0. 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

1. 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

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

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

9. 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

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

11. 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.

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

13. 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

14. 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)

15. 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

16. 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

17. 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

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

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

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

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

22. 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

23. 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

24. 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

25. 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

26. 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