Aortic Valve Stenosis with low EF : TAVR versus Replacement

1. ACC San Diego 2015
Joseph E. Bavaria M.D.
Roberts Professor andVice Chief, Division of CV Surgery
Hospital of the University of Pennsylvania

2.  LV Systolic dysfunction increases
perioperative mortality in AVR
▪ Morris et al; AnnThor Surg 1993, Pereira et al; JACC 2002, Tarantini et al; EJCTS 2003
 Despite this fact, AVR Patients who survive
benefit with longer survival and less
symptoms.This is also true for those with or
without Inotropic Reserve
▪ Levy et al, JACC 2008; Tribouilloy et al, JACC 2009; Quere et al, Circ 2006

3.  LVEF < 20% was an exclusion in theTAVI
randomized studies ….. Despite the Guideline
understanding that AVR with good
hemodynamics is especially important in Low
EF AS (avoid PPM)

4. Are There any
Differences between
AVR and TAVI in
patients with AS and
Low EF?

5. What is the Result of Low EF in TAVR?

6. Study Methodology
• Definitions
– Low flow (LF) SVI ≤ 35 mL/M²
– Low ejection fraction (LEF) LV EF ≤ 50%
– Low gradient (LG) Mean gradient ≤ 40 mmHg
• Study population included 971 patients (92%)
with evaluable echocardiograms.
• Major outcome = 2-year all cause mortality
(based on ITT).
• Multivariable analysis with Cox proportional
hazards model:
– Univariate predictors of mortality (baseline and echo variables
relating to flow, pairwise analyses, adjusted models)

7. Impact of Left Ventricular Function on
Outcomes of Transcatheter Aortic Valve
Replacement and Medical Therapy in
Inoperable Patients with Aortic Stenosis:
Insights from The PARTNER Trial
(Cohort B)
Sammy Elmariah, MD, MPH, FACC
on Behalf of The PARTNER Trial Investigators
and The PARTNER Publications Office
TCT 2013 | San Francisco | October 29, 2013

8. PARTNER Study Design
N = 179
N = 358Inoperable
Standard
Therapy
ASSESSMENT:
Transfemoral
Access
Not In Study
TF TAVR
Primary Endpoint: All-Cause Mortality
Over Length of Trial (Superiority)
Co-Primary Endpoint: Composite of All-Cause Mortality
and Repeat Hospitalization (Superiority)
1:1 Randomization
VS
Yes No
N = 179
Symptomatic Severe Aortic Stenosis
ASSESSMENT: High-Risk AVR Candidate
3,105 Total Patients Screened
Total = 1,057 patients
2 Parallel Trials:
Individually Powered
N = 699 High Risk
Echocardiograms
Baseline
Discharge / 7-day
30-day
6-month
1-year

9. Key Exclusion Criteria
Anatomic
• Aortic annulus diameter on echo < 18 mm or > 25 mm
• Severe LV dysfunction (LVEF < 20%)
• Untreated CAD requiring revascularization
Clinical
• Serum creatinine > 3.0 mg/dl or dialysis dependence
• Acute myocardial infarction within 1 month
• CVA or TIA within 6 months
• Hemodynamic instability

10. Baseline Patient Characteristics (1)
Demographics (AT)
Characteristic
TAVR ST
LVEF
<50%
(n=46)
LVEF
≥50%
(n=123)
p-value
LVEF
<50%
(n=59)
LVEF
≥50%
(n=114)
p-value
Age - yr 85 ± 8 83 ± 9 0.15 85 ± 7 82 ± 9 0.051
Male sex (%) 52.2 41.5 0.21 50.8 45.6 0.51
STS score 13.2 ± 6.4 10.5 ± 5.5 0.006 13.3 ± 5.3 11.1 ± 4.5 0.006
NYHA 0.61 0.31
II (%) 4.3 8.1 3.4 8.8
III or IV (%) 95.7 91.9 96.6 91.2
CAD (%) 73.9 65.9 0.32 78.0 71.9 0.39
Prior MI (%) 26.7 17.2 0.17 40.7 20.2 0.004
Prior PCI (%) 30.4 26.0 0.57 27.1 19.3 0.24
Prior CABG (%) 45.7 28.5 0.03 45.8 39.5 0.43
Prior BAV (%) 19.6 12.2 0.22 22.0 19.3 0.67

11. 0
10
20
30
40
50
60
70
1/1/00 2/1/00 3/1/00 4/1/00 5/1/00 6/1/00 7/1/00 8/1/00 9/1/00 10/1/00 11/1/00 12/1/00 1/1/01
TAVR Low LVEF
TAVR High LVEF
ST Low LVEF
ST High LVEF
Change in LVEF over Time
All subjects: Low EF cases improve EF well
LeftVentricularEjectionFraction(%)
Baseline
1month
6months
1year
11-14% point
improvement
in LVEF
*** ***
*** ***
Paired comparisons vs baseline:
* P < 0.05
** P < 0.005
*** P < 0.0005
*
**
***
*
‡ ‡
†
Between group comparisons :
† P < 0.05
‡ P < 0.005

12. All-Cause Mortality (AT)
Baseline LVEF (TAVR Patients): There is no
difference in Survival at 1 year!!
Deathfromanycause(%)
0
20
40
60
80
Time (months)
0 3 6 9 12
46 38 35 31 30
123 107 95 92 86
Number at risk:
TAVR-LVEF < 50%
TAVR-LVEF ≥ 50%
P = 0.550
HR: 1.20 [95% CI: 0.67, 2.15]
34.8%
30.1%
TAVR - LVEF < 50%
TAVR - LVEF ≥ 50%

13. Implications (Low EF)
Results from the inoperable PARTNER cohort B
indicate that…
• TAVR should be considered the standard of care for
patients with symptomatic severe aortic stenosis who are
not candidates for surgery irrespective of their baseline LV
function.
– Despite Higher STS score, prior CABG, and more MR ….. The
Low EF cases (20-49%; mean = 36%) did just as well!
• 14 point EF (approx 35%) improvement in EF at 1 year,
most notably in first month.

14. Lauten, JACC CI 2012
• 149 TAVR with LG, LEF
(<1cm², <40mmHg, <40%)
• Compared to 1153 high grad
TAVR in German registry
However ….TAVR in Low EF/LG AS
• Higher 30 d (13%) and
1 yr (37%) mortality

15. What about Very Low EF
and TAVI?

16. One-year Outcomes Following TAVI for
Severe Aortic Stenosis in Elderly Patients
with Low LV Ejection Fraction
Gerhard Schymik, MD
Klinikum Karlsruhe, Germany
on behalf of the SOURCE XT Investigators

17. Methods
Controls
EF > 30%
N = 2380
1855 pts with EF ≥ 50%
525 pts with EF >30%; <50%
Very Low
EF
EF ≤ 30%
N = 156
* Patients with missing EF at baseline are not included in this analysis

18. Baseline Characteristics
Characteristics
Controls
N = 2380
Very Low EF
N = 156
p-value
Age (mean±SD) 81.5±6.3 80.5±6.3 0.054
Female (%) 58.9 30.8 <0.0001
BMI (mean±SD) 26.8±4.9 25.8±4.4 0.017
Logistic EuroSCORE (mean±SD) 19.6±11.8 32.6±15.3 <0.0001
STS Score (mean±SD) 7.8±6.4 10.1±7.9 <0.0001
Previous Stroke (%) 8.2 6.4 0.544
Diabetes Mellitus (%) 29.2 30.1 0.786
COPD (%) 20.4 20.5 >0.999
Peripheral Vascular Disease (%) 21.0 22.4 0.685
Porcelain Aorta (%) 6.6 4.5 0.400
Renal Insufficiency (%) 28.3 34.6 0.100

19. Baseline Hemodynamics (echo)
44.5
51.6
0
10
20
30
40
50
60
Controls Very Low EF
Pulmonary Pressure
0.7 0.7
0.0
0.5
1.0
Controls Very Low EF
EOA
56.3
25.9
0
10
20
30
40
50
60
Controls Very Low EF
LVEF
48.5
35.0
0
10
20
30
40
50
60
Controls Very Low EF
Mean Gradient
p =0.346 p < 0.0001
p < 0.0001 p < 0.0001

20. Improvement in Quality of Life
12.8
18.4
20.8
11.0
16.9
19.9
0
5
10
15
20
25
Discharge 30 Days 1 Year
Change from Baseline (EQ-5D)
Controls
Very Low EF
All changes from baseline are statistically significant < 0.0001
p =0.756
p =0.532
p = 0.624

21. 1 Year Mortality
All-Cause MortalityCardiac Mortality
40%
60%
80%
100%
0 2 4 6 8 10 12Survival
Months
Very Low EF Controls
40%
60%
80%
100%
0 2 4 6 8 10 12
Survival
Months
Very Low EF Controls
Log-rank p =0.012
70.1%
81.5%
80.6%
89.9%
Log-rank p =0.0004
0-2 Months:
Log-rank p = 0.0003
0-4 Months:
Log-rank p = 0.6053
88.9%
95.6%
78.2%
88.9%
80%
85%
90%
95%
100%
0 5 10 15 20 25 30
Survival
Days
Very Low EF Controls

22. Improvement in EF Over Time
56.3 57.4 58.2 58.7
27.6
34.2
39.3
44.1
15
25
35
45
55
65
Baseline Discharge 30 Days 1 Year
LVEF
* p<0.0001 between the two groups
All changes from baseline are statistically significant p < 0.0001 (paired t-test)

23. 7.5
13.3
23.4
29.3
8.1
16.2
12.8
20.6
0
5
10
15
20
25
30
Cardiac
Mortality
Overall
Mortality
Cardiac
Mortality
Overall
Mortality
1YearMortality
Change in EF <5% Change in EF ≥5%
Controls Very Low EF
Mortality by EF Change

24. Conclusions
 Patients with very low EF undergoing TAVI are with
significantly higher risk and cardiovascular morbidity as
compared to patients with EF > 30%.
 Following TAVI procedure, there is a substantial improvement
in functional class and the quality of life regardless of the
baseline EF.
 Although, very low EF improves steadily and significantly over
the first year after the intervention, it is associated with
significantly higher mortality at 1 year. (?? Early effect)
 Failure of severe LV dysfunction to improve early after TAVI
portends an increased risk of late cardiac mortality with rates
twice higher compared to those who demonstrate early
improvement in LV function.

25. What about Comparing
AVR and TAVI in Low EF?

26. TAVI / AVR in Low EF AS
Clavel, Circ 2010
• 83 TAVR with LEF
(not necessarily LG or LF)
• Compared to 200 SAVR
(propensity score)
• TAVR better recovery EF
• Higher iAVA with TAVR

27. F. Bauer, et al (Rouen, France); Echocardiography 2013
Excellent
Improvement of LVEF
in Both TAVR and
SAVR at 3 months

29. Propensity Matched Population:
TAVR vs SAVR with Short term
outcomes
Results Equal
More Pacemakers with TAVI
More AI with TAVI
More Transfusion with SAVR
Trend towards higher Euroscore in
AVR patients: p = 0.1 (26 vs 21)

30. Randomized PARTNER Trial

31. Predictors of Mortality and
Outcomes of Therapy in
Low Flow Severe Aortic Stenosis
Howard C. Herrmann, MD
University of Pennsylvania, Philadelphia, PA
And the PARTNER A and B Investigators
TCT 2012 | Miami, FL | October 24, 2012: Circulation 2013

32. PARTNER Study Design
N = 179
N = 358Inoperable
Standard
Therapy
ASSESSMENT:
Transfemoral
Access
Not In Study
TF TAVR
Primary Endpoint: All-Cause Mortality
Over Length of Trial (Superiority)
Co-Primary Endpoint: Composite of All-Cause Mortality
and Repeat Hospitalization (Superiority)
1:1 Randomization
VS
Yes No
N = 179
TF TAVR AVR
Primary Endpoint: All-Cause Mortality at 1 yr
(Non-inferiority)
TA TAVR AVR
VSVS
N = 248 N = 104 N = 103N = 244
Symptomatic Severe Aortic Stenosis
ASSESSMENT: High-Risk AVR Candidate
3,105 Total Patients Screened
Total = 1,057 patients
2 Parallel Trials:
Individually Powered
N = 699 High Risk
ASSESSMENT:
Transfemoral
Access
Transapical (TA)Transfemoral (TF)
1:1 Randomization1:1 Randomization
Yes No

33. Treatment Comparison in
LF and LEF (both cohorts)
2-YearDeath(%)
0
10
20
30
40
50
60
70
80
90
Time in Days
0 60 120 180 240 300 360 420 480 540 600 660 720
76 68 62 56 53 52 49 46 44
77 58 56 54 53 50 47 46 41
34 29 26 21 20 17 17 17 17
38 32 23 18 16 13 9 9 7
Number At Risk
A-TAVR
A-Surgery
B-TAVR
B-Std Rx
Log Rank P= <.001
40.8%
37.4%
50.0%
79.9%
LF and LEF - A-TAVR
LF and LEF - A-Surgery
LF and LEF - B-TAVR
LF and LEF - B-Std Rx

34. Treatment Comparison AVR and TAVI in
LF, LEF, and LG (both cohorts)
(Classic Low EF AS cases)
2-YearDeath(%)
0
10
20
30
40
50
60
70
80
90
Time in Days
0 60 120 180 240 300 360 420 480 540 600 660 720
56 50 45 39 38 37 35 32 32
49 38 36 35 35 32 29 29 27
17 15 14 12 11 9 9 9 9
25 19 13 10 10 8 5 5 5
Number At Risk
A-TAVR
A-Surgery
B-TAVR
B-Std Rx
Log Rank P= 0.001
42.9%
37.1%
47.1%
80.0%
LF, LEF and LG - A-TAVR
LF, LEF and LG - A-Surgery
LF, LEF and LG - B-TAVR
LF, LEF and LG - B-Std Rx

35. Results
Paradoxical LF, Normal EF, and LG
0%
10%
20%
30%
40%
50%
60%
80%
90%
60 120 180 240 300 360 420 480 540 600 660 720
70%
2-YearDeath(%)
39.7%
41.1%
56.5%
76.9%
0
log rank p= 0.003
Numbers at Risk
A – TAVR 43 39 38 34 34 33 29 26 22
A – Surgery 44 33 30 30 28 27 27 26 23
B – TAVR 23 21 19 17 15 13 11 10 10
B – Std Rx 29 22 15 10 9 9 6 5 4
LF NEF LG – A - TAVR
LF NEF LG – A - Surgery
LF NEF LG – B - TAVR
LF NEF LG – B - Std Rx
Days

36.  AVR orTAVI should be performed in patients
with Low EF (Low Flow) and severeAS
 Inoperable and High Risk Low EF patients
should usually receive aTAVI (STS > 8 or
EuroScore > 25)
▪ Make sure there is noAI and need BigValve (PPM)
 Low Flow, Low gradient, NORMAL EF
patients (Paradoxical) may be better served
withTAVI