Inoperable Patients With Severe Aortic Stenosis: The PARTNER Trial - PowerPoint PPT Presentation

Three-Year Outcomes of Transcatheter Aortic Valve Replacement (TAVR) in “ Inoperable ” Patients With Severe Aortic Stenosis: The PARTNER Trial Samir R. Kapadia, MD On behalf of The PARTNER Trial Investigators TCT 2012 | Miami, FL | October 24, 2012

Background (1) • Transcatheter aortic valve replacement (TAVR) is the recommended treatment for “ inoperable ” patients with severe aortic stenosis (AS), based upon 1-year results of The PARTNER Trial which demonstrated reduced mortality and improved quality of life. • However, whether clinical benefit and valve performance are sustained beyond two years is unknown and longer term outcomes will importantly alter clinical practice decisions.

Background (2)

Objectives • To evaluate the clinical outcomes of TAVR compared to standard therapy at 3 years in “ inoperable ” aortic stenosis patients. • To assess valve hemodynamics and durability using echocardiography. • To perform subgroup analyses to better define the impact of co-morbidities on outcomes.

PARTNER Study Design Symptomatic Severe Aortic Stenosis n = 358 Inoperable ASSESSMENT: Transfemoral Access 1:1 Randomization Standard TF TAVR Therapy n = 179 VS n = 179 Primary Endpoint: All-Cause Mortality Over Length of Trial (Superiority) • Primary endpoint evaluated when all patients reached one year follow-up. • After primary endpoint analysis reached, patients were allowed to cross-over to TAVR.

Inclusion Criteria • Severe calcific aortic stenosis defined as echo derived valve area of < 0.8 cm 2 (EOA index < 0.5 cm 2 /m 2 ), and mean gradient > 40 mmHg or jet velocity > 4.0 m/s. • NYHA functional class ≥ II • Inoperable defined as risk of death or serious irreversible morbidity of AVR as assessed by cardiologist and two surgeons exceeding 50%.

Key End-Points for 3 Year Analysis • All cause mortality • Cardiac mortality • Rehospitalization • Adverse outcomes including stroke, bleeding, renal failure, and MI • NYHA functional class • Days alive and out of hospital • Echo-derived valve areas, transvalvular gradients, and paravalvular aortic regurgitation • Mortality outcomes stratified by STS score

Study Flow Inoperable Cohort n = 358 Randomized Inoperable n = 179 n = 179 Standard Therapy TAVR 85/85 patients 124/124 patients 100% followed at 1 Yr 100% followed at 1 Yr Cross over 11 pts 46/46 patients 101/102 patients* 100% followed at 2 Yr 99.0% followed at 2 Yr Cross over 9 pts 19/19 patients 80/82 patients** 100% followed at 3 Yr 97.6% followed at 3 Yr • *One TAVR patient was alive and censored prior to the window • **Two TAVR patients were alive and censored prior to the window (including the one in the same status at 2 years); one TAVR patient withdrew between 2 and 3 years • No patients were lost to follow-up

Statistical Method • Primary analysis was by “ intention-to-treat ” (ITT). • Clinical outcomes were analyzed by ITT with censoring of Standard Rx cross-over patients. • Additional analysis of death was performed by following cross-over patients with their randomized trial arms. • Event rates are given as Kaplan-Meier estimates. • Core lab echo results are presented from the valve implant population (valve retained in position).

Patient Characteristics (1) TAVR Standard Rx Characteristic p value n = 179 n = 179 Age – yr 83.1 ± 8.6 83.2 ± 8.3 0.95 Male sex (%) 45.8 46.9 0.92 11.2 ± 5.8 12.1 ± 6.1 STS Score 0.14 NYHA I or II (%) 7.8 6.1 0.68 III or IV (%) 92.2 93.9 0.68 CAD (%) 67.6 74.3 0.20 Prior MI (%) 18.6 26.4 0.10 Prior CABG (%) 37.4 45.6 0.17 Prior PCI (%) 30.5 24.8 0.31 Prior BAV (%) 16.2 24.4 0.09 CVD (%) 27.4 27.5 1.00 Note: Same as previously presented at TCT 2010 and published in the NEJM manuscript.

Patient Characteristics (2) TAVR Standard Rx Characteristic p value n = 179 n = 179 PVD (%) 30.3 25.1 0.29 COPD Any (%) 41.3 52.5 0.04 O 2 dependent (%) 21.2 25.7 0.38 Creatinine > 2 mg/dL (%) 5.6 9.6 0.23 Atrial fibrillation (%) 32.9 48.8 0.04 Perm. pacemaker (%) 22.9 19.5 0.49 Pulmonary HTN (%) 42.4 43.8 0.90 Frailty (%) 18.1 28.0 0.09 Porcelain aorta (%) 19.0 11.2 0.05 Chest wall radiation (%) 8.9 8.4 1.00 Chest wall deformity (%) 8.4 5.0 0.29 Liver disease (%) 3.4 3.4 1.00 Note: Same as previously presented at TCT 2010 and published in the NEJM manuscript.

All Cause Mortality (ITT) Crossover Patients Censored at Crossover 100% Standard Rx HR [95% CI] = 0.53 [0.41, 0.68] p (log rank) < 0.0001 TAVR 80.9% All Cause Mortality (%) 80% 68.0% 26.8% 60% 50.8% 25.0% 54.1% 20.1% 40% NNT = 3.7 pts 43.0% NNT = 4.0 pts 30.7% 20% NNT = 5.0 pts 0% 0 6 12 18 24 30 36 Months Numbers at Risk Standard Rx 179 121 85 62 46 27 17 TAVR 179 138 124 110 101 88 70

Cardiovascular Mortality (ITT) Crossover Patients Censored at Crossover 100% Standard Rx HR [95% CI] = 0.41 [0.30, 0.56] p (log rank) < 0.0001 TAVR Cardiovascular Mortality (%) 74.5% 80% 62.4% 60% 33.1% 44.6% 31.7% 40% 41.4% 24.1% NNT = 3.0 pts 30.7% 20% NNT = 3.2 pts 20.5% NNT = 4.1 pts 0% 0 6 12 18 24 30 36 Months Numbers at Risk Standard Rx 179 121 85 62 46 27 17 TAVR 179 138 124 110 101 88 70

All Cause Mortality (ITT) Landmark Analysis 100% Standard Rx HR [95% CI] = 0.53 [0.41, 0.68] p (log rank) < 0.0001 TAVR HR [95% CI] = 2.03 [1.36, 3.04] p (log rank) = 0.0005 80% All Cause Mortality (%) HR [95% CI] = 1.90 [1.05, 3.43] p (log rank) = 0.03 60% ∆ = 17.3% ∆ = 21.0% ∆ = 20.1% 50.8% NNT = 5.0 pts NNT = 5.8 pts NNT = 4.8 pts 40.3% 40% 35.1% 30.7% 20% 19.3% 17.8% 0% 0 6 12 18 24 30 36 Months Numbers at Risk Standard Rx 179 121 85 62 46 27 17 TAVR 179 138 124 110 101 88 70

Repeat Hospitalization (ITT) Rehospitalization Mortality or Rehospitalization 100% 100% Standard Rx HR [95% CI] = 0.39 [0.28, 0.54] 93.1% 88.0% Mortality or Rehospitalization (%) p (log rank) < 0.0001 TAVR 71.6% 75.7% 72.5% 80% 80% 26.8% Rehospitalization (%) 31.5% 53.9% 60% 60% 66.3% 33.4% 27.5% 37.6% NNT = 3.7 pts 56.5% NNT = 3.2 pts 26.9% 40% 40% 42.3% 44.1% NNT = 3.0 pts 34.9% NNT = 3.6 pts NNT = 2.7 pts 20% 20% 27.0% HR [95% CI] = 0.46 [0.36, 0.58] NNT = 3.7 pts p (log rank) < 0.0001 0% 0% 0 6 12 18 24 30 36 0 6 12 18 24 30 36 Months Months Days Alive Out of Hospital Median [IQR] p <.0001 TAVR 944 [233-1096] Standard Rx 368 [147-1096] Numbers at Risk Standard Rx 179 86 49 30 19 11 7 179 86 49 30 19 11 7 TAVR 179 115 100 89 77 64 49 179 115 100 89 77 64 49

NYHA Class Over Time (ITT) p = NS p < 0.0001 p < 0.0001 p < 0.0001 100% 34.7% 45.7% 80% 43.6% 45.3% 58.8% 59.3% 60% 76.9% 91.1% 40% Dead IV 20% III II I 0% TAVR Standard TAVR Standard TAVR Standard TAVR Standard Rx Rx Rx Rx N = 179 179 173 167 173 160 165 146 Baseline 1 Year 2 Year 3 Year

All Stroke (ITT) 50% TAVR HR [95% CI] = 2.77 [1.24, 6.19] p (log rank) = 0.0094 Standard Rx 40% Stroke (%) 30% NNT = 9.8 pts NNT = 12.2 pts 20% NNT = 17.5 pts 15.7% 13.7% 11.2% ∆ = 10.2% 10% ∆ = 8.2% ∆ = 5.7% 5.5% 5.5% 5.5% 0% 0 6 12 18 24 30 36 Months Numbers at Risk TAVR 179 128 116 105 96 82 65 Standard Rx 179 118 84 62 46 27 17

Stroke – Between year 2-3 Days post Comorbidity Procedure Device ITT arm Age Description Comments randomization related* related* TAVR 97 879 Ischemic Blood stream No No Cerebellar infarct; infection, Linear echodensity on Right carotid mitral valve, Ao valve: stenosis Mild AI (80%) TAVR 87 837 Acute infarct Atrial No No Cerebellar infarct/ with surrounding Fibrillation hemorrhage; intraparenchymal not on Ao valve: Ok bleed warfarin *CEC adjudicated

Mortality or Stroke (ITT) 100% Standard Rx HR [95% CI] = 0.60 [0.46, 0.77] p (log rank) < 0.0001 TAVR 80.9% Mortality or Stroke (%) 80% 68.0% 23.4% 60% 51.3% 22.2% 57.5% 16.1% NNT = 4.3 pts 40% 45.8% NNT = 4.5 pts 35.2% NNT = 6.2 pts 20% 0% 0 6 12 18 24 30 36 Months Numbers at Risk Standard Rx 179 118 84 62 46 27 17 TAVR 179 128 116 105 96 82 65

Mean Gradient & Valve Area 70 EOA 2.5 Mean Gradient 60 2 Mean Gradient (mmHg) 50 Valve Area (cm²) 1.6 1.6 1.6 1.5 44.2 1.5 1.5 40 30 1 20 0.6 0.5 10.2 10 11.0 10.9 11.3 10.8 0 0 Baseline 30 Day 6 Month 1 Year 2 Year 3 Year N = 159 137 96 86 70 43 Error bars = ± 1 Std Dev

Paravalvular Leak Valve Implant Patients (restricted to patients with 3 year values) 100% Percent of evaluable echos 80% 60% 40% Severe Moderate 20% Mild Trace None 0% 30 Day 6 Month 1 Year 2 Year 3 Year N = 44 45 44 45 46

Mortality Stratified by Paravalvular Leak Valve Implant Patients Mild 100% HR [95% CI] = 1.09 [0.82, 1.45] Moderate-Severe p (log rank) = 0.8059 None-Trace 80% 57.0% Mortality (%) 55.7% 44.9% 60% 43.5% 30.8% 40% 45.6% 30.4% 34.4% 26.6% 20% 0% 0 6 12 18 24 30 36 Months Numbers at Risk Mild 78 61 54 47 43 36 26 Mod.-Severe 23 17 16 15 13 12 9 None-Trace 64 51 47 43 41 37 29