1. TAVR or Surgery for Low Flow (LF) AS – Insights from the PARTNER Trial
Howard C. Herrmann, MD
University of Pennsylvania
Philadelphia

2. Howard C. Herrmann, MD
Consulting: Siemens AG and St. Jude Medical, Inc.
Grant Support: Abbott Vascular, Siemens AG, W. L. Gore and Associates, Inc., Medtronic, Inc., St. Jude Medical, Inc. and Edwards Lifesciences, LLC
Honoraria: Paieon, Inc
Stocks, Stock Options, other ownership interest: Micro Interventional Devices, Inc.
Off-Label: Use of investigational devices: Sapien, MitraClip, Endovalve, Permaseal

3. Background
Aortic valve replacement (AVR) is indicated for patients with severe AS and either symptoms or LV dysfunction
Classic definition of severe AS: AVA < 1 cm2 and mean transvalvular gradient > 40 mmHg.
However, many patients with symptomatic severe AS have lower gradients due to low flow (LF)
LV systolic dysfunction (low EF)
Pronounced concentric remodeling (“Paradoxical” LF with normal EF)
Errors or assumptions inherent in the measurements
AHA/ACC guidelines have no specific recommendation for LF, LG, LEF AS, while the ESC guidelines recommend surgery if there is evidence for flow reserve (IIa). Neither address paradoxical LF, LG, NEF.

4. Hemodynamic Profiles of Severe Aortic Stenosis (AVA <1.0 cm2)
Low Flow
(SVI < 35 ml/M2)
Low Gradient
(mean < 40 mmHg)
Low Ejection Fraction
(< 50%)
Classic low flow, low gradient, low EF
Paradoxical low flow with preserved EF

7. Pibarot and Dumesnil, JACC 2012

8. Cueff C et al. Heart 2011;97:

9. Background
Patients with low gradient (LG) severe AS have a worse prognosis whether treated medically or with AVR as compared to normal gradient
Little is known about the prognostic value of low flow (LF), independent of gradient and EF, and its treatment
TAVR has different effects on the LV and patients than surgery (SAVR)

10. Previous Studies of Outcomes of Surgery in LF LG severe AS
Series N
Peri-op or 30 day Mortality*
LF, LG, LEF
LF, LG, NEF
Blitz, 1998 52
11%
Monin, 2003 95
14%
Kulik, 2006 79 8%
Clavel, 2008 44
18%
Levy, 2008
217
16%
1-year (Mortality) 5-year
Blitz, 1998 52
29%
34%
Monin, 2003 95
25%
41 (no AVR)
60%
Kulik, 2006 79
11%
24%
Clavel, 2008 44
30%
57 (no AVR)
Levy, 2008
217
51%
Hachicha, 2007
80 (AVR) 5%
15%
91 (Std Rx)
20%
60%
Tarantini, 2011
73 (AVR)
10%
29 (Std Rx)
25%
80%
Jander, 2011
435 (Std Rx) 2%
10%#
*Percentages approximated by extrapolation from KM curves; #~50% AVR

11. How does TAVR differ from Surgery?
TAVR is less invasive:
Faster recovery
Less pericardial irritation with potential for less AF
Less healing, risk for infection
Shorter ventilator dependency
Cardiopulmonary bypass can be detrimental:
Systemic inflammatory response syndrome
Inflammatory activation by membrane oxygenator, heparin-coated circuits, UF
Ischemia-reperfusion injury to various organs (gut, kidneys, brain, etc)
Risk for adverse cerebral effects (cognitive decline)
Need for higher levels of anticoagulation
Need for cardiac standstill with cardioplegia and hypothermia
Larger effective orifice area (EOA) with transcatheter vs surgical prostheses:
Less Patient-Prosthesis Mismatch (PPM)
PPM may be more important in low flow, low EF with heightened afterload sensitivity

12. TAVR in LG AS Clavel, Circ 2010 Lauten, JACC CI 2012
83 TAVR with LEF (not necessarily LG or LF)
Compared to 200 SAVR (propensity score)
Lauten, JACC CI 2012
149 TAVR with LG, LEF (<1cm², <40mmHg, <40%)
Compared to 1153 high grad TAVR in German registry
TAVR better recovery EF
Higher iAVA with TAVR
Higher 30 d (13%) and 1 yr (37%) mortality

13. Flow Chart of Study Population
PARTNER (n = 971)
Normal Flow (n = 441, 45%)
Low Flow (n = 530, 55%)
TAVR (n = 170)
SAVR (n = 180)
TAVR (n = 85)
Std Rx (n = 95)
Grad 40±14 mmHg
EF ±14%
AVA ±0.16 cm²
A (n = 350)
B (n = 180)
A (n = 196)
TAVR (n = 93)
SAVR (n = 103)
TAVR (n = 51)
Std Rx (n = 57)
B (n = 108)
LF NEF (n = 304, 31%)
LF LEF (n = 225, 23%)
A (n = 153)
B (n = 72)
Grad 43±14 mmHg
EF ±5%
AVA ±0.15 cm2
Grad 37±14 mmHg
EF ±9%
AVA ±0.17 cm2
LF LEF NG (n = 78, 8%)
LF LEF LG (n = 147, 15%)
A (n = 105)
B (n = 42)
Grad 29±7 mmHg
EF ±9%
AVA ±0.16 cm2
LG (≤ 40 mmHg) in 45% and AVA ≥ 0.8 cm2 in 19% of patients

14. Results KM mortality for LF vs NF
ITT - Cohorts A & B
2-Yr Death (%) 0%
10%
20%
30%
40%
50%
60%
70%
80% 4 8 12 16 20 24
HR: 1.07 [95% CI: 0.83, 1.37]
Log-Rank p= 0.616
48.9%
46.1%
LF LEF
LF NEF 0%
10%
20%
30%
40%
50%
60%
70% 4 8 12 16 20 24
HR: 1.52 [95% CI: 1.24, 1.87]
Log-Rank p= <.001
47.2%
33.9%
ITT - Cohorts A & B
LF (Low Flow)
NF (Normal Flow)
Months
Numbers at Risk
LF LEF LG
225
177
154
142
128
119
100
NF LEF NG
304
214
213
193
179
162
134
2-Yr Death (%)
ITT - Cohorts A & B 4 8 12 16 20 24
2-Yr Death (%) 0%
10%
20%
30%
40%
50%
60%
70%
HR: 0.97 [95% CI: 0.65, 1.44]
Log-Rank p= 0.886
48.0%
50.9%
LF LEF LG
LF LEF NG
Months
Numbers at Risk LF
530
422
368
336
308
282
235 NF
441
342
317
300
274
239
Months
Numbers at Risk
LF LEF LG
147
115
100 94 83 76 67
NF LEF NG 78 62 54 48 45 43 33

15. Results All LF Patients by Treatment Received
log rank p= <.001 0%
10%
20%
30%
40%
50%
60%
70%
80% 60
120
180
240
300
360
420
480
540
600
660
720
LF – A - TAVR
LF – A - Surgery
LF – B - TAVR
LF – B - Standard Rx
76.2%
45.9%
39.3%
2-Year Death (%)
38.1%
25% to 16% (40% RR, p=0.04)
Days
Numbers at Risk
LF – A – TAVR
170
152
143
127
123
116
109
102 86
LF – A – Surgery
180
138
119
115
111
105 90
LF - B – TAVR 85 74 65 58 55 50 47 46 41
LF - B – Std Rx 95 78 60 39 35 26 25 18

16. Results Outcomes in LF vs NF by Treatment Received (Cohort A)60
120
180
240
300
360
420
480
540
600
660
720 0% 5%
10%
15%
20%
25%
30%
35%
40%
45%
39.3%
38.1%
25.4%
28.9%
log rank p= 0.030
LF – A - TAVR
LF – A - Surgery
NF – A - TAVR
NF – A - Surgery
2-Year Death (%)
Days
Numbers at Risk
LF – A – TAVR
170
152
143
127
123
116
109
102 86
LF – A – Surgery
180
138
119
115
111
105 90
NF – A – TAVR
139
135
124
120
117
110
107 95
NF – A – Surgery
145
106 97 89 77

17. Results Paradoxical LF and NEF
log rank p= <.001 0%
10%
20%
30%
40%
50%
60%
70%
80% 60
120
180
240
300
360
420
480
540
600
660
720
2-Year Death (%)
38.6%
38.5%
43.1%
73.4%
LF NEF – A - TAVR
LF NEF – A - Surgery
LF NEF – B - TAVR
LF NEF – B - Standard Rx
Days
Numbers at Risk
A – TAVR 93 83 80 70 69 63 59 55 44
A – Surgery
103 71 66 65 64 53
B – TAVR 51 45 39 37 35 33 30 29 26
B – Standard Rx 57 46 23 22 17 16 11

18. Results Paradoxical LF, NEF, and LG
2-Year Death (%) 10 20 30 40 50 60 70 80 90
Time in Days
120
180
240
300
360
420
480
540
600
660
720 43 39 38 34 33 29 26 22 44 28 27 23 21 19 17 15 13 11 9 6 5 4
Number At Risk
A-TAVR
A-Surgery
B-TAVR
B-Standard Rx
Log Rank P= 0.003
39.7%
41.1%
56.5%
76.9%
LF, NEF and LG - A-TAVR
LF, NEF and LG - A-Surgery
LF, NEF and LG - B-TAVR
LF, NEF and LG - B-Standard Rx

19. Multivariable analysis with Cox Proportional Hazards Model
LF was an independent predictor of 2-year mortality in all 3 groups
Study Group
Hazard Ratio [95% CI]
p value
Combined cohorts
1.42 [ ]
0.001
Cohort A (high risk)
1.43 [ ]
0.013
Cohort B (inoperable)
1.55 [ ]
0.007
However, the predictors were different in the two arms indicating differential impact of baseline characteristics based on approach. In the TAVR arm, BMI, mean gradient, renal function and prior vascular intervention impacted survival. Whereas in the surgery arm, prior CABG, STS score, liver disease and presence of MR were significant factors.
Other Predictors (Combined cohort)
Hazard Ratio [95% CI]
p value
STS Risk Score
1.06 [ ]
0.0001
Major Arrhythmia
1.31 [ ]
0.011
TAVR (Cohort B)
0.76 [ ]
0.008

20. Conclusions
In patients with severe AS, low flow (SVI ≤ 35 cc/M²) is associated with a significant ~50% increase in 2-year all-cause mortality as compared to patients with normal flow:
Independent in multivariable analysis
More powerful predictor than EF or gradient
Patients with severe AS and LF (with or without low EF or low gradient) had improved survival with TAVR relative to Standard Therapy and similar outcomes with TAVR vs SAVR:
Magnitude of benefit was similar to that in the overall trial
Suggestion of reduced mortality early with TAVR vs SAVR
Patients with paradoxical LF (with normal or low gradient) also had worse prognosis relative to NF, improved survival with TAVR vs Standard Therapy, and similar survival with TAVR vs SAVR.

21. Clinical Implications
LF is more important than EF:
LV contractile dysfunction may be a cause of LF, but other causes of LF may include high global afterload with a restrictive physiology, pronounced LV concentric hypertrophy, and reduced LV compliance and filling.
Current guidelines emphasize the importance of EF in the evaluation of patients with AS for surgery even when asymptomatic, but our data suggest that EF may be less important after adjustment for flow.
We believe that an assessment of flow (based on SVI) should be included in the evaluation of all patients with severe AS :
Further study is needed to determine whether a specific SVI or change in SV with dobutamine (flow reserve) should be used to guide the timing for valve replacement.
Treatment with SAVR or TAVR should be favored in patients with LF despite their increased mortality relative to patients with NF.