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TCT 2011 | San Francisco, CA | November 10, 2011 Two-Year Outcomes of Transcatheter Aortic Valve Replacement (TAVR) in Inoperable Patients With Severe.

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Presentation on theme: "TCT 2011 | San Francisco, CA | November 10, 2011 Two-Year Outcomes of Transcatheter Aortic Valve Replacement (TAVR) in Inoperable Patients With Severe."— Presentation transcript:

1 TCT 2011 | San Francisco, CA | November 10, 2011 Two-Year Outcomes of Transcatheter Aortic Valve Replacement (TAVR) in Inoperable Patients With Severe Aortic Stenosis: The PARTNER Trial Raj R. Makkar, MD On behalf of The PARTNER Trial Investigators

2 Disclosures Raj R. Makkar is a principal site investigator for The PARTNER Trial (US) for Edwards Lifesciences and is national principal investigator for the St Jude TAVR study. He has received consulting fees, grant support and lecture fees from Medtronic, equity from Entourage Medical Technologies and grant support from St Jude Medical.

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.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 one year is unknown and longer term outcomes will importantly alter clinical practice decisions.However, whether clinical benefit and valve performance are sustained beyond one year is unknown and longer term outcomes will importantly alter clinical practice decisions. 3

4 Background (2) Transcatheter Aortic Valve Replacement (TAVR) is the standard of care for inoperable patients with severe aortic stenosis (AS), demonstrating 1-year outcomes of the PARTNER Trial, offering reduced mortality and improved quality of life. 4 Published October 2010

5 Objectives To evaluate the clinical outcomes of TAVR compared to standard therapy at 2 years in inoperable aortic stenosis patients.To evaluate the clinical outcomes of TAVR compared to standard therapy at 2 years in inoperable aortic stenosis patients. To assess valve hemodynamics and durability using echocardiography.To assess valve hemodynamics and durability using echocardiography. To perform subgroup analyses to better define the impact of co-morbidities on outcomes.To perform subgroup analyses to better define the impact of co-morbidities on outcomes. 5

6 n = 358 Inoperable Standard Therapy n = 179 Standard Therapy n = 179 ASSESSMENT: Transfemoral Access TF TAVR n = 179 TF TAVR n = 179 Primary Endpoint: All-Cause Mortality Over Length of Trial (Superiority) 1:1 Randomization VS TF TAVR AVR Primary Endpoint: All-Cause Mortality (1 yr) (Non-inferiority) TA TAVR AVR VS PARTNER Study Design Symptomatic Severe Aortic Stenosis ASSESSMENT: High-Risk AVR Candidate 3,105 Total Patients Screened 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 High-Risk TA High-Risk TF 1:1 Randomization 6

7 Inclusion Criteria Severe calcific aortic stenosis defined as echo derived valve area of 40 mmHg or jet velocity > 4.0 m/s.Severe calcific aortic stenosis defined as echo derived valve area of 40 mmHg or jet velocity > 4.0 m/s. NYHA functional class II or greater.NYHA functional class II or greater. Risk of death or serious irreversible morbidity of AVR as assessed by cardiologist and two surgeons must exceed 50%.Risk of death or serious irreversible morbidity of AVR as assessed by cardiologist and two surgeons must exceed 50%. Surgeons must agree and attest that before PARTNER these patients would not have received AVR treatment! 7

8 Key End-Points for 2 Year Analysis All cause mortalityAll cause mortality Cardiac mortalityCardiac mortality RehospitalizationRehospitalization StrokeStroke NYHA functional classNYHA functional class Days alive and out of hospitalDays alive and out of hospital Echo-derived valve areas, transvalvular gradients, paravalvular aortic regurgitationEcho-derived valve areas, transvalvular gradients, paravalvular aortic regurgitation Mortality outcomes stratified by STS scoreMortality outcomes stratified by STS score 8

9 n = 358 Randomized Inoperable n = 358 Randomized Inoperable n = 179 TAVR n = 179 TAVR n = 179 Standard therapy n = 179 Standard therapy 124/124 patients 100% followed at 1 Yr 124/124 patients 100% followed at 1 Yr 85/85 patients 100% followed at 1 Yr 85/85 patients 100% followed at 1 Yr 99/102 patients* 97.1% followed at 2 Yr 99/102 patients* 97.1% followed at 2 Yr 56/56 patients 100% followed at 2 Yr 56/56 patients 100% followed at 2 Yr Study Flow Inoperable Cohort 9 5 withdrawals in the first year in Standard Rx arm5 withdrawals in the first year in Standard Rx arm *3 patients followed outside of protocol window in TAVR group*3 patients followed outside of protocol window in TAVR group No patients were lost to follow-upNo patients were lost to follow-up

10 Statistical Method Primary analysis was by intention-to-treat (ITT).Primary analysis was by intention-to-treat (ITT). Mortality was estimated by ITT, both with and without censoring of the cross-over patients (n = 11 cross-over patients from 1-2 years).Mortality was estimated by ITT, both with and without censoring of the cross-over patients (n = 11 cross-over patients from 1-2 years). Clinical outcomes were analyzed by ITT with censoring of Standard Rx cross-over patients.Clinical outcomes were analyzed by ITT with censoring of Standard Rx cross-over patients. Event rates are given as Kaplan-Meier estimates.Event rates are given as Kaplan-Meier estimates. Core lab echo results are presented from the as treated (AT) cohort.Core lab echo results are presented from the as treated (AT) cohort. 10

11 Patient Characteristics (1) 11 CharacteristicTAVR n = 179 Standard Rx n = 179 p value Age – yr 83.1 ± ± Male sex (%) STS Score 11.2 ± ± NYHA I or II (%) I or II (%) III or IV (%) III or IV (%) CAD (%) Prior MI (%) Prior CABG (%) Prior PCI (%) Prior BAV (%) CVD (%)

12 Patient Characteristics (2) 12 Characteristic TAVR n = 179 Standard Rx n = 179 p value PVD (%) COPD Any (%) Any (%) O 2 dependent (%) O 2 dependent (%) Creatinine > 2 mg/dL (%) Atrial fibrillation (%) Perm. pacemaker (%) Pulmonary HTN (%) Frailty (%) Porcelain aorta (%) Chest wall radiation (%) Chest wall deformity (%) Liver disease (%)

13 All Cause Mortality (ITT) Crossover Patients Followed Numbers at Risk TAVR TAVR Standard Rx Standard Rx All Cause Mortality (%) Standard Rx TAVR at 2 yr = 24.3% NNT = 4.1 pts 67.6% 43.3% at 1 yr = 20.0% NNT = 5.0 pts 50.7% 30.7% 13 Months HR [95% CI] = 0.57 [0.44, 0.75] p (log rank) <

14 All Cause Mortality (ITT) Crossover Patients Censored Numbers at Risk TAVR TAVR Standard Rx Standard Rx All Cause Mortality (%) Standard Rx TAVR at 2 yr = 24.7% NNT = 4.0 pts 68.0% 43.3% at 1 yr = 20.0% NNT = 5.0 pts 50.7% 30.7% 14 Months HR [95% CI] = 0.56 [0.43, 0.73] p (log rank) <

15 All Cause Mortality (ITT) Landmark Analysis All Cause Mortality (%) Months Mortality 0-1 yr Mortality 1-2yr Standard Rx TAVR HR [95% CI] = 0.57 [0.44, 0.75] p (log rank) < HR [95% CI] = 0.58 [0.37, 0.92] p (log rank) = % 30.7% 35.1% 18.2% Numbers at Risk TAVR TAVR Standard Rx Standard Rx

16 Cardiovascular Mortality (ITT) Crossover Patients Censored Numbers at Risk TAVR TAVR Standard Rx Standard Rx Cardiovascular Mortality (%) Standard Rx TAVR at 2 yr = 31.4% NNT = 3.2 pts 62.4% 31.0% at 1 yr = 24.1% NNT = 4.1 pts 44.6% 20.5% 16 Months HR [95% CI] = 0.44 [0.32, 0.60] p (log rank) <

17 Cardiovascular Mortality (ITT) Landmark Analysis Cardiovascular Mortality (%) Months Cardiovascular Mortality 0-1 yr Cardiovascular Mortality 1-2 yr Standard Rx TAVR HR [95% CI] = 0.44 [0.32, 0.60] p (log rank) < HR [95% CI] = 0.48 [0.29, 0.81] p (log rank) = % 20.5% 32.1% 13.2% Numbers at Risk TAVR TAVR Standard Rx Standard Rx

18 Repeat Hospitalization (ITT) Numbers at Risk TAVR TAVR Standard Rx Standard Rx Repeat Hospitalization (%) Standard Rx TAVR at 2 yr = 37.5% NNT = 2.7 pts 72.5% 35.0% at 1 yr = 26.9% NNT = 3.7 pts 53.9% 27.0% 18 Months HR [95% CI] = 0.41 [0.30, 0.58] p (log rank) <

19 Hospitalization Through 2 Years TAVR Standard Tx p value Repeat Hospitalizations (No.) 78151<.0001 Repeat Hospitalizations (%) 35.0%72.5%<.0001 Days Alive Out of Hospital Median [IQR] 699 [ ] 355 [ ]

20 Percent Treatment Visit Baseline1 Year2 Year p = 0.61p < % 57.5% 16.9% 23.7% 60.8% 93.9% NYHA Class Over Time Survivors 20

21 All Stroke (ITT) Numbers at Risk TAVR TAVR Standard Rx Standard Rx Incidence (%) Months Standard Rx TAVR at 2 yr = 8.3% 5.5% 13.8% at 1 yr = 5.7% 5.5% 11.2% 21 HR [95% CI] = 2.79 [1.25, 6.22] p (log rank) = 0.009

22 All Cerebrovascular Events (%) Days 30 Days 31 Days – 1 Year 1 Year – 2 Years All CVAp = 0.010p = 0.387p = Ischemic Strokep = 0.017p = 0.155p = Hemorrhagic Strokep = 0.316p = 0.121p = Events Note: Percents are of patients in the trial (n/179).

23 All Strokes (%) Days 30 Days 31 Days – 2 Years All Strokep=0.010P=0.319 Ischemic Strokep = 0.017p = Hemorrhagic Strokep = 0.316p = Events Note: Percents are of patients in the trial (n/179).

24 All Strokes (# pts) Days 30 Days 31 Days – 2 Years All strokep=0.010p=0.319 Ischemic Strokep = 0.017p = Hemorrhagic Strokep = 0.316p = Events

25 Stroke - Hemorrhagic 25 ITT arm Age Days post randomization DescriptionTraumaMedication Procedure related* Device related* TAVR919 Right sided hemorrhage No Coumadin on admission YesNo TAVR8453 Traumatic subarachnoid FallCoumadinNo TAVR8554 Intraparenchy- mal and subdural FallNot statedNo TAVR84124IntracranialFallNot statedNo TAVR88155 Subdural hematoma Not statedDAPTNo Standard therapy (BAV) "Massive cerebral hemorrhage" Not stated Non/a *CEC adjudicated

26 Mortality or Stroke (ITT) Numbers at Risk TAVR TAVR Standard Rx Standard Rx All Cause Mortality or Stroke (%) Months Standard Rx TAVR at 2 yr = 21.9% NNT = 4.6 pts 68.0% 46.1% at 1 yr = 16.1% NNT = 6.2 pts 51.3% 35.2% 26 HR [95% CI] = 0.64 [0.49, 0.84] p (log rank) =

27 1 Year n = 179 OutcomeTAVR Standard Rx P value 2 Year 2 Year n = 179 TAVR Standard Rx P value Acute kidney injury Creatinine > 3 mg/dL, % (n) 1.1 (2) 2.8 (5) (2) 2.8 (5) Renal failure (CEC), % (n) Renal failure (CEC), % (n) 2.3 (4) 4.7 (7) (5) 7.6 (9) Cardiac re-intervention BAV, % (n) 1.1 (2) 82.3 (138) < (4) 85.3 (140) <.0001 Re-TAVR, % (n) Re-TAVR, % (n) 1.7* (3) NA- NA- AVR, % (n) AVR, % (n) 0 (0) 7.6 (10) (1) 8.9 (11) Endocarditis, % (n) 1.4 (2) 0.8 (1) (3) 0.8 (1) Bleeding – major, % (n) 24.2 (42) 14.9 (21) (48) 20.1 (25) New pacemaker, % (n) 4.7 (8) 8.6 (14) (10) 8.6 (14) Myocardial infarction All, % (n) All, % (n) 0.8 (1) 0.7 (1) (2) 2.5 (2) Clinical Outcomes 1 Year and 2 Year (ITT) 27

28 All Cause Mortality (ITT) Control Patients Alive on First Crossover Date Numbers at Risk Not Crossed-Over Crossed-Over All Cause Mortality (%) at 1 yr = 11.0% 10.0% 21.0% 28 Months past first cross-over Crossed-Over Not Crossed-Over HR [95% CI] = 0.58 [0.37, 0.92] p (log rank) =

29 All Cause Mortality (ITT) Control Patients Alive on First Crossover Date Numbers at Risk Not Crossed-Over Crossed-Over All Cause Mortality (%) at 1 yr = 11.0% 10.0% 21.0% 29 Months past first cross-over Crossed-Over Not Crossed-Over

30 Mean Gradient (mm Hg) Error bars = ± 1 Std Dev EOA Mean Gradient N = 158 N = 162 N = 137 N = 143 N = 84 N = 89 N = 65 N = 9 AVA (cm ² ) Mean Gradient & Valve Area 30

31 Numbers at Risk None to Mild None to Mild Moderate or Severe Moderate or Severe Death Incidence (%) Months Moderate or Severe None to Mild 41.2% 40.5% 35.3% 27.2% Mortality Stratified by Paravalvular Leak (ITT) Starting at Discharge 31 p (log rank) = 0.891

32 Echo Analysis PV Leak Changes 30 Days Compared to 2 Years % Progressed 42.6% Improved 41.0% Unchanged 30 Day 2 Year NoneTraceMildModerateSevere None Trace75600 Mild Moderate04300 Severe00100 Of the 61 patients alive with data at 2 years: Patients With Data at Both Time Points

33 Death Incidence (%) Months STS <5 STS Months STS 15 p value (log rank) = p value (log rank) = Mortality Stratified by STS Score (ITT) TAVR Standard Rx Numbers at Risk 33

34 Conclusions (1) At 2 years, in patients with symptomatic severe AS who are not suitable candidates for surgery… TAVR remained superior to standard therapy with incremental benefit from 1 to 2 years, markedly reducing the rates of…TAVR remained superior to standard therapy with incremental benefit from 1 to 2 years, markedly reducing the rates of… All cause mortality All cause mortality Cardiovascular mortality Cardiovascular mortality Repeat hospitalization Repeat hospitalization TAVR improved NYHA functional status and decreased Class III/IV symptoms compared to standard therapy (17% vs 64%; p < 0.001).TAVR improved NYHA functional status and decreased Class III/IV symptoms compared to standard therapy (17% vs 64%; p < 0.001). 34

35 Conclusions (2) At 2 years, in patients with symptomatic severe AS who are not suitable candidates for surgery… There were more neurologic events in TAVR patients vs Standard Rx (16.2% vs 5.5%; p = 0.003) with 5 new events (3 strokes and 2 TIAs) between 1-2 years in TAVR patients.There were more neurologic events in TAVR patients vs Standard Rx (16.2% vs 5.5%; p = 0.003) with 5 new events (3 strokes and 2 TIAs) between 1-2 years in TAVR patients. After 30 days, differences in stroke frequency were largely due to increased hemorrhagic strokes in TAVR patients.After 30 days, differences in stroke frequency were largely due to increased hemorrhagic strokes in TAVR patients. A subgroup analysis according to surgical risk score suggests that the most pronounced benefit of TAVR is in patients without extreme clinical co-morbidities.A subgroup analysis according to surgical risk score suggests that the most pronounced benefit of TAVR is in patients without extreme clinical co-morbidities. 35

36 Conclusions (3) At 2 years, in patients with symptomatic severe AS who are not suitable candidates for surgery… TAVR hemodynamics by echo showed durable improvements in AVA and mean gradients up to 3 years after implantation.TAVR hemodynamics by echo showed durable improvements in AVA and mean gradients up to 3 years after implantation. Moderate or severe paravalvular AR in the TAVR patients did not influence 2-year survival and there was a trend towards reduced paravalvular AR between 1 and 2 years.Moderate or severe paravalvular AR in the TAVR patients did not influence 2-year survival and there was a trend towards reduced paravalvular AR between 1 and 2 years. 36

37 Clinical Implications Two year data continues to support the role of TAVR as the standard-of-care for symptomatic patients with aortic stenosis who are not surgical candidates.Two year data continues to support the role of TAVR as the standard-of-care for symptomatic patients with aortic stenosis who are not surgical candidates. The ultimate value of TAVR in inoperable patients will depend on careful selection of patients who are not surgical candidates, and yet do not have extreme co-morbidities that overwhelm the benefits of TAVR and render the intervention futile.The ultimate value of TAVR in inoperable patients will depend on careful selection of patients who are not surgical candidates, and yet do not have extreme co-morbidities that overwhelm the benefits of TAVR and render the intervention futile. 37

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


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