Pivotal studies that support current use for TAVR.

1. TAVR
Evolution of a Groundbreaking Therapy
LUIS A. RAMIREZ-VALDIVIA MD
CTS FELLOW
October 8, 2020.

2. Aortic Valve stenosis
-Most Common Valvular Heart
Disease
-Prevalence ~5% in population >75
yrs.
-30% Symptomatic patients not
eligible for Surgical Replacement.
-Ancona A. e-Journal of Cardiology Practice .2020.Vol. 18, N° 10 - 12
-Praz, F, Siontis, G. et.al. Curr Opin Cardiology. 2017; 32:2.

3. Historical Background:
1992
• Henning Rud
Andersen:
• First report
Animal
implant of a
Transcatheter
Heart Valve
1995
• Patent
granted
2002
• Alain Cribier:
• First in
Human TAVR
4
Kumar, Vinayar. J Am Heart Assoc. 2020;9:e015921
European Heart Journal, Volume 13, Issue 5, May 1992, Pages 704–708,.

4. History: First TAVR in human
April 16 2002.
-57 yr old male, EF 12%,
-PMH:
-Lung cancer (lobectomy, 1999)
-Chronic pancreatitis
-Subacute leg ischemia (eventual cause of death 4 months
after TAVR)
-Recurrent schock after Balloon AV angioplasty.
-Performed ANTEGRADE (femoral vein-transeptal)
Cribier, Alain. Glob Cardiol Sci Pract. 2016 Dec 30; 2016(4): e201632

5. 2002-2004: Single Centre Feasibility
Trials
Rouen, FR: trials on 38 patients restricted to
compassionate use (imminent death).
- 80% PROCEDURAL SUCCESS rate (trans septal
approach)
-High (25%) incidence of > grade 2 paravalvular
regurgitation : need to develop larger size
bioprosthesis ( >23 mm).
-Cribier A. J Am Coll Cardiol. 2004;43:698–703.
- Cribier A. J Am Coll Cardiol. 2004;43:698–703.
-Cribier A. J Am Coll Cardiol. 2006;47:1214–23.

6. 2004 Edwards & Medtronic :
Gamechanger
-Easier delivery system
-New approaches were developed
- 2004 Medtronic : CoreValve
◦ Auto-expandable nitinol frame +
porcine pericardial valve
◦ Transfemoral approach
◦ Smaller sheath sizes (21F then 18F)
than those required for Edwards
devices (22F and 24F).
◦ The Conformité Européenne (CE)
approval for both models in 2007.
Cribier, Alain. Glob Cardiol Sci Pract. 2016 Dec 30; 2016(4): e201632

7. 2003-2006: Multi Center Feasibility
Alternate Approaches
Genereaux, P. et.al. European Heart Journal (2012) 33, 2388–2400
~80%succes
rate

8. Edwards
SAPIEN
SAPIEN
SAPIEN XT
SAPIEN 3
Medtronic
Evolut
CoreValve
EvolutR
Evolut Pro
Boston
Scientific
Lotus

9. Edwards Sapien
Medtronic Evolut
Pivotal Clinical Trials
PARTNER:
- (cohort B)Inoperable patients (2010)
- (cohort A)High Surgical risk (2011)
PARTNER 3: Low Risk Patients (2019)
CoreValve: Extreme risk (2014)
CoreValve: High risk (2014)
PARTNER 2 : Intermediate risk (2016)
SURTAVI: Intermediate risk (2017)
Evolut: Low risk (2019)

10. INOPERABLE / HIGH RISK

11. PARTNER I: Design
Leon, MB, Smith CR, et.al. N Eng J Med . 2010. 363; 17: 1597-1607.
Cohort A
Cohort B

12. PARTNER IB: Results
Leon, MB, Smith CR, et.al. N Eng J Med . 2010. 363; 17: 1597-1607.
∆ =
−𝟏𝟗%
−𝟐𝟐. 𝟑%

13. PARTNER IA: Results
Smith, CR. Et.al. N Engl J Med 2011; 364:2187-2198
Similar outcomes vs
SAVR for High Risk
Patients

14. Given PARTNER B Cohort Results:
No comparison vs Inoperable
patients.
-Compared Mortalitiy rate after
CoreValve at 1 yr vs an estimated
Mortality Rate with Medical
treatment (set as 43%). Included
489 patients.
JACC Vol. 63, No. 19, 2014 Popma et al. May 20, 2014:1972–81
CORE VALVE

15. 30 d 1 Yr
TAVR SAVR TAVR SAVR
All Cause Death +Stroke (%) 3.3 4.5 14.2 19.1
MACCE (%) 7.7 10.4 20.4 27.3
Major Stroke (%) 3.9 3.1 5.8 7.0
Permanent Pacemaker (%) 19.8 7.1 22.3 11.3
Major Vasc Complic (%) 5.9 1.7 6.2 2.0
Core Valve: results in High Risk Patients
Adams, DH, Popma, JJ. et.al. N Engl J Med 2014. 370; 19
Statistically significant for
superiority in primary End point

16. 5 years later… Trend Remain
SAPIEN
-Death Rate
◦ Inoperable: (TAVR 71.8% vs 93.6%
in SAVR)
◦ High Risk: No difference
-Aortic Regurgitation
◦ Moderate to severe: 14% TAVR vs
1% SAVR)
Kumar et.al. J Am Heart Assoc. 2020; 9:e015921
Core Vave
-Death Rate
◦ High Risk: similar (55.3 vs 55.4%)
-Aortic Regurgitation
◦ Moderate to severe: 50% TAVR vs
23% SAVR)
-Permanent PM : TAVR 33 % VS
19.8% SAVR

17. TAVR Superior to Non
Inferior to Standard
Medical therapy in High
Risk patients.
TAVR Superior to
Standard Medical
therapy in Non
operable patients.

18. INTERMEDIATE RISK

19. Second Generation Devices
SAPIEN XT
29 mm added
-Smaller Sheaths
Evolut R
Figure S1: Study Timeline and Devices

20. PARTNER 2: Results
-No Significant
difference at 24
months for Primary
Endpoint.
(21 vs 18.9%)
-Major Vascular
complications at 2 yrs:
TAVR 8.6 vs SAVR 5.5%.
TAVR more associated
with Aortic
Regurgitaion
Leon MB, Sith CR. Et.al. N Engl J Med 2016. 374;17

21. SURTAVI (2017):
Intermediate Risk
TAVR vs SAVR (respectively):
-All cause death + Disabling stroke:
12.6 vs 14% (nss)
-Rehospitalization:
13.2 vs 9.7 % (ss)
-Aortic Valve Reintervention:
2.8 vs 0.7% (ss).
Non inferior
Reardon, MJ. N Engl J Med 2017; 376:1321-1331
Intermediate Risk:
TAVR NON INFERIOR
Each proceddure has a different
Adverse event Profile

22. PROBLEMS TO SOLVE:
AORTIC INSUFFICIENCY
PERIPHERAL VASCULAR COMPLICATIONS
PERMANENT PM REQUIREMENT

23. LOW RISK

24. Third Generation Devices
SAPIEN 3
20 mm added
-Smaller Sheaths
EvolutPRO
FIGURES
Figure S1. Self-Expanding Transcatheter Heart Valves
CoreValve Evolut R Evolut PRO
3.6% 74.1% 22.3%

25. PARTNER 3:
Mack, MJ, Leon MB. N Engl J Med 2019; 380:1695-1705

26. PARTNER 3:
Multicenter Randomized Trial
Low Risk definition: Agreement by Heart Team as <4% risk of death within 30 days of
procedure.
Important considerations:
-Primary endpoint : Composite of
All Cause Mortality, Disabling Stroke or Rehospitalization at 1 year
-PPM and Aortic Regurgitation not considered Key Secondary Endpoints
Mack, MJ, Leon MB. N Engl J Med 2019; 380:1695-1705

27. PARTNER 3: Low Risk. SAPIEN 3 Valve
1000 patients from 71 sites
Treated : 950 pt
-496 TAVR
-454 SAVR
Follow Up planned for 10
years.
Mack, MJ, Leon MB. N Engl J Med 2019; 380:1695-1705

28. PARTNER 3:
Low Risk
Baseline TAVR -SAVR
-Mean Age: 73 Yrs
-Male 68 and 71%
-STS score 1.9%
-EuroSCORE II: 1.5
-NYHA III/IV: 31 vs 23%
Mack, MJ, Leon MB. N Engl J Med 2019; 380:1695-1705

29. PARTNER 3: Results
At 1 year TAVR vs SAVR:
Primary Endpoint: Death, Stroke or
Rehospitalization:
8.5 vs 15.1%
Requirements for both Noninferiority
and Superiority were met: difference
between the TAVR group and the SAVR
group of −6.6 %
(95% [CI], −10.8 to −2.5; P<0.001 for noninferiority) and a HR of 0.54
(95% CI, 0.37 to 0.79; P=0.001 for superiority)
Mack, MJ, Leon MB. N Engl J Med 2019; 380:1695-1705

30. PARTNER 3: Results
CONTROVERSY: Most of the Advantage for TAVR in the COMPOSITE given by Lower
Rehospitalization inclusion??
Mack, MJ, Leon MB. N Engl J Med 2019; 380:1695-1705

31. PARTNER 3: Key Secondary Endpoints
TAVR:
-Less New A fib
-Shorter LOS
Mack, MJ, Leon MB. N Engl J Med 2019; 380:1695-1705

32. PARTNER 3: Other Secondary Endpoints
New Permanent
Pacemaker (%)
>Moderate PV Aortic
Regurgitation (%)
Vascular
Complications (%)
30 d 1 yr 30 d 1 yr 30d 1 yr
SAVR 4.0 5.4 0.0 0.5 1.5 1.5
TAVR 6.5 7.3 0.8 0.6 2.2 2.8
Mack, MJ, Leon MB. N Engl J Med 2019; 380:1695-1705
Less PVL and PPM (no difference to SAVR)

33. PARTNER 3: Conclusions
TAVR:
-Non Inferior and Superior(*) for Primary endpoint.
-Similar to SAVR for Death for any cause
-Significant Less Stroke Risk
-Much less PPM and PVL

34. Evolut Low Risk Trial
-Low Risk Definition:
No more than a predicted 3% risk of death
by 30 days with surgery, as assessed by
members of the local heart team.
-Primary end point:
Composite of Death from any cause or
Disabling stroke at 24 months
-Used 3 Generations of devices: CoreValve,
Evolut R, or Evolut PRO.
Popma JJ, Deeb GM. N Engl J Med 2019; 380:1706-1715
FIGURES
Figure S1. Self-Expanding Transcatheter Heart Valves
CoreValve Evolut R Evolut PRO
3.6% 74.1% 22.3%

35. Evolut Low Risk Trial
Baseline TAVR vs SAVR
- Age 74 yrs
-Male 64 vs 62%
-STS PROM 1.9%
-NYHA III/IV: 25.1 vs 28.4%
-LVEF 61%
Popma JJ, Deeb GM. N Engl J Med 2019; 380:1706-1715

36. Evolut Low Risk Trial
*Additional patients were randomized to permit completion of the LTI substudy and to enroll a Japanese cohort.
Patient Flow
Popma JJ, Deeb GM. N Engl J Med 2019; 380:1706-1715

37. Evolut Low Risk Trial : RESULTS
-Composite of Death from
any cause or Disabling stroke
at 24 months TAVR vs SAVR
5.3 vs 6.7% (Not Inferior, Not
Superior)
-Less Disabling stroke at 24
months
1.1 vs 3.5%
Popma JJ, Deeb GM. N Engl J Med 2019; 380:1706-1715

38. Evolut Low Risk Trial : RESULTS
Stroke:
Similar in both
groups, slightly
favors TAVR.
Popma JJ, Deeb GM. N Engl J Med 2019; 380:1706-1715

39. Evolut Low Risk Trial : RESULTS
New Permanent Pacemaker
(%)
>Moderate PV Aortic
Regurgitation (%)
Vascular Complications
(%)
30 d 1 yr 1 Yr 2 yr 30d 1 yr
SAVR 6.1 6.7 1.5 0 3.2 3.5
TAVR 17.4 19.4 4.3 5.8 3.8 3.8
Popma JJ, Deeb GM. N Engl J Med 2019; 380:1706-1715

40. Evolut Low Risk Trial : RESULTS
Marginally Better
Hemodynamic Performance
for TAVR
Clinical Significance to be
determined

41. Figure S4: New York Heart Association Class Over Time (As-Treated Population)
Baseline 30 Days 1 Year
No. (%)
TAVR
N=725
Surgery
N=678
TAVR
N=706
Surgery
N=625
TAVR
N=428
Surgery
N=342
NYHA I 76 (10.5) 63 (9.3) 545 (77.2) 416 (66.6) 336 (78.5) 279 (81.6)
NYHA II 467 (64.4) 422 (62.2) 149 (21.1) 179 (28.6) 84 (19.6) 59 (17.3)
NYHA III 181 (25.0) 190 (28.0) 12 (1.7) 29 (4.6) 7 (1.6) 4 (1.2)
NYHA IV 1 (0.1) 3 (0.4) 0 (0.0) 1 (0.2) 1 (0.2) 0 (0.0)
REFERENCES
Evolut: Other Secondary Endpoints
Popma JJ, Deeb GM. N Engl J Med 2019; 380:1706-1715
-Comparable
Improvement in
Functional Class.

42. Evolut Low Risk :Conclusions
TAVR:
-Not Inferior and Not Superior to SAVR for Primary Endpoint
-Better Hemodynamic Performance
SAVR:
-Less new PPM
-Less PVL
Similar Stroke and vascular complications Rates
Popma JJ, Deeb GM. N Engl J Med 2019; 380:1706-1715

43. Inoperable/High
Risk
-2010
-2011
-2014
Intermediate risk
-2016
-2017
Low Risk
-2019
FUTURE:
-YOUNGER PATIENTS?
ASYMPTOMATICS?

44. Conclusions
-TAVR devices improvement: Better clinical outcome
-Longer Follow up needed: (Suitable for younger patients?)
-Indications will continue to expand

45. THANK YOU