic valve, it almost always affects the mitral valve as well. (5) About 1% to 2% of babies are born with a bicuspid (rather than a tricuspid) aortic valve. Stenosis in bicuspid aortic valves occurs about 20 years earlier than it does in tricuspid aortic valves. (5) Diagnosis AVS is initially detected by auscultation of the heart sounds. There is usually a typical crescendodecrescendo systolic ejection murmur radiating to the neck. As AVS progresses, the murmur becomes louder and is associated with a thrill. With further worsening of stenosis, the stroke volume decreases, leading the murmur intensity to lessen. (5) Doppler echocardiography, M-mode, and 2-dimensional echocardiography are used to diagnose and determine the severity of stenosis. The primary hemodynamic parameters for evaluating the severity of stenosis are aortic valve area (AVA), transaortic gradient, and jet velocity. (6) Table 1 shows the degree of AVS according to hemodynamic parameters. TAVI Preliminary Report Part A (2009) 6

7 Table 1: Hemodynamic Parameters Used for Diagnosis of AVS Parameter Aortic Valve Sclerosis AVS Mild Moderate Severe AVA, cm 2 > < 1.0 Mean transaortic gradient, mm Hg < 30 a < 20 b a > 50 a b > 40 b Aortic jet velocity, m/s < > 4.0 Indexed AVA, cm 2 > < 0.6 Velocity ratio, cm 2 /m 2 > < 0.25 Abbreviations: AVA, aortic valve area, AVS, aortic valve stenosis. a European Society of Cardiology guidelines. b American Heart Association/American College of Cardiology guidelines. Source: Baumgartner et al, 2009 (6) Prevalence AVS occurs in 4.6% of adults over 75 years of age. (7) In industrialized countries, the etiology of valvular disease has shifted from rheumatic to degenerative, leading to important changes in patient characteristics. In developing countries, however, rheumatic heart disease is still a leading cause of valvular heart disease. Technology/Technique TAVI has become an alternative to surgical aortic valve replacement (savr) for patients with AVS in whom surgical treatment is contraindicated or is associated with a high risk of morbidity and mortality. Currently, there are 2 prostheses used in clinical practice in Ontario: the Edwards SAPIEN valve (Edwards Lifesciences, Irvine, California, United States) and the CoreValve Revalving System (Medtronic Inc., Minneapolis, Minnesota, United States). The Edwards SAPIEN transcatheter aortic valve is a bioprosthetic valve made of bovine pericardial tissue mounted into a balloon-expandable stainless steel frame. The 23 mm and 26 mm Edwards SAPIEN transcatheter aortic valves are suitable for a native aortic annulus measuring 18 to 25 mm. The thirdgeneration Edwards SAPIEN XT THV cobalt-chromium bovine pericardial valve has a lower crimp profile and a modified leaflet design. The SAPIEN valve is placed using a retrograde (transarterial traditionally transfemoral) or antegrade (transapical) approach for patients who have compromised peripheral arteries. The CoreValve transcatheter aortic valve is a trileaflet bioprosthetic porcine pericardium prosthesis mounted into a self-expanding nitinol frame. The CoreValve 26 mm and 29 mm prostheses are suitable for an aortic annulus measuring 20 to 27 mm. TAVI Preliminary Report Part A (2009) 7

8 Evidence-Based Analysis Research Questions 1. Is the risk of death following TAVI lower than that following savr? 2. How effective is TAVI in improving valve and left ventricular function? 3. What are the complications of TAVI? 4. Does TAVI improve quality of life? Research Methods Literature Search Search Strategy A literature search was performed on May 20, 2009, using OVID MEDLINE, OVID MEDLINE In- Process and Other Non-Indexed Citations, OVID EMBASE, EBSCO Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Wiley Cochrane Library, and the Centre for Reviews and Dissemination database, for studies published from January 1, 2007, until May 20, Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Inclusion Criteria English-language full reports prospective studies investigating clinical outcomes following TAVI prospective registries of TAVI studies reporting mortality studies including at least 10 patients Exclusion Criteria retrospective studies studies reporting on technical aspects of TAVI studies with fewer than 10 patients Outcomes of Interest Primary Outcome procedural, 30-day, and follow-up mortality Secondary Outcomes rate of emergent conversion to surgery new valve function changes in AVA changes in transaortic pressure gradient TAVI Preliminary Report Part A (2009) 8

9 paravalvular aortic regurgitation left ventricular function changes in left ventricular mass index (LVMI) changes in left ventricular dimensions changes in New York Heart Association (NYHA) class postprocedural complications arrhythmia myocardial infarction (MI) need for permanent pacemaker renal failure stroke surgical wound infection vascular injuries changes in quality of life Statistical Analysis A meta-analysis using RevMan version 5 (8) was performed to summarize the results of the studies for variables reported as mean and standard deviation. A descriptive analysis served to summarize the reports on all other variables. Quality of Evidence The quality of the body of evidence for each outcome is examined according to the GRADE Working Group criteria. (9) The overall quality is determined to be very low, low, moderate, or high using a stepwise, structural methodology. design is the first consideration; the starting assumption is that randomized, controlled trials are high quality, whereas observational studies are low quality. Five additional factors risk of bias, inconsistency, indirectness, imprecision, and publication bias are then taken into account. Limitations or serious limitations in these areas result in downgrading the quality of evidence. Finally, 3 main factors that may raise the quality of evidence are considered: large magnitude of effect, dose response gradient, and accounting for all residual confounding. (9) For more detailed information, please refer to the latest series of GRADE articles. (9) As stated by the GRADE Working Group, the final quality score can be interpreted using the following definitions: High Very confident that the true effect lies close to that of the estimate of the effect Moderate Low Very Low Moderately confident in the effect estimate the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Confidence in the effect estimate is limited the true effect may be substantially different from the estimate of the effect Very little confidence in the effect estimate the true effect is likely to be substantially different from the estimate of effect TAVI Preliminary Report Part A (2009) 9

10 Results of Evidence-Based Analysis The database search yielded 914 citations published between January 1, 1996, and May 20, 2009 (with duplicates removed). Articles were excluded based on information in the title and abstract. The full texts of potentially relevant articles were obtained for further assessment. A total of 18 studies met the inclusion criteria (2 non-randomized studies with contemporaneous controls and 16 case series). Fourteen studies reported mainly on transfemoral (TF) TAVI using Edwards SAPIEN and CoreValve devices, (10-23) and 4 studies reported on transapical (TA) TAVI. (24-27) Five studies used both TF and TA approaches and reported the results in combination. (11;13-15;17) For the purposes of this analysis, these studies were categorized as TF, because the majority of subjects underwent this procedure. Two studies compared mortality following TAVI, savr, balloon valvuloplasty (BV), and medical management. (12;14) For each included study, the study design was identified and is summarized below in Table 2, which is a modified version of a hierarchy of study design by Goodman. (28) Table 2: Body of Evidence Examined According to Design Design Number of Eligible Studies Large RCT, systematic review of RCTs Large RCT unpublished but reported to an international scientific meeting Small RCT Small RCT unpublished but reported to an international scientific meeting Non-RCT with contemporaneous controls 2 Non-RCT with historical controls Non-RCT presented at international conference Surveillance (database or register) Case series (multisite) 5 Case series (single site) 11 Retrospective review, modelling Case series presented at international conference Total 18 Abbreviations: RCT, randomized controlled trial. The 14 studies using the TF approach included 1260 patients, and the 4 studies using the TA approach included 142 patients. The largest study, in which 646 patients underwent TF TAVI using the CoreValve device, was based on data from a European registry of 6 centres. (21) Characteristics of the studies are shown in Tables 3 to 5. TAVI Preliminary Report Part A (2009) 10

11 Table 3: Characteristics and Patient Clinical Data: TF Implantation of Edwards SAPIEN Valve Country Design Period Patients, n Patient Condition M/F, n Mean Age, years ± SD (range) Mean Predicted Mortality, % ± SD (range) Type of Valve Webb et al (10) Canada (BC) Single-arm prospective cohort 25 Symptomatic AVS at high risk for savr 12/13 85 (79 88) Logistic EuroSCORE: 21 (5 30) STS: 8.9 (6 12.4) Edwards SAPIEN: 22 SAPIEN XT: 3 Fusari et al (11) Italy Single-arm prospective cohort Dec 2007 Oct (15 TF, 7 TA) Symptomatic severe AVS at high risk for savr 8/14 80 ± 5 (69 89) Logistic EuroSCORE: ±12.55 Edwards SAPIEN Descoutures et al (12) France Prospective registry Oct 2006 Apr High-risk (12 TF, 4 savr, 7 BV 16 MM) Low-risk (27 savr) TF: symptomatic severe AVS at high risk for savr 8/4 a 85 ± 6 Logistic EuroSCORE: 31.1 ± 14.4 (15 59) STS: 18.8 ± 4.3 (13 26) Edwards SAPIEN Rodes- Cabau et al (13) Canada (QC) Prospective registry Apr 2007 Jan (10 TF, 12 TA) Symptomatic severe AVS at high risk for savr 10/12 84 ± 7 Logistic EuroSCORE: 26 ± 16 Edwards SAPIEN Dewey et al (14) United States Prospective registry Dec 2005 Dec (21 TF/TA, 16 savr, 16 BV, 52 MM) TAVI: high risk for savr or refused surgical intervention 12/9 b 81.3 ± 8.7 Logistic EuroSCORE: 33.1 ± 13.7 STS: 10.9 ± 3.5 Edwards SAPIEN Spargias et al (15) Webb et al (16) Greece Canada (BC) Single-arm prospective Single-arm prospective cohort Nov 2007 Feb (8 TF, 4 TA) Symptomatic severe AVS at high risk for savr 50 Symptomatic severe AVS at high risk for savr 3/ ± 4.6 Logistic EuroSCORE: 34 ± 15 (11 61) 30/20 82 ± 7 (62 94) Logistic EuroSCORE: 28 Edwards SAPIEN Cribier Edwards c Abbreviations: AVS, aortic valve stenosis; BV, balloon valvuloplasty; EuroSCORE, European System for Cardiac Operative Risk Evaluation; MM, medical management;, not reported; savr, surgical aortic valve replacement; SD, standard deviation; STS, Society of Thoracic Surgeons; TA, transapical; TAVI, transcatheter aortic valve implantation; TF, transfemoral. a Data for comparison based on patients who underwent TAVI (n = 12). b Data for comparison based on patients who underwent TAVI (n = 21). c Cribier was the first generation of Edwards valve, subsequently updated to the Edwards SAPIEN. TAVI Preliminary Report Part A (2009) 11

12 Table 4: Characteristics and Patient Clinical Data: TF Implantation of CoreValve Country Design Period Patients, n Patient Condition M/F, n Mean Age, years ± SD Mean Predicted Mortality, % ± SD a Type of Valve Bleiziffer et al (17) Germany Single-arm prospective Jun 2007 Aug TF: 109 (105 CoreValve, 4 Edwards SAPIEN) Subclavian: 3 (CoreValve) TA: 23 (5 CoreValve, 18 Edwards SAPIEN) Ascending aorta: 2 (CoreValve) Symptomatic severe AVS at high risk for savr 59/ ± 6.7 Logistic EuroSCORE: 24.3 ± 14.9 STS: 23.4 ± 10.1 CoreValve: 115 Edwards SAPIEN: 22 Tamburino et al (18) Italy Single-arm prospective Jan 2007 Jul Symptomatic severe AVS at high risk for savr 13/17 82 ± 5 Logistic EuroSCORE: 25.3 ± 8.1 CoreValve, 3rd gen Jilaihawi et al (19) United Kingdom Single-arm prospective, multicentre Jan 2007 Jul Symptomatic severe AVS 5/ ± 4.5 Logistic EuroSCORE: 15.3 ± 5 CoreValve, 3rd gen De Jaegere et al (20) Piazza et al (21) Crube et al (22) Berry et al (23) Netherlands Netherlands, Germany, Italy, France, Austria, Switzerland Germany, Canada (QC) Canada (QC), France Single-arm prospective Expanded evaluation registry, multicentre (51 centres) Single-arm prospective, multicentre Single-arm prospective, multicentre Nov 2005 Dec 2007 Apr 2007 Apr nd gen: Aug 2005 Sept rd gen: Oct 2006 Feb 2007 Mar 2005 Aug Symptomatic severe AVS 646 Symptomatic severe AVS at high risk for savr 86 Symptomatic severe AVS 11 Symptomatic severe AVS at high risk for savr 17/16 81 ± 7 Logistic EuroSCORE: 20 ± / ± 6.6 Logistic EuroSCORE 23.1 ± / ± 5.9 Logistic EuroSCORE: Overall: 21.7 ± nd gen: 23.4 ± rd gen: 19.1 ± /5 82 ± 10 Logistic EuroSCORE: median, 36 CoreValve 2nd gen: 5 3rd gen: 28 CoreValve, 3rd gen CoreValve 2nd gen: 50 3rd gen: 36 CoreValve, 2nd gen Abbreviations: AVS, aortic valve stenosis; EuroSCORE, European System for Cardiac Operative Risk Evaluation; gen, generation; savr, surgical aortic valve replacement; SD, standard deviation; STS, Society of Thoracic Surgeons; TA, transapical; TF, transfemoral. a Unless otherwise indicated. TAVI Preliminary Report Part A (2009) 12

13 Table 5: Characteristics and Patient Clinical Data: TA Implantation of Edwards SAPIEN Valve Ye et al (24) Walther et al (25) Svensson et al (26) Zierer et al (27) Country Canada (BC) Germany United States (FDA multicentre approved study) Germany Design Single-arm prospective Single-arm prospective Single-arm prospective Single-arm prospective Period Oct 2005 Jan 2007 Feb 2006 Mar 2007 Dec 2006 Feb 2008 Feb 2006 Feb 2008 Patients, n Patient Condition 26 a Symptomatic AVS at high risk for savr and not a candidate for TF 50 Symptomatic AVS at high risk for savr 40 Symptomatic AVS at high risk for savr and not a candidate for TF 26 Symptomatic AVS at high risk for savr M/F, n Mean Age, years ± SD (range) Mean Predicted Mortality, % ± SD (range) 13/13 80 ± 9 Logistic EuroSCORE: 37 ± 20 STS: 11 ± 6 11/ ± 4.6 Logistic EuroSCORE: 27.6 ± /19 83 ± 75.2 (69 93) STS: 15.8 ± 9.1 EuroSCORE: 35.5 ± 15.3 STS: 13.4 (4 47) 6/ ± 6.5 Logistic EuroSCORE: 36.5 ± 5.8 Type of Valve Edwards SAPIEN Edwards SAPIEN Edwards SAPIEN Cribier Edwards b Abbreviations: AVS, aortic valve stenosis; EuroSCORE, European System for Cardiac Operative Risk Evaluation; FDA, Food and Drug Administration; savr, surgical aortic valve replacement; SD, standard deviation; STS, Society of Thoracic Surgeons; TA, transapical; TF, transfemoral. a Data for comparison based on 17 patients who survived. b Cribier was the first generation of Edwards valve, subsequently updated to the Edwards SAPIEN. TAVI Preliminary Report Part A (2009) 13

14 Mortality rate Mortality rate Mortality The pooled procedural mortality was 2.07% in the TF studies and 4.23% in the TA studies. Pooled rates for 30-day mortality and follow-up mortality (after 30 days) are shown in Figure 1. % Follow-up mortality (after day mortality days) TF TA Abbreviations: TA, transapical; TF, transfemoral Figure 1: Pooled 30-Day and Follow-up Mortality Rates Two registry studies compared mortality rates in patients who underwent TAVI versus those who underwent savr, BV, or received only medical management. (12;14) Figures 2 and 3 show the mortality data from these studies. % % 29% 29% Abbreviations: BV, balloon valvuloplasty; MM, medical management; savr, surgical aortic valve replacement; TAVI, transcatheter aortic valve implantation. 30-day mortality 20 Follow-up mortality (after 30 days) 10 3% 0% 0% 0% 0% 0 TAVI savr BV MM Figure 2: Mortality Rates Reported by One European Registry With 6 Months Follow-up Source: Descoutures et al, 2008 (12) TAVI Preliminary Report Part A (2009) 14

15 Rate of emergent conversion Mortality rate % % 42.3% Abbreviations: BV, balloon valvuloplasty; MM, medical management; savr, surgical aortic valve replacement; TAVI, transcatheter aortic valve implantation % 19.1% 6.3% 12.5% 12.5% 13.5% 30-day mortality Follow-up mortality (after 30 days) 0 TAVI savr BV MM Figure 3: Mortality Rates Reported by One United States Registry With 5.3 Months Follow-up Source: Dewey et al, 2008 (14) Emergent Conversion to Surgery As shown in Figure 4, studies using the TA approach demonstrated a higher rate of emergent conversion to savr than studies that used a TF approach. % Abbreviations: savr, surgical aortic valve replacement; TA, transapical; TF, transfemoral TF TA Figure 4: Pooled Rate of Emergent Conversion to savr TAVI Preliminary Report Part B (2009) 15

16 New Valve Function Aortic Valve Area Overall, the mean AVA increased by a significant 1.04 cm 2 (95% confidence interval [CI], ) in 11 TF studies that reported this outcome (Figure 5). or Subgroup Berry et al 2007 Webb et al 2007 Descoutures et al 2008 Spargias et al 2008 De Jaegere et al 2008 Rodes-Cabau et al 2008 Tamburino et al 2009 Fusari et al 2009 Webb et al 2009 Bleiziffer et al 2009 Jilaihawi et al 2009 Postprocedure Baseline Mean Difference Mean Difference Mean SD Total Mean SD Total Weight IV, Fixed, 95% CI Year IV, Fixed, 95% CI % 0.74 [0.48, 1.00] % 1.10 [0.98, 1.22] % 1.20 [0.91, 1.49] % 1.19 [1.08, 1.30] % 1.22 [0.92, 1.52] % 0.85 [0.70, 1.00] % 0.88 [0.73, 1.03] % 1.55 [1.37, 1.73] % 1.01 [0.89, 1.13] % 1.00 [0.93, 1.07] % 0.77 [0.59, 0.95] 2009 Total (95% CI) 369 Heterogeneity: Chi² = 67.76, df = 10 (P < ); I² = 85% Test for overall effect: Z = (P < ) % 1.04 [1.00, 1.08] Favours baseline Favours postprocedure Figure 5: Mean AVA Before and After TF TAVI Abbreviations: AVA, aortic valve area; CI, confidence interval; IV, inverse variance; SD, standard deviation; TAVI, transcatheter aortic valve implantation; TF, transfemoral. Two TA studies reported mean AVA before and after the procedure. In both studies, mean AVA significantly increased after TAVI (Table 6). Table 6: Mean AVA Before and After TA TAVI 2 P value, Baseline vs. Mean AVA, cm Postprocedure Ye et al (24) Baseline: 0.5 ± 0.1 Postprocedure: 1.7 ± 0.5 Svensson et al (26) Baseline: 0.62 ± days: 1.61 ± months: 1.60 ± months: 1.49 ± 0.24 Abbreviations: AVA, aortic valve area; TA, transapical; TAVI, transcatheter aortic valve implantation. < < TAVI Preliminary Report Part B (2009) 16

17 Transaortic Pressure Gradient Mean transaortic pressure gradient decreased by a significant mm Hg (95% CI, ) in 12 TF studies (Figure 6). or Subgroup Webb et al 2007 Berry et al 2007 De Jaegere et al 2008 Piazza et al 2008 Descouture et al 2008 Spargias et al 2008 Rodes-Cabau et al 2008 Tamburino et al 2009 Jilaihawi et al 2009 Bleiziffer et al 2009 Webb et al 2009 Fusari et al 2009 Postprocedure Baseline Mean Difference Mean Difference Mean SD Total Mean SD Total Weight IV, Fixed, 95% CI Year IV, Fixed, 95% CI % 0.4% 1.6% 48.1% 0.5% 0.3% 3.0% 1.4% 0.6% 39.7% 1.1% 1.0% [-40.91, ] [-53.47, ] [-39.96, ] [-47.48, ] [-49.88, ] [-60.12, ] [-29.36, ] [-55.36, ] [-46.60, ] [-41.79, ] [-45.81, ] [-49.35, ] Total (95% CI) % [-43.57, ] Heterogeneity: Chi² = , df = 11 (P < ); I² = 92% Test for overall effect: Z = (P < ) Favours postprocedure Favours baseline Figure 6: Mean Transaortic Pressure Gradient Before and After TF TAVI Abbreviations: CI, confidence interval; IV, inverse variance; SD, standard deviation; TAVI, transcatheter aortic valve implantation; TF, transfemoral. Two TA studies reported mean transaortic pressure gradient before and after the procedure. Both studies reported that pressure gradient was significantly reduced after TAVI (Table 7). Table 7: Mean Transaortic Pressure Gradient Before and After TA TAVI Mean Transaortic Pressure Gradient, mm Hg P value, Baseline vs. Postprocedure Ye et al (24) Baseline: 44.5 ± 13.7 Postprocedure: 8.9 ± 0.5 Svensson et al (26) Baseline: 40.2 ± days: 7.7 ± months: 7.5 ± months: 7.4 ± 2.4 Abbreviations: TA, transapical; TAVI, transcatheter aortic valve implantation. < < Aortic Regurgitation Most studies reported that paravalvular aortic regurgitation occurred frequently after implantation. About 3.2% of the patients in TA studies had to undergo a second valve (valve-in-valve) procedure. Ventricular Function Only 6 TF studies reported postprocedural measurement of left ventricular ejection fraction (LVEF). Webb et al (16) reported an immediate and significant in-hospital increase in LVEF (from 53 ± 15 to 57 ± 13), and Berry et al (23) reported a significant increase in LVEF (from 49 ± 17 to 56 ± 11) at follow-up. The remaining studies reported a nonsignificant increase in LVEF at follow-up, although some studies reported an improvement in LVEF in the subset of patients with poor left ventricular function. Table 8 shows the mean LVEF before and after TAVI. Figure 7 shows the pooled mean change in LVEF in the TF studies. TAVI Preliminary Report Part B (2009) 17

18 Table 8: LVEF Before and After TF TAVI Mean LVEF, % ± SD Baseline Postprocedure Fusari et al (11) 51.8 ± 12.5 In hospital: 52.8 ± month: 51.4 ± 13.9 P value > 0.05 Rodes-Cabau et al (13) 51 ± 0.16 Follow-up: 54 ± Webb et al (16) 53 ± 15 In hospital: 57 ± 13 < Jilaihawi et al (19) 54.8 ± 8 Follow-up: 57.5 ± De Jaegere et al (20) 41 ± 12 In hospital: 46 ± 15 Follow-up: 44 ± Berry et al (23) 49 ± day: 54 ± 14 Follow-up: 56 ± 11 < Abbreviations: LVEF, left ventricular ejection fraction; SD, standard deviation; TAVI, transcatheter aortic valve implantation; TF, transfemoral. or Subgroup Berry et al 2007 Webb et al 2007 De Jaegere et al 2008 Rodes-Cabau et al 2008 Fusari et al 2009 Jilaihawi et al 2009 Postprocedure Baseline Mean Difference Mean Difference Mean SD Total Mean SD Total IV, Fixed, 95% CI Year IV, Fixed, 95% CI [-4.97, 18.97] 4.00 [-1.50, 9.50] 5.00 [-1.55, 11.55] 3.00 [-6.19, 12.19] 1.00 [-6.04, 8.04] 2.70 [-2.33, 7.73] Total (95% CI) 153 Heterogeneity: Chi² = 1.15, df = 5 (P = 0.95); I² = 0% Test for overall effect: Z = 2.45 (P = 0.01) [0.69, 6.13] Favours baseline Favours postprocedure Figure 7: LVEF Before and After TF TAVI Abbreviations: CI, confidence interval; IV, inverse variance; LVEF, left ventricular ejection fraction; SD, standard deviation; TAVI, transcatheter aortic valve implantation; TF, transfemoral. Table 9 shows the mean LVEF before and after TAVI in the TA studies. Table 9: LVEF Before and After TA TAVI Mean LVEF, % ± SD Baseline Postprocedure P value Ye et al (24) 56 ± 13 Follow-up: 63 ± 9 > 0.05 Svensson et al (26) 51.5 ± 15.1 After 30 days: 55 ± 19.2 Follow-up: 58 ± 16.7 > 0.05 Abbreviations: LVEF, left ventricular ejection fraction; SD, standard deviation; TA, transapical; TAVI, transcatheter aortic valve implantation. TAVI Preliminary Report Part B (2009) 18

19 New York Heart Association Class Four TF studies reported mean NYHA class before and after the procedure. In these studies, NYHA class significantly improved after TAVI (Figure 8). or Subgroup Bleiziffer et al 2009 Crube et al 2007 Spargias et al 2008 Tamburino et al 2009 Postprocedural Baseline Mean Difference Mean Difference Mean SD Total Mean SD Total Weight IV, Fixed, 95% CI IV, Fixed, 95% CI % 28.8% 2.4% 8.0% [-1.30, -1.10] [-1.14, -0.86] [-1.99, -1.01] [-1.68, -1.14] Total (95% CI) 265 Heterogeneity: Chi² = 10.68, df = 3 (P = 0.01); I² = 72% Test for overall effect: Z = (P < ) % [-1.24, -1.09] Favours experimental Favours control Figure 8: Mean NYHA Class Before and After TF TAVI Abbreviations: CI, confidence interval; IV, inverse variance; NYHA, New York Heart Association; SD, standard deviation; TAVI, transcatheter aortic valve implantation; TF, transfemoral. Only 1 TA study (26) reported mean NYHA class before and after the procedure. In this study, mean NYHA class decreased from 3.33 ± 0.47 at baseline to 2.08 ± 0.51 at 5 months follow-up. Ventricular Dimensions Two studies (19;20) provided measures of ventricular dimensions. As shown in Table 10, LVMI, a measure that predicts systolic function and heart failure, did not significantly change in these studies. Table 10: Ventricular and Atrial Measurements Before and After TF TAVI Measurement Baseline vs. Postprocedure, Mean ± SD De Gaegere et al 2008 a (20) Jilaihawi et al 2009 b (19) LVMI, g/m ± 44 vs. 128 ± 37, P = ± 48.8 vs ± 35.3, P > 0.05 LV end-diastolic dimension, mm 51 ± 8 vs. 49 ± 7, P = 0.61 LV end-systolic dimension, mm 37 ± 13 vs. 38 ± 10, P = 0.95 LV posterior wall thickness, mm 12 ± 2 vs. 11 ± 2, P = ± 3.6 vs ± 3.1, P = 0.86 Septal thickness, mm 14 ± 3 vs. 13 ± 2, P = ± 3 vs ± 2.7, P = Thickness at mitral valve level, mm 10.9 ± 1.2 vs ± 1.4, P = 0.21 Left atrial dimension, mm 48 ± 9 vs. 44 ± 9, P = 0.32 Abbreviations: LV, left ventricular; LVMI, left ventricular mass index; SD, standard deviation. a 80 ± 64 days follow-up (n = 24). b 1 month follow-up (n = 14). TAVI Preliminary Report Part B (2009) 19

20 Postprocedural Complications The rate of MI was higher in the TA studies than in the TF studies, while the rate of stroke was similar in both study types. Pooled estimates for postprocedural complications are shown in Table 11. Table 11: Pooled Estimates for Postprocedural Complications Procedure Arrhythmia, % MI, % Permanent Pacemaker, % Stroke, % Vascular Injury, % Additional Procedures, % TF TAVI AF: 7.84 VF: TA TAVI SVA: Abbreviations: AF, atrial fibrillation; MI, myocardial infarction; SVA, supraventricular arrhythmia; TA, transapical; TAVI, transcatheter aortic valve implantation; TF, transfemoral; VF, ventricular fibrillation. Quality of Life Only 2 studies reported changes in quality of life scores (Table 12). Svensson et al (26) reported a significant improvement in the physical component of the Short Form 12 (SF-12) survey in patients who underwent TA TAVI, but no significant changes in the mental component. Bleizziffer et al (17) reported a nonsignificant increase in self-assessed general health scores in patients who underwent TAVI. Table 12: Quality of Life Scores Reported by TAVI Studies Quality of Life Score, Baseline vs. Postprocedure Svensson et al (26) (6 months) SF-12 physical: 28.6 vs. 35.2, P = SF-12 mental: 48.1 vs. 50.4, P > 0.05 Bleiziffer et al (17) (30 days) Self-assessed general health scores (scale 0 100): 55 ± 17 vs. 68 ± 16 Abbreviations: SF-12, Short Form 12; TAVI, transcatheter aortic valve implantation. TAVI Preliminary Report Part B (2009) 20

21 Conclusions This report reflects on initial experience with TAVI in many centres across the world; therefore, it includes the learning curve experience with this technology. The observation of several peri- and postprocedural complications has led to some modifications in devices, approaches, implantation techniques, and operating room configurations, as well as improvement in imaging equipment and patient selection. The current clinical evidence demonstrates that treatment of severe AVS in high-risk patients with TAVI is feasible. However, with respect to the mortality and adverse events following TAVI in comparison to savr, no reasonable conclusion can be made from the current evidence. A direct comparison with savr through randomized controlled trials and studies with longer-term follow-ups is required. TAVI Preliminary Report Part B (2009) 21

22 Appendices Appendix 1: Search Strategies Search date: May 20, 2009 Databases searched: OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, OVID EMBASE, Wiley Cochrane, Centre for Reviews and Dissemination/International Agency for Health Technology Assessment Database: Ovid MEDLINE(R) <1996 to May Week > Search Strategy: exp Heart Valve Prosthesis Implantation/ or exp Heart Valve Prosthesis/ (11651) 2 (core-valve or corevalve or Cribier-Edwards or Edwards-Sapien).mp. [mp=title, original title, abstract, name of substance word, subject heading word] (36) 3 (aort* valv* adj2 (replace* or implant* or prosthe* or bioprosthe* or transplant*)).mp. [mp=title, original title, abstract, name of substance word, subject heading word] (3970) 4 AVR.mp. (1255) 5 or/1-4 (13209) 6 exp Aortic Valve Stenosis/ (8977) 7 ((supravalvular or subvalvular or aort*) adj2 stenos?s).mp. [mp=title, original title, abstract, name of substance word, subject heading word] (5714) 8 6 or 7 (10189) 9 8 and 5 (2197) 10 limit 9 to (english language and humans and yr=" ") (1002) 11 exp Surgical Procedures, Minimally Invasive/ (122875) 12 (transcatheter* or trans-catheter* or transfemoral or trans-femoral or transapical or trans-apical or percutaneous).mp. [mp=title, original title, abstract, name of substance word, subject heading word] (52879) 13 (minimal* adj3 (surgery or surgeries or surgical or procedure* or invasive)).mp. [mp=title, original title, abstract, name of substance word, subject heading word] (23205) or 13 or 12 (177411) and 14 (178) Database: EMBASE <1980 to 2009 Week 20> Search Strategy: exp Aorta Valve Replacement/ (6600) 2 (core-valve or corevalve or Cribier-Edwards or Edwards-Sapien).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name] (65) 3 (aort* valv* adj2 (replace* or implant* or prosthe* or bioprosthe* or transplant*)).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name] (9879) 4 exp aorta valve prosthesis/ or avr.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name] (3271) 5 3 or 4 or 1 or 2 (10447) 6 exp Aorta Valve Stenosis/ (2653) 7 ((supravalvular or subvalvular or aort*) adj2 stenos?s).ti,ab. (6533) TAVI Preliminary Report Part B (2009) 22

23 8 7 or 6 (7474) 9 8 and 5 (2085) 10 exp Minimally Invasive Surgery/ (10545) 11 (transcatheter* or trans-catheter* or transfemoral or trans-femoral or transapical or trans-apical or percutaneous).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name] (81371) 12 (aort* valv* adj2 (replace* or implant* or prosthe* or bioprosthe* or transplant*)).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name] (9879) 13 or/10-12 (100177) and 9 (2077) 15 limit 14 to (human and english language and yr=" ") (736) TAVI Preliminary Report Part B (2009) 23

24 Appendix 2: Quality of Studies and GRADE Tables Table A1: GRADE Quality of Evidence for TAVI No. of Studies (Design) Outcome A 18 (case series) Risk of Bias Inconsistency Indirectness Imprecision Publication Bias Very serious limitations ( 2) a No serious limitations Abbreviations: NA, not applicable; TAVI, transcatheter aortic valve implantation. a Studies were case series. No serious limitations No serious limitations Upgrade Considerations Quality Undetected NA Low TAVI Preliminary Report Part A (2009) 24

25 Appendix 3: Clinical Data Table A2: Periprocedural Outcomes, Studies on TF Implantation of Edwards SAPIEN Valve Webb et al (10) Procedural Success, n (%) Procedural Death, n Emergent Conversion to Cardiac Surgery, n Use of Bypass, n 25/25 (100) femoral-femoral support Procedural Complications, n 0 Fusari et al (11) 21/22 (95.5) 1 due to aortic dissection and emergent conversion to open heart surgery 1 due to aortic dissection (patient died) 1 for conversion to open heart surgery 1 iliac artery injury required abdominal surgery 2 pericardial effusion 3 pleural effusion Descoutures et al (12) 10/12 (83) 1 female patient (age 94 years) died due to perforation of left ventricle by the wire cardiac tamponade Rodes-Cabau et al (13) 20/22 (91) 1 female patient (age 82 years) died due to electromechanical dissociation 1 severe bleeding due to myocardial apical tear following TA procedure 1 femoral-femoral bypass for surgical repair of myocardial apex tear 1 massive aortic regurgitation 1 cardiac tamponade 1 myocardial tear Dewey et al (14) Spargias et al (15) 12/12 (100) for intraprocedural complication due to severe central aortic valve insufficiency after implantation 1 patient required electrical cardioversion, direct heart compression, femoral-femoral bypass, and a second valve-in-valve prosthesis 1 patient developed marked reduction of diastolic arterial pressure after implantation due to paravalvular aortic valve insufficiency and required BV Webb et al (16) 43/50 (86) 1 patient died due to perforation of abdominal aorta Abbreviations: BV, balloon valvuloplasty;, not reported; TA, transapical, TF, transfemoral malpositioning of the valve 1 cardiac tamponade TAVI Preliminary Report Part B (2009) 25

26 Table A3: Hemodynamic Changes, Studies on TF Implantation of Edwards SAPIEN Valve Transaortic Pressure Gradient, mm Hg Mean ± SD Peak Transaortic Pressure Gradient, mm Hg Mean ± SD Aortic Valve Area, cm 2 Mean ± SD NYHA Class, a LVEF, % Mean ± SD a Webb et al (10) Fusari et al (11) Descoutures et al (12) Rodes-Cabau et al (13) Dewey et al (14) Spargias et al (15) Webb et al (16) Pre Post Pre Post Pre Post Pre Post Pre Post 49.3 ± 17.9 IH: 10.6 ± ± 0.15 IH: 1.60 ± 0.27 I/II: ± 17.1 IH: 12.4 ± mo: 10.8 ± ± 0.14 IH: 2.2 ± mo: 2.4 ± 0.3 III/IV: 22 Median, class III 50 ± 19 IH: 11 ± ± 0.1 IH: 1.7 ± 0.5 I/II: 0 III/IV: 12 (100) 34 ± 10 IH: 9 ± 3 56 ± 15 IH: 17 ± ± 0.18 IH: 1.48 ± 0.31 II: ± 21.4 III: 19 IV: 2 <50%: 4 FU: Median, class III FU b : I: 2 (22) II: 5 (56) III: 2 (22) IV: 0 (0) I: 2 (10) II: 14 (70) III: 4 (20) IV: 0 (0) 51.8 ± 12.5 IH: 52.8 ± mo: 1.4 ± ± ± 0.16 FU: 54 ± ± ± ± 23 IH: 10 ± 3 91 ± 33 IH: 22 ± ± 0.14 IH: 1.83 ± 0.14 Mean, 2.8 ± 0.7 III/IV: 8 (67) FU: Mean, 1.3 ± ± 17 IH: 11 ± ± 0.2 IH: 1.7 ± 0.4 III/IV: 45 (90) FU c : III/IV: 0 I: 7 (41) II: 7 (41) III: 3 (18) Abbreviations: FU, follow-up; IH, in-hospital; LVEF, left ventricular ejection fraction;, not reported; NYHA, New York Heart Association; SD, standard deviation, TF, transfemoral. a Unless otherwise indicated. b Follow-up in 60 survivors (9 in TAVI arm). c Data estimated from the graph. 53 ± 15 IH: 57 ± 13 TAVI Preliminary Report Part B (2009) 26

27 Table A4: Hospital and Mortality Outcomes, Studies on TF Implantation of Edwards SAPIEN Valve Webb et al (10) Fusari et al (11) Descoutures et al (12) Rodes- Cabau et al (13) Dewey et al (14) Spargias et al (15) Webb et al (16) CCU/ICU Stay, h Mean ± SD Hospital Stay, d Mean ± SD a Follow-up, months Mean ± SD Hospital Readmission, Additional Procedures, n Death up to 30 Days Postprocedure, b TAVI Preliminary Report Part B (2009) 27 Death After 30 Days and Up to the Follow-up, ± 12 9 ± 5 2 ± (23.8) (1 intermittent claudication due to femoral artery stenosis; 4 lymphorrhage) 3 (1 femoral artery stenosis and claudication, 2 repair of lymphorrhage) 17 ± valve-in-valve TAVI: 3/12 (25) savr: 1 (3) BV: 0 MM: 0 7 ± 3 1 (n = 21) 6 ± 3 (n = 7) 3 (1 valve-in-valve, 1 pericardiocentesis, 1 surgical repair of myocardial tear) 5.3 ± 4.9 TF/TA: 2/21 (9.5) savr: 1/16 (6.3) BV: 2/16 (12.5) MM: 7/52 (13.5) 2.9 ± ± ± (1 valve-in-valve, 1 BV) Median, 5 12 (for those who had successful implantation) 6 (1 TA on day 11, 1 savr on day 103, 1 savr on day 466, 2 for iliac artery injury, 1 abdominal aortic perforation) 1/22 (4.5) 0 TAVI: 0 savr: 0 BV: 2 (29) MM: 4 (29) 2 (9) 0 TF/TA: 4/21 (19.1) savr: 2/16 (12.5) BV: 6/16 (37.5) MM: 22/52 (42.3) (12) (1 procedural, 1 VA, 1 left main artery occlusion, 1 iliac artery injury, 1 stroke, 1 MOF) Abbreviations: BV, balloon valvuloplasty; CCU, coronary care unit, ICU, intensive care unit; MM, medical management; MOF, multiorgan failure;, not reported; savr, surgical aortic valve replacement; SD, standard deviation; TA, transapical; TAVI, transcatheter aortic valve implantation; TF, transfemoral; VA, ventricular arrhythmia a Unless otherwise indicated. b Includes procedural deaths. 2

28 Table A5: Postprocedural Complications, Studies on TF Implantation of Edwards SAPIEN Valve Webb et al (10) Fusari et al (11) Descoutures et al (12) Rodes-Cabau et al (13) Dewey et al (14) Spargias et al (15) Paravalvular Aortic Regurgitation Grade a, IH: Moderate: 1 FU: I: 16 (76.2) II: 4 (19) III: 1 (4.7) IH: 0 I: 6 (60) II: 3 (30) III: 1 (10) FU: 1+: 9 (41) 2+: 4 (18) Webb et al (16) FU b : MI, Stroke, Arrhythmia, Heart Block, Renal Failure, No new dialysis Thromboembolism, Vascular Injury, Blood Transfusion, > 3 units: (28.6) 0 7 (33.3) 0 3 (13.6) > 2 units: 3 (12) 3 (14.3) Surgical Wound Infection, (8) 2 (17) 2 (17) 0 0 AF: 1 (18) (9) 0 3 AF: 4 (19) 1 (5) 0 2 (9.5) Severe: 2 (16.7) 1 common femoral artery dissection requiring surgery None/trivial: 15 (30) Mild: 25 (50) Moderate: 10 (20) 1 (2) died 2 (4) 1 died VF: 2 (4) 2 (4) (1 patient died of renal failure) Abbreviations; AF, atrial fibrillation; FU, follow-up; IH, in-hospital; MI, myocardial infarction;, not reported; TF, transfemoral; VF, ventricular fibrillation. a Grade scores given as reported in each study. b Data estimated from graph. 2 iliac artery injury requiring major vascular repair (1 died) 1 perforation of abdominal aorta (died) >3 units: 9 (18) 2 (4) TAVI Preliminary Report Part B (2009) 28

29 Table A6: Periprocedural Outcomes, Studies on TF Implantation of CoreValve Procedural Success, Procedural Death, Emergent Conversion to Cardiac Surgery, Procedural Complications, Bleiziffer et al (17) 135/137 (98.5) 1 (0.7) Defibrillation: 2/29 (7) Resuscitation: 8/29 (28) Tamburino et al (18) 28/30 (93) cardiac tamponade Jilaihawi et al (19) 0 De Jaegere et al (20) 33/33 (100) 1/33 (3.0) 1 cardiac tamponade (patient died on day 6) Piazza et al (21) 628/646 (97) 10/646 (1.6) 3 (0.5) 9 cardiac tamponades Grube et al (22) 76/86 (88) 2nd gen: 44/50 (88) 3rd gen: 32/36 (89) 5/86 (6.6) 2nd gen: 2/50 (4.0) 3rd gen: 3/36 (8.3) 6/86 (7.0) 2nd gen: 4/50 (8.0) 3rd gen: 2/36 (5.5) 11 ventricular perforations 4 aortic root dissections 4 retroperitoneal hemorrhages 8 cardiac tamponades 2nd gen: 3/50 (6.0) 3rd gen: 5/36 (13.9) Berry et al (23) 11/11 (100) 0 0 Occlusion of left subclavian artery due to displacement of vascular tissue causing massive stroke: 1 (9) Abbreviations: gen, generation;, not reported; TF, transfemoral. TAVI Preliminary Report Part B (2009) 29

30 Table A7: Hemodynamic Changes, Studies on TF Implantation of CoreValve Transaortic Pressure Gradient, mm Hg Mean ± SD Peak Transaortic Pressure Gradient, mm Hg Mean ± SD Aortic Valve Area, cm 2 Mean ± SD NYHA Class, Mean ± SD a LVEF, % Mean ± SD a Pre Post Pre Post Pre Post Pre Post Pre Post LV Mass Index, g/m 2 Mean ± SD Bleiziffer et al (17) 52.5 ± 5.6 IH: 11.9 ± 4.4 FU: 11 ± ± 0.1 IH: 1.6 ± 0.4 FU: 1.6 ± ± 0.3 IH: 1.7 ± 0.6 FU: 1.9 ± 0.5 > 50%: 81 (59) 35 50%: 29 (21) < 35%: 27 (20) Tamburin o et al (18) 58.1 ± 17.6 IH: 9.2 ± 4 Peak to peak: 85.6 ± 22 IH peak to peak: 1.8 ± ± 0.18 IH: 1.49 ± 0.39 I/II: 10 (33) III/IV: 20 (67) 2.72 ± 0.59 IH: 1.31 ± ± 8.4 Jilaihawi et al (19) De Jaegere et al (20) Piazza et al (21) 45.3 ± 18.4 IH: 8.2 ± ± 16 IH: 12 ± 7 FU: 9 ± ± 28.1 IH: 16.3 ± ± 28 IH: 20 ± 12 FU: 18 ± ± ± 0.23 IH: 1.5 ± 0.3 IH: 1.97 ± 0.85 FU: 1.72 ± 0.45 I: 10 (67) III: 5 (33) 54.8 ± 8 FU: 57.5 ± ± 12 IH: 46 ± ± 13.9 IH: 3 ± ± ± 0.2 III/IV: 532 (85) 51.5 ± 13.9 FU: 44 ± ± 44 IH: 148 ± 44 FU: 128 ± 37 Grube et al (22) Berry et al (23) 43.7 ± nd gen: 39.5 ± rd gen: 49.7 ± b 70.9 ± nd gen: 66.0 ± rd gen: 78.3 ± ± nd gen: 0.66 ± rd gen: 0.54 ± ± 19 IH: 9 ± ± 0.19 III/IV: 71/86 (82) FU: 1.3 ± 0.4 2nd gen: 43/50 (86) 3rd gen: 28/36 (78) 2.85 ± 0.3 III/IV: 11 (100) FU: 1.85 ± 0.6 FU: 1 point improvement 54 ± 16 2nd gen: 52 ± 18 3rd gen: 57 ± ± 17 FU: 56 ± 11 Abbreviations: FU, follow-up; IH, in-hospital; LV, left ventricular; LVEF, left ventricular ejection fraction;, not reported; NYHA, New York Heart Association; SD, standard deviation, TF, transfemoral. a Unless otherwise indicated. b Data calculated from graph. 147 ± 52 TAVI Preliminary Report Part B (2009) 30

31 Table A8: Hospital and Mortality Outcomes, Studies on TF Implantation of CoreValve Bleiziffer et al (17) ICU Stay, h Mean (range) Hospital Stay, d Mean (range) Follow-up, months, Mean ± SD a Hospital Readmissions, Additional Procedures, Death Up to 30 Days Postprocedure, b Death After 30 Days and up to Follow-up, 3.2 ± /137 (12.4) 12/137 (8.8) Tamburino et al (18) Jilaihawi et al (19) 4.9 ± 4 Valve-in-valve: 1 (3.3) BV: 4 9 (13.3) 2/30 (6.7) (20) De Jaegere et al (20) Piazza et al (21) Grube et al (22) Berry et al (23) 2.7 ± 2 Valve-in-valve: 4 (12.1) BV: 5 (15.2) 1 Valve-in-valve: 17/646 (2.6) BV: 137/646 (21.2) 1 Valve-in-valve: 2 (2.3) BV: 21 (24.4) /646 (8) 10/86 (12) 2nd gen: 5/50 (10) 3rd gen: 5/36 (14) 4 (1 7) 13.5 (8.5 18) Median,10 PTA: 2 (18.2) 2/11 (18) 3/11 (27.3) Abbreviations: BV, balloon valvuloplasty; gen, generation; ICU, intensive care unit;, not reported; PTA, peripheral transluminal angioplasty; SD, standard deviation; TF, transfemoral. a Unless otherwise indicated. b Includes procedural deaths. TAVI Preliminary Report Part B (2009) 31

32 Table A9: Postprocedural Complications, Studies on TF Implantation of CoreValve Paravalvular Aortic Regurgitation Grade, a MI, Stroke, Arrhythmia, Permanent Pacemaker, Renal Failure, Thromboembolism, Vascular Injury, Blood Transfusion, Surgical Wound Infection, n Bleiziffer et al (17) Grade II, IH: 16/137 (12) 7/137 (5.1) 27/137 (19.7) 16/137 (11.7) FU: 11/137 (8) Tamburino et al (18) IH: 1+: 15 (50) 0 2/30 (6.7) Both died 5/25 (20) 0 5/30 (16.6) 1 major bleeding 2+: 13 (43.3) 3+: 1 (3.3) FU:1+: 12 (40); 2+: 2 6.7) Jilaihawi et al (19) De Jaegere et al (20) Mild: 22/33 (67) Moderate to severe: 9/33 (27) Piazza et al (21) 2: 637/646 (98.6) Moderate to severe: 9/646 (1.4) 3/646 (0.5) 12/646 (1.9) 60/646 (9.3) 12/646 (1.9) Grube et al (22) IH: Unchanged: 51/76 (66) 1+: 11 (14) 2+: 15 (20) Severe: 0 (0) Overall: 1/86 (1) 21F: 1/50 (2) 18F: 0 Overall: 9 (10) 21F 5/50 (10) 18F 4/36 (11) Berry et al (23) Grade 1: 7/11 (64) Grade 2: 4/11 (36) 0 2 (18.2) Both died 3/11 (27) 1 (9.1) Abbreviations: FU, follow-up; gen, generation; IH, in-hospital; MI, myocardial infarction;, not reported; TF, transfemoral. a Grade scores given as reported in each study. TAVI Preliminary Report Part B (2009) 32