A Prospective, Randomized Trial of Transapical Transcatheter Aortic Valve Implantation vs. Surgical Aortic Valve Replacement in Operable Elderly Patients with Aortic Stenosis The STACCATO Trial Hans H. M. Nielsen, Kaj E. Klaaborg, Henrik Nissen, Kim Terp, Poul E. Mortensen, Bo J. Kjeldsen, Carl-Johan Jakobsen, Henning R. Andersen, Lars R. Krusell, Henrik Egeblad, Evald H. Christiansen, Jacob R. Greissen, Erik Sloth, Leif Thuesen, Vibeke E. Hjortdal

Conflicts of interests for Leif Thuesen, M.D. A Prospective, Randomized Trial of Transapical Transcatheter Aortic Valve Implantation vs. Surgical Aortic Valve Replacement in Operable Elderly Patients with Aortic Stenosis The STACCATO Trial Conflicts of interests for Leif Thuesen, M.D. Edwards Lifesciences: Physician proctor 1

Background Transcatheter aortic valve implantation (TAVI) has become a treatment option for patients with aortic valve stenosis, who are not amenable or at high risk to surgical valve replacement (SAVR) The role of TAVI in surgically lower risk patients remains to be defined 2 2

Purpose In a prospective, randomized trial to compare transapical transcatheter aortic valve implantation (a-TAVI) with surgical aortic valve replacement (SAVR) in operable elderly patients 3

Funding Academic study funded by the participating centers We received a study grant from the Danish Heart Foundation The study was conducted without relationship to the industry 4

Material and methods Planned number of patients n= 200 Randomization 1:1 Participating centers Departments of Cardiothoracic Surgery and Cardiology, Aarhus University Hospital and Odense University Hospital, Denmark Ascertained from 5

Criteria of inclusion Valvular aortic stenosis (valve area <1cm2) Age ≥70 or 75 yrs Condition accessible both by SAVR and a-TAVI Expected survival >1 year following successful treatment Ascertained from 6

Criteria of exclusion Coronary artery disease to be treated by PCI or CABG Previous myocardial infarction or cardiac surgery or PCI within 12 months Need for emergency surgery Unstable cardiac condition (assist device or inotropes) Stroke within 1 month Reduced pulmonary function Renal failure to be treated by hemodialysis Ascertained from 7

Primary endpoint The composite of 30-day all cause mortality, major stroke, and/or renal failure

Secondary endpoints Myocardial infarction Operation for bleeding Permanent pacemaker treatment Duration of hospital stay Echocardiographic parameters (aortic valve area, peak aortic valve gradient, aortic valve leakage, left ventricular ejection fraction) NYHA class, SF-36 composite physical and mental functional scores

Definitions For endpoint definitions, we used the Valve Academic Research Consortium recommendations

Sample size We anticipated a primary endpoint rate of 13.5% in the SAVR group based on Western Denmark Heart Registry SAVR data on patients aged ≥70 yrs from 1998 through 2008. The estimated event rate of 2.5% in the a-TAVI group was based on our experience from non-operable patients with significantly higher risk than the study population. At study initiation, our a-TAVI event rates were 0%. Given an alpha of 5% and a beta of 80%, 96 patients should be included in each group to document the difference. Therefore, we planned for inclusion of 200 patients.

Premature termination After inclusion of 70 patients, the study was terminated prematurely after advice from the Data Safety Monitoring Board 12

Conduct of the study June 2008; protocol Scenario; a-TAVI safe, predictable procedure September 2008; MEC approval November 2008; 1. patient included Study on hold after inclusion of 11 patients 3 potentially severe adverse events in the a-TAVI group Contact with DSMB and MEC Inclusion and exclusion criteria modified (age limit increased to 75 yrs, earlier heart operation reason for exclusion) Inclusion resumed Study on hold May 2011 DSMB advised study termination due to an excess of events in the a-TAVI group 13

Patient flow-diagram Assessed for eligibility (n= 525) Excluded (n = 453) Medical Tx (n=24) Surgical Tx (n=285) TAVI (n= 144) Randomized (n= 72) Excluded after randomization (n= 2) a-TAVI (n=34) SAVR (n=36)

Baseline characteristics a-TAVI SAVR p Value Age (yrs) 80±3.6 82±4.4 0.15 Male sex 9/34 (26.5) 12/36 (33.3) 0.61 Diabetes 1/34 (2.9) 3/36 (8.3) 0.62 Cerebral vascular disease 1/36 (2.8) 1.00 Peripheral vascular disease 2/34 (5.9) COPD Creatinine level >200µmol/L 0/36 (0.0) 0.49 Logistic EuroSCORE 9.4±3.9 10.3±5.8 0.25 STS score 3.1±1.5 3.4±1.2 0.43 NYHA class III or IV 18/34 (58.1) 16/36 (44.4) 0.63 EF (%) 56.5±9.7 56.3±10 0.92 Aortic valve area (cm2) 0.66±0.17 0.71±0.17 0.21

Primary endpoint events Allocation Sex, age Adverse event Time for event Outcome a-TAVI ♀, 80 Death On waiting list Not treatment related ♀, 70 Left coronary artery blockage Perioperative Acute CABG/SAVR, death day 1 ♀, 79 Major stroke Day 27 Severe disability, death day 34 ♀, 86 Day 16 Severe disability ♀, 76 Renal failure requiring dialysis Day 8 Hemodialysis SAVR ♀,81 p=0.07

Other events at 3 months Allocation Sex, age Adverse event Time for event Outcome a-TAVI ♀, 81 Transient ischemic attack with later major stroke Perioperative Partial recovery ♂, 80 Left main occlusion during balloon valvuloplasty SAVR, recovery ♀, 79 Aortic rupture Emergency implantation of homograft, recovery ♂, 75 Severe paravalvular leakage ♀, 82 SAVR, death day 38 a-TAV ♂, 78 THV embolization upstream Implantation of another THV, recovery ♀, 80 Abnormally positioned heart ♀, 86 Bleeding Postoperative Re-operation, recovery SAVR ♀,83 Conversion to a-TAVI because of intrathoracic goiter a-TAVI, recovery ♂,82

Aortic valve area Baseline and after treatment cm2 p=0.15 p=0.15 ‡ ‡ ‡ p<0.0001 as compared to pretreatment values

Peak aortic gradient Baseline and after treatment mmHg p=0.07 ‡ ‡ ‡ p<0.0001 as compared to pretreatment values

Paravalvular leakage after treatment (6%) n=4 (13%) n=13 (43%) n=33 (94%) n=13 (43%) p<0.001

NYHA class Baseline and at 3 months p=0.16 p=0.01 p=0.001

Other outcome parameters a-TAVI SAVR p Value Myocardial infarction * n/N (%) 0/0 (0) 1.00 Permanent pacemaker 2/34 (5.8) 1/36 (2.7) 0.52 Hospital stay (days) 8.8±6.7 7.6±2.4 0.32 Composite physical functional score before treatment (%) 35±10, n=27 37±12, n=32 0.48 Composite physical functional score 3 months after treatment (%) 42±14, n=27‡ 43±15, n=32‡ 0.91 Composite mental functional score before treatment (%) 47±10, n=27 46±17, n=32 0.66 Composite mental functional score 3 months after treatment (%) 53±14, n=27‡ 50±17, n=32‡ 0.44 * Valve Academic Research Consortium definition ‡ ns; as compared to pretreatment values

Limitations Premature study termination; only one third of the anticipated number of patients included The excess of adverse events in the a-TAVI group might be a play of chance Only two centers were actively including. The SAVR results were excellent, but a-TAVI results might have been different with participation of more centers Multi-slice computed tomography (MSCT) was not used in the preoperative assessment Ascertained from 23

Issues for discussion Stroke Paravalvular leakage Perioperative; 1 major stroke in the SAVR group, 1 TIA in the a-TAVI group Two major strokes after 2-4 weeks in the a-TAVI group during dual antiplatelet treatment Paravalvular leakage Absent in the SAVR group Moderate to severe leakage in 13% of a-TAVI patients, probably because of valve under sizing. Preoperative MSCT might have optimized valve sizing Perioperative coronary artery occlusion Might have been avoided by preoperative MSCT assessment of annulus to left main distance and valve/left main relation Ascertained from 24

Conclusion In its present phase of development, transapical transcatheter aortic valve implantation seems inferior to surgical aortic valve replacement in operable elderly patients Ascertained from 25

Final remarks After study termination, our procedures have been optimized by routine preoperative MSCT assessment and by availability of the 29 mm valve Further improvement is likely to take place with improved devices and pre-procedure assessment Ascertained from 26