LOW RISK TAVR. WHAT THE FUTURE HOLDS

Transcription

1 LOW RISK TAVR. WHAT THE FUTURE HOLDS Michael J. Reardon, M.D. Professor of Cardiothoracic Surgery Allison Family Distinguish Chair of Cardiovascular Research Houston Methodist DeBakey Heart & Vascular Center

2 COI Steering committees CoreValve Evolut R SurTAVI Reprise III National Surgical PI SurTAVI Reprise III Evolut R low risk trial

3 EXTREME RISK DONE DONE

4 RANDOMIZED HIGH RISK DONE DONE

5 HIGH RISK CLINICAL OUTCOMES

6 Other Endpoints at 3 Years ACC2016 Events TAVR SAVR P Value Life threatening or disabling bleeding <0.001 Acute kidney injury <0.001 Atrial fibrillation <0.001 Reintervention Major vascular complications Pacemaker implant <0.001 Aortic valve hospitalization Endocarditis

7 Estimated Hazard Rate Hazard Rate 0,007 0,006 HR Pivotal TAVR HR Pivotal SAVR 0,005 0,004 0,003 0,002 0,001 Periprocedural Elevated Hazard Delayed Recovery Constant Hazard Days Post Procedure

8 What do randomized trial tell us? TAVR vs. AVR must show equivalent or better mortality hemodynamics morbidity quality of life durability patient acceptance PVL/ Pace maker?

9 INTERMEDIATE RISK Partner IIA SurTAVI

10 The PARTNER 2A Trial Study Design Symptomatic Severe Aortic Stenosis ASSESSMENT by Heart Valve Team Operable (STS 4%) Randomized Patients n = 2032 Yes ASSESSMENT: Transfemoral Access No Transfemoral (TF) Transapical (TA) / TransAortic (TAo) 1:1 Randomization (n = 1550) 1:1 Randomization (n = 482) TF TAVR (n = 775) VS. Surgical AVR (n = 775) TA/TAo TAVR (n = 236) VS. Surgical AVR (n = 246) Primary Endpoint: All-Cause Mortality or Disabling Stroke at Two Years

11 Baseline Patient Characteristics Demographics and Vascular Disease Characteristic TAVR (n = 1011) Surgery (n = 1021) p-value Age - yrs 81.5 ± ± Male - % STS Score - % 5.8 ± ± NYHA Class III or IV - % CAD - % Prior CABG - % Cerebrovascular Disease - % PVD - %

12 All-Cause Mortality or Disabling Stroke (%) Primary Endpoint (ITT) All-Cause Mortality or Disabling Stroke Surgery TAVR HR [95% CI] = 0.89 [0.73, 1.09] p (log rank) = % % 16.4% 14.5% 19.3% 0 6.1% Number at risk: Months from Procedure Surgery TAVR

13 All-Cause Mortality or Disabling Stroke (%) TF Primary Endpoint (AT) All-Cause Mortality or Disabling Stroke TF Surgery TF TAVR HR: 0.78 [95% CI: 0.61, 0.99] p (log rank) = % 20.0% % 11.7% 16.3% 0 4.5% Number at risk: Months from Procedure TF Surgery TF TAVR

14 Other Clinical Endpoints (ITT) At 30 Days and 2 Years Events (%) TAVR (n = 1011) 30 Days 2 Years Surgery (n = 1021) p-value* TAVR (n = 1011) Surgery (n = 1021) p-value* Rehospitalization MI Major Vascular Complications Life-Threatening / Disabling Bleeding < <0.001 AKI (Stage III) New Atrial Fibrillation < <0.001 New Permanent Pacemaker Re-intervention Endocarditis NA *Event rates are KM estimates, p-values are point in time

15 Valve Area (cm²) Echocardiography Findings (VI) Aortic Valve Area 2,50 Surgery TAVR 2,00 1,50 1,68 1,47 1,57 1,42 1,54 1,40 1,00 0,50 0,70 p = NS 0,69 p < p < p < ,00 Baseline 30 Day 1 Year 2 Year No. of Echos Surgery TAVR Error bars represent ± Standard Deviation

16 Paravalvular Regurgitation (VI) 3-Class Grading Scheme P < P < % 80% Moderate 8.0% Mild 26.8% Moderate 0.6% Mild 3.5% 60% 40% Severe Moderate Mild None/Trace 20% 0% TAVR Surgery TAVR Surgery No. of echos 30 Days 2 Years TAVR Surgery

17 SURTAVI Trial Design Intermediate Surgical Risk Predicted risk of operative mortality 3% and <15% Heart Team Evaluation Assess inclusion/exclusion Risk classification Screening Committee Confirmed eligibility Randomization Stratified by need for revascularization Baseline neurological assessments TAVR SAVR TAVR only TAVR + PCI SAVR only SAVR + CABG 17

18 Study Endpoints Primary endpoint All-cause mortality or disabling stroke at 24 months Key secondary endpoints Safety: All-cause mortality All stroke Aortic valve reintervention Major vascular complications Life-threatening or major bleeding Pacemaker implantation Efficacy: Mean gradient EOA Moderate/severe AR Quality of life: KCCQ Major adverse cardiovascular and cerebrovascular events (MACCE) 18

19 Study Timeline April First patient enrolled June 19, 2012 Enrollment completed June 30, 2016 CoreValve: 23, 26 and 29 mm (US) Evolut R (US) CoreValve: 23, 26 and 29 mm (CAN, EU) CoreValve: 31 mm (US, CAN, EU) Primary endpoint assessment Dec % 94% TF 4% DA 2% SCA 16% CoreValve (n=724) Evolut R (n=139) 19

20 Bayesian Analysis of the 24-Month Primary Endpoint Number of Subjects A pre-specified interim analysis occurred when 1400 patients reached 12-month follow-up. Observed 24-month Interim outcomes Bayesian Analysis were of the used 2Year to Primary Endpoint timed to occur when 1400 subjects inform have been modeling. followed for 12 months Analysis Subjects using modeling who to had include not all patient data reached 24-month follow-up had their outcomes imputed using their last known event status. Combining imputed and observed data, the posterior distribution of the difference in 24-month event rates was calculated. Complete 24 month follow-up Complete 12 month FU Information used to inform modeling 2012 ~50% N=1400 ~35% <12 month FU Attempted Procedure Date Analysis Trigger Final outcomes modeled ~15% 20

21 Standard of Success for Noninferiority of the Primary Endpoint Posterior Distribution of the Difference (TAVR rate SAVR rate) Standard of Success: PP(π T - π C < 0.07) > (0.971 chosen to keep α 0.05) Area > ,1-0,05 0 0,05 0,1 PP = Posterior Probability; π T = TAVR rate; π C = SAVR rate 21

22 Patient Flow 1,746 patients randomized TAVR ITT group: N=879 SAVR ITT group: N= not attempted: - 4 died - 6 withdrew consent - 5 physician withdrew 71 not attempted: - 4 died - 43 withdrew consent - 23 physician withdrew - 1 lost to follow-up TAVR mitt* group: N=864 SAVR mitt* group: N=796 2 not implanted 1 went to SAVR 2 surgical patients received TAVR 1 not implanted 2 went to TAVR 1 TAVR patient received SAVR TAVR implanted group: N=863 SAVR implanted group: N=794 *The modified intention-to-treat (mitt) population includes all subjects with an attempted procedure 22

23 Baseline Characteristics* n (%) or mean ± SD TAVR (N=864) SAVR (N=796) Age, years 79.9 ± ± 6.1 Male sex 498 (57.6) 438 (55.0) Body surface area, m ± ± 0.2 STS PROM, % 4.4 ± ± 1.6 Logistic EuroSCORE, % 11.9 ± ± 8.0 Diabetes mellitus 295 (34.1) 277 (34.8) Serum creatinine >2 mg/dl 14 (1.6) 17 (2.1) Prior stroke 57 (6.6) 57 (7.2) Prior TIA 58 (6.7) 46 (5.8) Peripheral vascular disease 266 (30.8) 238 (29.9) Permanent pacemaker 84 (9.7) 72 (9.0) *mitt population; no significant difference in any baseline characteristics 23

24 Baseline Cardiac Risk Factors* n (%) TAVR (N=864) SAVR (N=796) Coronary artery disease 541 (62.6) 511 (64.2) Prior CABG 138 (16.0) 137 (17.2) Prior PCI 184 (21.3) 169 (21.2) Prior myocardial infarction 125 (14.5) 111 (13.9) Congestive heart failure 824 (95.4) 769 (96.6) History of arrhythmia 275 (31.8) 250 (31.4) Atrial fibrillation 243 (28.1) 211 (26.5) NYHA Class III/IV 520 (60.2) 463 (58.2) *mitt population; no significant difference in any baseline characteristics 24

25 Baseline Frailty, Disabilities and Comorbidities* n (%) or mean ± SD TAVR (N=864) SAVR (N=796) Body mass index <21 kg/m 2 20 (2.3) 21 (2.6) Falls in past 6 months 102 (11.8) 101 (12.7) 5 meter gait speed >6 s 428 (51.8) 403 (52.9) 6 minute walk test (meters) ± ± Grip strength below threshold 519 (62.5) 490 (63.1) Does not live independently 18 (2.1) 22 (2.8) Chronic lung disease (mod/severe) 115 (13.3) 106 (13.3) Home oxygen 18 (2.1) 21 (2.6) Cirrhosis of the liver 4 (0.5) 5 (0.6) Immunosuppressive therapy 64 (7.4) 68 (8.5) *mitt population; no significant difference in any baseline characteristics 25

26 All-Cause Mortality or Disabling Stroke All-Cause Mortality or Disabling Stroke 30% 25% 20% 24 Months TAVR SAVR 12.6% 14.0% 15% 10% 5% No. at Risk SAVR TAVR 0% Months Post-Procedure

27 Primary Endpoint Posterior Probability distribution Noninferiority margin PP >0.999 meets noninferiority -0,10-0,05 0,00 0,05 0,10 Difference in 24-month incidence TAVR - SAVR TAVR (95% CI) SAVR (95% CI) Difference (95% CI) 12.6% (10.2%, 15.3%) 14.0% (11.4%, 17.0%) 1.4% ( 5.2%, 2.3%) 27

28 All-Cause Mortality All-Cause Mortality 30% 25% 24 Months 20% TAVR SAVR 95% CI for Difference 11.4% 11.6% -3.8, % 10% 30 Day SAVR 1.7% O:E 0.38 TAVR 2.2% O:E % No. at Risk SAVR TAVR 0% Months Post-Procedure

29 Estimated Hazard Rate Instantaneous Hazard of Mortality 0,004 0,0035 0,003 SURTAVI TAVR High-Risk TAVR SURTAVI SAVR High-Risk SAVR 0,0025 0,002 0,0015 0,001 0, Days Post Procedure Guadiani V. Deeb GM, Popma JJ, et al. J Thorac Cardiovasc Surg

30 12- Month All-Cause Mortality 1-YEAR ALL-CAUSE MORTALITY BY STS SCORE 30% 25% 20% TAVR SAVR R² = 0,9345 SAVR 3% Rate of Increase TAVR 2.6% Rate of Increase 15% R² = 0, % 5% 0% NOTION 0 STS TAVR STS TAVR STS TAVR STS 46.7 STS 56.9 STS 7.36 TAVR STS TAVR 8 STS SAVR SURTAVI STS SAVR P2 A STS SAVR RIII Lotus RIII CV CV High Risk STS SAVR PI A STS SAVR SURGICAL RISK CONTINUUM NOTION: Thyregold, JACC SURTAVI: Reardon, NEJM PARTNER 2A: Leon, NEJM REPRISE III: Feldman, PCR CoreValve High Risk: Adams, NEJM PARTNER 1A: Smith, NEJM The Lotus Valve System / LOTUS Edge Valve System may only be used in countries where it is approved for use. The Lotus Valve System / LOTUS Edge Valve System is not available for sale in the European Economic Area. For educational purposes only. SH AA MAY 2017

31 Disabling Stroke Disabling Stroke 10% 8% 6% TAVR 24 Months SAVR 95% CI for Difference 2.6% 4.5% -4.0, 0.1 4% 2% No. at Risk SAVR TAVR 0% Months Post-Procedure

32 Procedural Characteristics Characteristic, mean ± SD TAVR (n=864) SAVR (n=796) 95% CI for difference Procedure time, min 52.3 ± ± 69.1 (-156.7, ) Total time in cath lab or OR, min Aortic cross-clamp time, min ± ± 81.6 (-111.7, -97.6) NA 74.3 ± 30.4 NA CPB time, min NA 97.8 ± 39.3 NA Length of index procedure hospital stay, days Length of ICU stay, hours 5.75 ± ± 8.03 (-4.65, -3.36) (n=767) 48.6 ± 44.0 (n=778) 70.4 ± 96.2 (-29.3, -14.3) 32

33 30-Day Safety and Procedure-related Complications TAVR (N=864) SAVR (N=796) 95% CI for Difference All-cause mortality or disabling stroke , 0.7 All-cause mortality , 1.8 Disabling stroke , 0.1 All stroke , -0.2 Overt life-threatening or major bleeding , 5.9 Transfusion of PRBCs* - n (%) 0 units 2 4 units 756 (87.5) 469 (58.9) 24.4, units 48 (5.6) 136 (17.1) -14.5, (3.6) 101 (12.7) -11.7, -6.5 Acute kidney injury, stage , -1.0 Major vascular complication , 6.7 Cardiac perforation , 2.0 Cardiogenic shock , -1.1 Permanent pacemaker implant , 22.7 Atrial fibrillation , *Percentage rates, all others are Bayesian rates 33

34 SURTAVI CLINICAL TRIAL 30-DAY OUTCOMES At 30 days, TAVR was significantly better than SAVR in several key areas, including all-stroke, atrial fibrillation and acute kidney injury. Significantly better for TAVR Significantly better for SAVR 50% 40% 41,1% 43,4% 30% 25,9% 20% 10% 0% 5,6% 3,4% Stroke 12,5% Transfusion use 1,7% AKI 4,4% 12,9% Atrial fibrillation 1,1% 3,8% Cardiogenic shock 6,0% 1,1% Major Vasc Comp 6,6% Pacemaker use TAVR SAVR Reardon, et al., ACC,

35 All-Cause Mortality by Pacemaker Implantation All-Cause Mortality 50% 40% PPI Prior to Procedure With New PPI Without New PPI P-value (log-rank) = % 20% 10% 16.3% 10.5% 10.1% 0% No. at Risk PPI Prior With New PPI Without New PPI Months Post-Procedure

36 Hemodynamics* TAVR had significantly better valve performance over SAVR at all follow-up visits Aortic Valve Area, cm 2 AV Mean Gradient, mm Hg *Core lab adjudicated 37

37 Percentage of Patients NYHA Functional Class 100% 5,0% 4,4% 0,2% 1.0% 0.3% 0,2% 6% 5% 5% 4% 6% 10% 80% 31% 36% 24% 26% 33% 36% 55% 54% 60% NYHA IV NYHA III 40% NYHA II NYHA I 64% 53% 71% 69% 63% 58% 20% 40% 41% 0.8% 0% TAVR (N=860) SAVR (N=789) TAVR (N=822) SAVR (N=708) TAVR (N=607) SAVR (N=513) TAVR (N=302) SAVR (N=255) Baseline 30 Days 12 Months 24 Months 38

38 KCCQ Summary Score KCCQ Summary Score Over Time 100 Patients recover quality of life sooner after TAVR than SAVR TAVR SAVR Baseline 30 Days 6 Months 12 Months Change from Baseline TAVR 18.4 ± ± ± 22.2 SAVR 5.9 ± ± ± % CI for difference (10.0, 15.1) (-1.9, 2.8) (-2.2, 2.9) 39

39

40 Total Aortic Regurgitation* 100% 90% 3% 1% 7% 5% 1% 9% 5% 1% 9% 80% 70% 36% 34% 35% 60% 50% 40% 30% 61% 93% 61% 90% 60% 90% Severe Moderate Mild None/trace 20% 10% 0% TAVR (N=832) SAVR (N=707) TAVR (N=599) SAVR (N=506) TAVR (N=299) SAVR (N=244) Discharge 12 Months 24 Months * Implanted population, core lab adjudicated 41

41 RANDOMIZED INTERMEDIATE RISK DONE DONE

42 The PARTNER 2A and S3i Trials Study Design Intermediate Risk Symptomatic Severe Aortic Stenosis Intermediate Risk ASSESSMENT by Heart Valve Team P2 S3i n = 1078 P2A n = 2032 ASSESSMENT: Optimal Valve Delivery Access Yes ASSESSMENT: Transfemoral Access No Transfemoral (TF) Transapical / Transaortic (TA/TAo) Transfemoral (TF) Transapical / TransAortic (TA/TAo) 1:1 Randomization 1:1 Randomization TF TAVR SAPIEN 3 TA/TAo TAVR SAPIEN 3 TF TAVR SAPIEN XT VS Surgical AVR TA/Tao TAVR SAPIEN 3 VS Surgical AVR Primary Endpoint: All-Cause Mortality, All Stroke, or Mod/Sev AR at One Year (Non-inferiority Propensity Score Analysis)

43 Baseline Patient Characteristics Demographics (AT) Characteristic TAVR (n = 1077) Surgery (n = 944) p-value Age - yrs 81.9 ± ± Male - % BMI - kg/m ± ± Median STS Score - % 5.2 [4.3, 6.3] 5.4 [4.4, 6.7] NYHA Class III or IV - % mean ± SD, median [IQR]

44 Primary Endpoint - Non-inferiority Death, Stroke, or AR Mod at 1 Year (VI) Weighted Difference -9.2% Upper 1-sided 95% CI -6.0% Non-Inferiority p-value < Pre-specified non-inferiority margin = 7.5% Favors TAVR Favors Surgery Primary Non-Inferiority Endpoint Met

45 Primary Endpoint - Superiority Death, Stroke, or AR Mod at 1 Year (VI) Weighted Difference -9.2% Upper 2-sided 95.0% CI -5.4% Superiority Testing p-value < Favors TAVR Favors Surgery Superiority Achieved

46 Superiority Analysis Components of Primary Endpoint (VI) Mortality Favors TAVR Favors Surgery Weighted Difference -5.2% Upper 2-sided 95% CI -2.4% Superiority Testing p-value < Stroke Weighted Difference -3.5% Upper 2-sided 95% CI -1.1% Superiority Testing p-value = AR > Moderate Weighted Difference +1.2% Lower 2-sided 95% CI +0.2% Superiority Testing p-value =

47 Unadjusted Clinical Events At 30 Days and 1 Year (AT) Events (%) 30 Days 1 Year TAVR Surgery TAVR Surgery Death All-cause Cardiovascular Neurological Events Disabling Stroke All Stroke All-cause Death and Disabling Stroke

48 All-Cause Mortality / Stroke Rate (%) Unadjusted Time-to-Event Analysis All-Cause Mortality and All Stroke (AT) 40 P2A Surgery SAPIEN 3 TAVR % % 10.8% 3.7% 0 Number at risk: P2A Surgery S3 TAVR Months from Procedure

49 All-Cause Mortality (%) Unadjusted Time-to-Event Analysis All-Cause Mortality (AT) 40 P2A Surgery SAPIEN 3 TAVR % % 7.4% 0 1.1% Number at risk: P2A Surgery S3 TAVR Months from Procedure

50 All Stroke (%) Unadjusted Time-to-Event Analysis All Stroke (AT) 40 P2A Surgery SAPIEN 3 TAVR % 8.2% 0 2.7% 4.6% Number at risk: P2A Surgery S3 TAVR Months from Procedure

51 Paravalvular Regurgitation 3-Class Grading Scheme (VI) P < P < % Moderate 1.5% 80% Mild 39.8% 60% 40% Severe Moderate Mild None/Trace 20% 0% TAVR Surgery TAVR Surgery No. of echos 30 Days 1 Year P2A Surgery S3i TAVR

52 SURTAVI CAS SURTAVI RCT STUDY FEATURES 17 sites 65 sites 94% TF 4% DA 2% SCA 16% second generation valves 5 sites CoreValve (n=724) Evolut R (n=139) 59 sites 95.6% TF 0.4% DA 4% SCA 93% second generation valves CoreValve (n=20) Evolut R (n=254) 53

53 SURTAVI CAS

54 SURTAVI CAS

55 SURTAVI CAS

56 SURTAVI AND CAS

57

58 THE EVOLUT PRO VALVE Supra-Annular Valve Self-expanding nitinol frame Porcine Pericardial Tissue Cell Size Enables Coronary Access Pericardial wrap increases surface contact with native anatomy Skirt Height 13 mm 59

59 EVOLUT PRO VALVE PERFORMANCE Core Laboratory Assessments 60

60 EVOLUT PRO PARAVALVULAR LEAK Core Laboratory Assessments 61

61 EVOLUT PRO SAFETY OUTCOMES Event, K-M rates (no. of patients) 30 Days N=60 6 Months N=60 All-cause mortality 1.7 (1) 5.0 (3) Cardiovascular 1.7 (1) 3.3 (2) Disabling stroke 1.7 (1) 1.7 (1) Major vascular complications 10.0 (6) 10.0 (6) Major bleeding 6.7 (4) 6.7 (4) Embolization or migration 1.7 (1) 1.7 (1) Endocarditis 0.0 (0) 0.0 (0) Coronary obstruction 0.0 (0) 0.0 (0) Valve thrombosis 0.0 (0) 0.0 (0) Pacemaker 11.7 (7) 11.7 (7)

62 Intermediate risk TAVR vs. AVR must show equivalent or better mortality hemodynamics morbidity quality of life durability patient acceptance PVL/ Pace maker?

63 PARTNER 3 Low Risk, Symptomatic AS STS <4 Age >65 years RCT- TAVR vs SAVR 1,228 patients Nested Registries-3 50 Sites One year Composite Endpoint Death Stroke Rehospitalization 4D CT Imaging Substudy -400 patients CoreValve Evolut R Low Risk Symptomatic AS STS < 3 No Age Floor RCT TAVR vs. SAVR 1,200 patients 80 sites Two Year Endpoint Death Disabling Stroke Adaptive Design 4D CT Imaging Study- 400 Patients

64 Both US Low Risk Randomized Trials Will Have Data Available in 2019

65 NOTION ALL-CAUSE MORTALITY, STROKE, OR MI

66 NOTION ALL-CAUSE MORTALITY

67 NOTION STROKE

68 NOTION MYOCARDIAL INFARCTION

69 NOTION ALL-CAUSE MORTALITY, STROKE, OR MI: STS<4%

70 Echocardiographic Findings for TAVR vs SAVR Stroke Volume by Doppler (LVEF 50%) ,1 76,06 78,71 80,07 80, ,4 74,49 76,32 68, ,89 TAVR 50 SAVR 40 Baseline Discharge 30 days 6 months 12 mo

71 RV FUNCTION

72 PREDICTIONS FOR 2020 SAVR hurts the heart for at least 6 months and this is unlikely to change by 2020

73 HEMODYNAMICS

74 HEMODYNAMICS Aortic Flow (cc/sec systolic flow)

75 Durability

76 NOTION

77 ADVANCE

78 EXTREME RISK

79 PREDICTIONS FOR 2020 SAVR is a mature technique while TAVR is young and likely to under go substantial improvements Technical disasters have already decreased and will decrease further

80 PREDICTIONS FOR 2020 SAVR is technique driven TAVR is technology driven TAVR will enjoy a wider adoption than SAVR

81 Surgical Risk PREDICTIONS FOR 2020 Low Risk Intermediate Risk High Risk Extreme Risk Both dividing lines moving to the left but how far? Durablity

82 Thank You