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

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

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.

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

Pibarot and Dumesnil, JACC 2012

Cueff C et al. Heart 2011;97:721-726

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)

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

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

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

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 49±14% AVA 0.56±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 58±5% AVA 0.57±0.15 cm2 Grad 37±14 mmHg EF 37±9% AVA 0.56±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 36±9% AVA 0.62±0.16 cm2 LG (≤ 40 mmHg) in 45% and AVA ≥ 0.8 cm2 in 19% of patients

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

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

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

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

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

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 [1.16-1.76] 0.001 Cohort A (high risk) 1.43 [1.08-1.90] 0.013 Cohort B (inoperable) 1.55 [1.13-2.12] 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 [1.03-1.08] 0.0001 Major Arrhythmia 1.31 [1.06-1.60] 0.011 TAVR (Cohort B) 0.76 [0.62-0.93] 0.008

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.

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.