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Samir R. Kapadia , MD On behalf of The PARTNER Trial Investigators

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. Samir Kapadia

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Samir R. Kapadia , MD On behalf of The PARTNER Trial Investigators

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  1. 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

  2. Samir Kapadia • No financial disclosures • Member of PARTNER Trial steering committee • Murat Tuzcu • No financial disclosures • Member of PARTNER Trial executive committee

  3. 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.

  4. Background (2)

  5. 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.

  6. PARTNER Study Design Symptomatic Severe Aortic Stenosis Inoperable n = 358 ASSESSMENT: Transfemoral Access 1:1 Randomization Standard Therapy n = 179 TF TAVR n = 179 VS 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.

  7. Inclusion Criteria • Severe calcific aortic stenosis defined as echo derived valve area of < 0.8 cm2 (EOA index < 0.5 cm2/m2), 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%.

  8. 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

  9. Study FlowInoperable Cohort n = 358 Randomized Inoperable • *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 n = 179 Standard Therapy n = 179 TAVR 85/85 patients 100% followed at 1 Yr 124/124 patients 100% followed at 1 Yr Cross over 11 pts 46/46 patients 100% followed at 2 Yr 101/102 patients* 99.0% followed at 2 Yr Cross over 9 pts 19/19 patients 100% followed at 3 Yr 80/82 patients** 97.6% followed at 3 Yr

  10. 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).

  11. Patient Characteristics (1) Note: Same as previously presented at TCT 2010 and published in the NEJM manuscript.

  12. Patient Characteristics (2) Note: Same as previously presented at TCT 2010 and published in the NEJM manuscript.

  13. All Cause Mortality (ITT)Crossover Patients Censored at Crossover Standard Rx TAVR • HR [95% CI] = 0.53 [0.41, 0.68] • p (log rank) < 0.0001 80.9% 68.0% 26.8% 50.8% 25.0% All Cause Mortality (%) 54.1% 20.1% NNT = 3.7 pts 43.0% NNT = 4.0 pts 30.7% NNT = 5.0 pts Months

  14. Cardiovascular Mortality (ITT)Crossover Patients Censored at Crossover Standard Rx TAVR • HR [95% CI] = 0.41 [0.30, 0.56] • p (log rank) < 0.0001 74.5% 62.4% 33.1% 31.7% 44.6% Cardiovascular Mortality (%) 24.1% 41.4% NNT = 3.0 pts 30.7% NNT = 3.2 pts 20.5% NNT = 4.1 pts Months

  15. All Cause Mortality (ITT)Landmark Analysis Standard Rx TAVR • HR [95% CI] = 0.53 [0.41, 0.68] • p (log rank) < 0.0001 • HR [95% CI] = 2.03 [1.36, 3.04] • p (log rank) = 0.0005 • HR [95% CI] = 1.90 [1.05, 3.43] • p (log rank) = 0.03 ∆ = 20.1% ∆ = 21.0% ∆ = 17.3% 50.8% All Cause Mortality (%) NNT = 5.0 pts NNT = 5.8 pts NNT = 4.8 pts 40.3% 35.1% 30.7% 19.3% 17.8% Months

  16. Repeat Hospitalization (ITT) Standard Rx TAVR Rehospitalization MortalityorRehospitalization • HR [95% CI] = 0.39 [0.28, 0.54] • p (log rank) < 0.0001 93.1% 88.0% 26.8% 71.6% 75.7% 31.5% 72.5% 33.4% 37.6% 27.5% 53.9% 66.3% NNT = 3.7 pts Rehospitalization (%) Mortality or Rehospitalization (%) 56.5% 26.9% NNT = 3.2 pts 42.3% 44.1% NNT = 3.0 pts 34.9% NNT = 3.6 pts NNT = 2.7 pts 27.0% • HR [95% CI] = 0.46 [0.36, 0.58] • p (log rank) < 0.0001 NNT = 3.7 pts Months Months • Days Alive Out of Hospital Median [IQR] • p <.0001

  17. NYHA Class Over Time (ITT) p < 0.0001 p = NS p < 0.0001 p < 0.0001 34.7% 45.7% 43.6% 45.3% 58.8% 59.3% 76.9% 91.1% N = Baseline 1 Year 2 Year 3 Year

  18. All Stroke (ITT) Standard Rx TAVR • HR [95% CI] = 2.77 [1.24, 6.19] • p (log rank) = 0.0094 Stroke (%) NNT = 9.8 pts NNT = 12.2 pts NNT = 17.5 pts 15.7% 13.7% 11.2% ∆ = 10.2% ∆ = 8.2% ∆ = 5.7% 5.5% 5.5% 5.5% Months

  19. Mortality or Stroke (ITT) Standard Rx TAVR • HR [95% CI] = 0.60 [0.46, 0.77] • p (log rank) < 0.0001 80.9% 68.0% 23.4% 51.3% 22.2% 57.5% Mortality or Stroke (%) 16.1% NNT = 4.3 pts 45.8% NNT = 4.5 pts 35.2% NNT = 6.2 pts Months

  20. Mean Gradient & Valve Area EOA Mean Gradient Valve Area (cm²) Mean Gradient (mmHg) N = • Error bars = ± 1 Std Dev

  21. Paravalvular Leak Percent of evaluable echos N =

  22. Mortality Stratified by STS Score (ITT) Standard Rx TAVR STS: 0 - 4.9 STS: 5.0 - 14.9 STS ≥ 15 100% 86.6% ∆ = 66.8% ∆ = 22.3% ∆ = 20.8% 77.5% NNT = 1.5 pts NNT = 4.5 pts NNT = 4.8 pts 55.2% 65.8% Mortality (%) 33.2% Months Months Months

  23. PARTNER Secondary Analysis Pooled Cohort (ITT) 2007 2008 2009 Non-Randomized Continued Access Cohort B:235 Patients Randomized PARTNER Cohort B: 358 Patients Randomized PARTNER Cohort BRandomized Continued Access: 91 Patients May 2007 – March 2009 March 2009 – September 2009 September 2009 – July 2011 • Non-Randomized Continued Access • Cohort A:1,833 Patients • Randomized PARTNER • Cohort A: 699 Patients May 2007 – September 2009 September 2009 – January 2012

  24. Primary Outcome (Composite)All Cause Mortality

  25. Conclusions (1) • At 3 years follow-up benefits of TAVR were sustained as measured by: • All cause mortality • Cardiovascular mortality • Repeat hospitalization • Functional status • Valve durability was demonstrated with no increase in transvalvular gradient or attrition of valve area. • Detailed analysis of all randomized inoperable patients showed consistent results for all outcomes.

  26. Conclusions (2) • Survival benefit of TAVR is dependent on the presence of comorbid illness. • Without TAVR, mortality is similar irrespective of comorbid illness.

  27. Clinical Implications • Three year data continue to support the role of TAVR as the standard-of-care for symptomatic patients with aortic stenosis who are not surgical candidates. • These data underscore the importance of patient selection before TAVR and the need for aggressive management of illnesses after TAVR.

  28. Thank You to the Dedicated Study Teams at All PARTNER Investigational Sites

  29. Backup Slides

  30. Study FlowInoperable Cohort – Crossover Patients Followed in Standard Therapy Arm n = 358 Randomized Inoperable • *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 n = 179 Standard Therapy n = 179 TAVR 85/85 patients 100% followed at 1 Yr 124/124 patients 100% followed at 1 Yr 56/56 patients 100% followed at 2 Yr 101/102 patients* 99.0% followed at 2 Yr 34/34 patients 100% followed at 3 Yr 80/82 patients** 97.6% followed at 3 Yr

  31. Survival of Crossover Patients • No patients crossed over after three years

  32. Survival of Crossover Patients

  33. Cardiovascular Mortality (ITT)Landmark Analysis Standard Rx TAVR • HR [95% CI] = 0.41 [0.30, 0.56] • p (log rank) < 0.0001 • HR [95% CI] = 2.48 [1.56, 3.95] • p (log rank) < 0.0001 • HR [95% CI] = 2.09 [1.05, 4.16] • p (log rank) = 0.0314 ∆ = 19.4% ∆ = 17.1% ∆ = 24.1% Cardiovascular Mortality (%) NNT = 5.8 pts NNT = 4.1 pts NNT = 5.2 pts 44.6% 32.1% 32.2% 20.5% 12.7% 15.1% Months

  34. NYHA Class Over Time (ITT)Survivors p < 0.0001 p = NS p = NS p < 0.0001 17.7% 23.7% 29.0% 50.0% 60.8% 56.1% 92.2% 93.9% N = Baseline 1 Year 2 Year 3 Year

  35. Adverse EventsBetween 2 and 3 years (ITT)

  36. Mortality Stratified by Paravalvular Leak Valve Implant Patients Mild-Severe None-Trace • HR [95% CI] = 1.15 [0.76, 1.74] • p (log rank) = 0.5114 56.0% Mortality (%) 44.6% 45.6% 30.7% ∆ = 10.4% 34.4% NNT = 9.6 pts ∆ = 10.2% 26.6% NNT = 9.8 pts ∆ = 4.1% NNT = 24.4 pts Months

  37. Echo Analysis PV Leak Changes 30 Days Compared to 3 Years Patients With Data at Both Time Points Of the 44 patients alive with data at both 30 days and 3 years: 31.8% Improved 16.0% Progressed 52.3% Unchanged

  38. TAVR Mortality Stratified by STS Score (ITT) 5 - 15 < 5 > 15 • p (log rank) = 0.0503 65.8% 60.5% 55.2% 47.4% Mortality (%) 42.5% 33.2% 30.1% 21.6% 10.7% Months

  39. Patient Characteristics (1)Pooled

  40. Patient Characteristics (2)Pooled

  41. Primary Outcome (Composite)Functional Status

  42. Primary Outcome (Composite)Mean Gradient & AVA

  43. Univariate and Multivariate Predictors of Mortality after TAVR

  44. Pooled Randomized

  45. All Cause Mortality (ITT)Pooled RandomizedCrossover Patients Censored at Crossover Standard Rx TAVR • HR [95% CI] = 0.60 [0.47, 0.76] • p (log rank) < 0.0001 78.0% 64.3% 23.1% 19.5% 45.5% All Cause Mortality (%) 54.9% NNT = 4.3 pts 14.1% 44.8% NNT = 5.1 pts 31.4% NNT = 7.1 pts Months

  46. Cardiovascular Mortality (ITT)Pooled RandomizedCrossover Patients Censored at Crossover Standard Rx TAVR • HR [95% CI] = 0.47 [0.36, 0.63] • p (log rank) < 0.0001 70.2% 56.9% 28.8% Cardiovascular Mortality (%) 38.4% 25.7% 41.4% 17.4% NNT = 3.5 pts 31.2% NNT = 3.9 pts 21.0% NNT = 5.7 pts Months

  47. All Cause Mortality (ITT)Pooled Randomized – Landmark Analysis Standard Rx TAVR • HR [95% CI] = 0.60 [0.47, 0.76] • p (log rank) < 0.0001 • HR [95% CI] = 1.94 [1.33, 2.83] • p (log rank) = 0.0004 • HR [95% CI] = 1.94 [1.09, 3.45] • p (log rank) = 0.0223 All Cause Mortality (%) ∆ = 14.1% ∆ = 14.8% ∆ = 20.2% 45.5% NNT = 7.1 pts NNT = 6.8 pts NNT = 5.0 pts 38.5% 34.4% 31.4% 18.3% 19.6% Months

  48. Cardiovascular Mortality (ITT)Pooled Randomized – Landmark Analysis Standard Rx TAVR • HR [95% CI] = 0.47 [0.36, 0.63] • p (log rank) < 0.0001 • HR [95% CI] = 2.44 [1.57, 3.78] • p (log rank) < 0.0001 • HR [95% CI] = 2.13 [1.09, 4.16] • p (log rank) = 0.0229 Cardiovascular Mortality (%) ∆ = 17.4% ∆ = 16.1% ∆ = 17.2% NNT = 5.7 pts NNT = 6.2 pts NNT = 5.8 pts 38.4% 30.9% 30.1% 21.0% 12.9% 14.8% Months

  49. Repeat Hospitalization (ITT)Pooled Randomized Standard Rx TAVR Rehospitalization MortalityorRehospitalization • HR [95% CI] = 0.45 [0.33, 0.61] • p (log rank) < 0.0001 • HR [95% CI] = 0.54 [0.44, 0.68] • p (log rank) < 0.0001 90.6% 83.8% 23.1% 71.4% 65.4% 66.5% 25.3% 67.5% 47.4% 29.0% 20.8% NNT = 4.3 pts Rehospitalization (%) Mortality or Rehospitalization (%) 31.5% 58.5% NNT = 4.0 pts 21.0% 42.4% 44.6% 35.0% NNT = 3.4 pts NNT = 4.8 pts NNT = 3.2 pts 26.4% NNT = 4.8 pts Months Months

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